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Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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7
Vitamins

FAT-SOLUBLE VITAMINS

Vitamin A and Carotenoids

The term vitamin A as used here applies to all derivatives of ß-ionone (other than the provitamin A carotenoids) that have the biologic activity of all-trans-retinol. Vitamin A, also known as retinol, is found in foods of animal origin and in some microorganisms, either as the alcohol or as fatty acid esters, mostly palmitate and stearate (Baker, 1995; Ross, 1999). Vitamin A functions in vision as the metabolite 11-cis-retinal combined with proteins (opsins) to form the visual pigments rhodopsin (in rod cells) and iodopsin (in cone cells). When light strikes those pigments, 11-cis-retinal is converted to all-trans-retinal, triggering chemical events that lead to communication of neuronal cells with the visual cortex of the brain. Vitamin A also functions in cellular differentiation, embryologic development, spermatogenesis, cell-to-cell communication, and the immune response. The mechanisms of those functions have not been well elucidated, but retinoic acid appears to be a potent metabolite of vitamin A that may be involved in most of them, except for vision (Olson, 1996, 1999; Ross, 1999).

MEASURES OF BIOLOGIC ACTIVITY

The biologic activity of vitamin A can be expressed in international units (IU) or US Pharmacopeia (USP) units: 1 IU or 1 USP unit of vitamin A activity is equivalent to the activity provided by 0.3 µg of all-trans-retinol, 0.344 µg of all-trans-retinyl acetate, or 0.55 µg of all-trans-retinyl palmitate. Thus, 1 µg of all-trans-retinol provides 3.33 IU of vitamin A activity. Vitamin A activity also has been expressed in retinol equivalents (RE): 1 RE of vitamin A is equivalent to the activity provided by 1 µg of all-transretinol (Baker, 1995). An isomer of vitamin A found in freshwater fish, 3,4-didehydroretinol, has about 40% of the biologic activity of crystalline all-trans-retinol (Ross, 1999).

Most plants and some animal foods contain carotenoids. Over 600 have been identified, and about 50 have provitamin A activity. Of the provitamin A carotenoids, ß-carotene, a-carotene, cryptoxanthin, ß-zeacarotene, and the ß-apocarotenals are of particular importance (Bauernfeind, 1981). Provitamin A carotenoids contribute to vitamin A nutriture after central cleavage to retinal, primarily in the gut mucosa. Conversion of dietary carotenoids to vitamin A has been demonstrated in rhesus monkeys (Macaca mulatta) (Krinsky et al., 1990), but the efficiency of the conversion has not been studied. On the basis of rat studies with synthetic crystalline ß-carotene, 0.60 µg of all-trans-ß-carotene is equivalent to 0.30 µg of all-trans-retinol. Later research with other species, including humans, showed that this quantitative relationship does not apply under natural conditions of carotenoid intake. Mixed carotenoids in a natural diet are used less efficiently than ß-carotene, and crystalline ß-carotene is more efficiently used than natural ß-carotene in the various matrices in which it occurs in foods and feeds (Baker, 1995; Lee et al., 1999; Huang et al., 2000; van het Hof et al., 2000). It has been assumed that 6 µg of all-trans-ß-carotene or 12 µg of other provitamin A carotenoids is equivalent to 1 µg (1 RE) of retinol in the human diet (National Research Council, 1989). Recently, it was proposed that this relationship be modified so that 12 µg of all-trans-ß-carotene or 24 µg of other provitamin A carotenoids in the human diet would equal 1 retinol activity equivalent (RAE). One RAE would equal 1 µg of all-trans-retinol, as was the case for the previously used RE (Institute of Medicine, 2001). In the absence of more specific data, bioequivalence values similar to those used for humans can reasonably be used for provitamin A carotenoids in the diets of nonhuman primates. Thus, 1 µg of ß-carotene in the nonhuman-primate diet would provide 0.555 IU of vitamin A activity, whereas 1 µg of other provitamin A carotenoids would provide 0.2775 IU.

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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ABSORPTION AND CIRCULATION OF CAROTENOIDS

ß-Carotene and other carotenoids appear to be absorbed by some animal species but not others. Individuals and species that do not circulate carotenoids in plasma, even though they are present in the diet, might convert dietary carotenoids to vitamin A in the intestine more efficiently than the ones that do circulate carotenoids (Olson, J.A., 1999). Although the efficiency of the conversion has not been specifically studied in nonhuman primates, serum or plasma concentrations of total carotenoids or of ß-carotene, a-carotene, a-cryptoxanthin, ß-cryptoxanthin, lutein plus zeaxanthin, or lycopene (both provitamin A and non-provitamin A compounds) have been measured in several species (de La Pena et al., 1972; Cornwell and Boots, 1981; Boots et al., 1983; Sabrah et al., 1990; Snodderly et al., 1990; Crissey et al., 1999; Slifka et al., 1999, 2000). Attempts were made in some studies to estimate carotenoid concentrations in the average diet, but individual primates were able to self-select preferred foods, so it was difficult to measure carotenoid intakes precisely.

Very low or nonmeasurable concentrations of serum carotenoids have been found in tamarins (Saguinus oedipus) and capuchins (Cebus albifrons), whereas high concentrations were found in serum of the sooty mangabey (Cerocebus torquatus) and the orangutan (Pongo pygmaeus). Rhesus (Macaca mulatta), cynomolgus (Macaca fascicularis), and squirrel (Saimiri sciureus) monkeys did not have significant concentrations of non-polar carotenoids, such as ß-carotene, in their plasma, but appreciable concentrations of polar carotenoids, such as lutein and zeaxanthin, were found if they were in the diet (Krinsky et al., 1990; Snodderly et al., 1990). It is not clear whether the variability in plasma carotenoid concentration results from differences in carotenoid metabolism among primate species or from the presence of different dietary carotenoids or of different dietary carotenoid concentrations.

VITAMIN A AND CAROTENOIDS IN FEEDSTUFFS

Vitamin A and carotene concentrations in feedstuffs vary with origin—including species and growing conditions of plant feedstuffs, species and vitamin A and carotene intakes of animals used as food, and feedstuff processing and storage. To ensure an adequate vitamin A supply, primates in captivity are usually provided diets to which synthetic vitamin A has been added. Synthetic retinyl palmitate and retinyl acetate are the usual supplemental forms, and these are commonly microencapsulated with antioxidants to improve their stability. Nevertheless, if unaccounted for, heat, moisture, manufacturing procedures, and extended storage times can lead to lower than expected dietary vitamin A activity (Camire et al., 1990; Baker, 1995).

ABSORPTION, CIRCULATION, AND STORAGE OF VITAMIN A

Retinyl esters are hydrolyzed in the gut by pancreatic and intestinal brush-border ester hydrolases and the released retinol emulsified with bile salts and lipid. Retinol is absorbed rapidly by the intestinal villi, esterified primarily with palmitic and stearic acids in the mucosal cell, and transported to the liver as retinyl esters in the lipid core of chylomicra. The liver stores much of the retinol, mostly in ester form, and regulates its secretion into the plasma for transport to other tissues in association with retinol-binding protein (RBP) and a cotransport prealbumin, transthyretin (Olson, 1991, 1996; Ross, 1999). In humans, when vitamin A intake is adequate, 50-85% or more of body vitamin A is stored in the liver. Thus, liver levels of the vitamin are good indicators of vitamin A status.

Plasma retinol has proved useful in assessing vitamin A status in humans when plasma concentrations were very low (under 10 µg·dl-1) or very high (over 100 µg·dl-1). Very low concentrations were associated with depletion of vitamin A reserves, whereas very high concentrations were associated with vitamin A intakes exceeding need. When liver reserves (expressed as retinol) are adequate but not excessive (20-520 µg·g-1 of wet liver tissue), plasma vitamin A concentration tended to be homeostatically controlled at a point in each person that was largely independent of total body reserves (Olson, 1991). Although normally it is a small fraction (2-20%) of total plasma vitamin A, retinyl ester was highly concentrated relative to free retinol in humans with vitamin A intakes exceeding the storage capacity of the liver; this phenomenon might reflect conversion of excess vitamin A to a less toxic form (Lee and Nieman, 1993). A transient increase in plasma retinyl esters also occurs after consumption of a vitamin A-rich meal, so fasting blood samples should be used for status-assessment (Olson, 1996).

Plasma or serum vitamin A concentrations have been measured in captive rhesus monkeys (Macaca mulatta), cynomolgus monkeys (Macaca fascicularis), African green monkeys (Cercopithecus aethiops), capuchins (Cebus spp.), marmosets (Callithrix jacchus), tamarins (Saguinus fuscicolis), squirrel monkeys (Saimiri sciureus), owl monkeys (Aotus trigatus), spider monkeys (Ateles geoffroyi), colobus monkeys (Colobus guereza), sooty mangabeys (Cercocebus torquatus), Schmidt’s monkeys (Cercopithecus ascanius), baboons (Papio cynocephalus), mandrills (Papio sphinx), chimpanzees (Pan troglodytes), orangutans (Pongo pygmaeus), and gorillas (Gorilla gorrilla) (O’Toole et al., 1974; Cornwell and Boots, 1981; Meydani et al., 1983; McGuire et al., 1989; Flurer and Schweigert, 1990; Rogers et al., 1993; Crissey et al., 1999). Circulating vitamin A concentrations varied between species and between studies. In one study, tamarins, squirrel monkeys, capuchins, and owl monkeys had plasma vitamin A concentrations that were

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

about one-fourth those in rhesus, cynomolgus, and African green monkeys. The concentrations in the latter group were comparable with those in humans. Plasma retinol in gorillas appeared to be somewhat higher than in humans and that in baboons lower. However, there was considerable variability in observed values in both gorillas and baboons. Free-ranging black spider monkeys (Ateles paniscus chamek) in Bolivia had plasma retinol concentrations of 12-25 µg·dl-1, with a mean of 19.7 µg·dl-1 (Karesh et al., 1998). Captive spider monkeys (Ateles geoffroyi) had a mean serum retinol concentration of 17.5 µg·dl-1 and a mean serum retinyl palmitate concentration of 0.8 µg·dl-1. Calculated vitamin A activity (from retinol and carotenoids) in the captive diet was 14,000 IU·kg-1, on a dry-matter (DM) basis (Crissey et al., 1999).

Adequate dietary zinc is necessary for maintenance of normal plasma concentrations of vitamin A. When pregnant rhesus monkeys were rendered marginally deficient in zinc, plasma zinc was positively correlated with plasma vitamin A at 135 days of pregnancy and 2-3 months postpartum. There also was a positive correlation between plasma zinc and RBP concentrations. The ratio of RBP to vitamin A tended to be higher in zinc-deficient animals; this suggests that the relationship between zinc, vitamin A, and RBP is complex (Baly et al., 1984).

VITAMIN A DEFICIENCY

Signs of vitamin A deficiency have been described in rhesus and capuchin monkeys (Harden and Zilva, 1919; Saiki, 1929; Tilden and Miller, 1930; Turner and Loew, 1932; Grinker and Kandel, 1933; Hetler, 1934; Verder and Petran, 1937; Ramalingaswami et al., 1955; Rodger et al, 1961; Hayes, 1974b; O’Toole et al., 1974). The early studies were reviewed by Day (1944). The first manifestations of deficiency were weakness, diarrhea, loss of appetite, growth cessation, and an apparent increase in susceptibility to respiratory infection. Keratinization of the epithelial tissues also was observed. With a longer, chronic deficiency, pathologic changes in the eye became apparent; these changes were characterized by keratomalacia, xerophthalmia, night blindness, and eventual loss of day vision (Hetler, 1934: Verder and Petran, 1937; Ramalingaswami et al., 1955; Hayes, 1974b). In adult monkeys, the first sign of deficiency appeared after about a year of dietary vitamin A deficiency, by which time plasma vitamin A concentration had fallen from 26 µg·dl-1 to 10 µg·dl-1 or less in rhesus monkeys (O’Toole et al., 1974), and from 15-20 µg·dl-1 to less than 5 µg·dl-1 in capuchin monkeys (Hayes, 1974b). Two of four pregnancies carried to term by rhesus monkeys that were maintained on marginal intakes of vitamin A (400 IU twice a week after plasma vitamin A concentrations dropped below 10 µg·dl-1 on a vitamin A-deficient diet) produced infants with congenital xerophthalmia; a third infant developed xerophthalmia after receiving a vitamin A-deficient diet for 2 years.

VITAMIN A REQUIREMENTS

Despite relatively extensive studies of the deficiency syndrome, minimal requirements for vitamin A are not well established. It is apparent that 400 IU of vitamin A twice a week is insufficient for correction of vitamin A deficiency in adult female rhesus monkeys, although this amount will maintain plasma concentrations of about 10 µg·dl-1 (O’Toole et al., 1974). Control animals weighing 2-3 kg and receiving 175-700 IU of vitamin A per day appeared to be in satisfactory health (Tilden and Miller, 1930). Ramalingaswami et al. (1955) administered 1,500 IU of vitamin A twice a week to control animals that were receiving 100 g of air-dry diet per day. That dosage, which is roughly equal to 4,760 IU·kg-1 of dietary DM, was sufficient to prevent ocular lesions.

The transport of vitamin A in plasma and its metabolism by nonhuman primates that have been studied are similar to those in humans (Vahlquist, 1972; Muto et al., 1973; Burri et al., 1993), so it is reasonable to assume that the requirements of some nonhuman primates are comparable with those of humans. The estimated average requirement (EAR) to ensure adequate stores of vitamin A in adult male humans has been estimated to be 625 µg of all-trans-retinol per day (Institute of Medicine, 2001), roughly equivalent to 4,000 IU·kg-1 of dietary DM. The recommended daily allowance (RDA) for the human adult male is 900 µg of all-trans-retinol per day (Institute of Medicine, 2001), roughly equivalent to 6,000 IU·kg-1 of dietary DM. The RDA contains a safety factor so it should meet or exceed the needs of nonhuman primates. Commercial diets containing vitamin A activity at 20,000-30,000 IU·kg-1 appear to support normal growth, good health, and reproduction in nonhuman primates. Although there are few direct supporting data, vitamin A at 10,000 IU·kg-1 of dietary DM should be safe and adequate to meet the needs of primates. That is somewhat below the intake (12,000 IU·kg-1 of DM) used in purified diets for squirrel monkeys (Ausman et al., 1985).

Although effects of carotenoids (such as quenching singlet oxygen), beyond provitamin A activity, have been described in biologic systems, there are insufficient data to set minimal requirements for carotenoids.

HYPERVITAMINOSIS A

Signs of hypervitaminosis A have been described in young cynomolgus monkeys (Macaca fascicularis) weighing 1-1.8 kg and receiving single intramuscular injections of a water-miscible preparation containing retinyl acetate at 500,000 IU·ml-1, vitamin E at 50 IU·ml-1, and vitamin

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

D2 at 50,000 IU·ml-1 (Macapinlac and Olson, 1981). The injections provided the equivalent of retinol at 100-500 mg·kg-1 of body mass (bodyweight [BW]). Neither toxicity signs nor deaths were seen in monkeys given the equivalent of retinol at 100 mg·BWkg-1. The first signs of toxicity appeared within 3-35 minutes in those receiving the equivalent of retinol at 200-500 mg·BWkg-1. Most frequent were recurrent yawning, droopiness of the eyelids, and drowsiness, with transient and repeated closure of the eyes. Hyperextension of the neck, rapid jerky shaking of the head, hyperactivity, ataxia, and bouts of nausea and vomiting were seen in monkeys receiving 300-500 mg. Of those receiving the 200-mg dose, 67% died, whereas mortality was 100% in those receiving higher dosages, most dying in less than 3 days. The possibility that these effects were due in part to excesses of vitamins D and E was considered by the researchers but judged unlikely.

Subtoxic concentrations of retinyl esters at 17.0 ± 6.3 umol· µg-1 of liver were found in 3.5- to 28.2-year-old rhesus monkeys (Macacca mulatta) fed a widely used dry commercial diet with 40 IU vitamin A (label guarantee), as retinyl acetate, per gram. Histologic examination of the livers revealed Ito cell hypertrophy and hyperplasia, and it was suggested that preformed vitamin A concentrations in the diet were excessive (Penniston and Tanumihardjo, 2001).

Vitamin D

For the primate species that have been studied, vitamin D is not an essential component of the diet as long as they have adequate exposure to sunlight (Holick, 1994). But it appears to be essential in the tissues of most primates for maintenance of calcium and phosphorus homeostasis and for normal bone mineralization (Holick, 1996). In the absence of solar exposure, these primates must be exposed to sources of artificial light of appropriate wavelengths or must receive sufficient vitamin D in the diet. In this review we will try to put into perspective what is known about vitamin D in humans and to compare this information with what is known about its role in nonhuman primates and other vertebrates.

PHOTOBIOLOGY, METABOLISM, AND FUNCTION OF VITAMIN D

Vitamin D is a secosteroid (a split- or open-ringed steroid) that originates from a four-ringed steroid known as provitamin D, with double bonds at carbons 5 and 7. The 5,7-diene of the sterol has maximal ultraviolet (UV) radiation absorption at wavelengths of 265, 272, 281, and 295 nm and does not absorb radiation above 315 nm. Thus, when provitamin D3 (7-dehydrocholesterol, the 5,7-diene counterpart of cholesterol) or provitamin D2 (ergosterol, the 5,7-diene sterol found in fungi and plants) is exposed to solar UV radiation up to 315 nm, the 5,7-diene absorbs it and undergoes a transformation of the double bonds; the result is an opening of the B ring to yield previtamin D. Previtamin D exists in two conformers, the cis, cis and cis, trans forms. Although the cis, trans conformer is thermodynamically stable and therefore favored, only the cis, cis form ultimately can be converted to vitamin D. In nonbiologic systems (such as in organic solvents) at 37°C, it takes about 24 hours for 50% of previtamin D to be converted to vitamin D. However, in biologic systems, the previtamin D is sandwiched between fatty acids of the bilipid layer of the cell membrane. In that location, only the cis, cis conformer exists, and it is rapidly converted to vitamin D. This is evolutionarily important because cold-blooded vertebrates would have been unable to make vitamin D3 in their skin efficiently at usual ambient temperatures in light of the slow conversion of previtamin D3 to vitamin D3.

During exposure to sunlight, 7-dehydrocholesterol in the epidermis and dermis of humans absorbs UV radiation between 290 and 315 nm, the shortest wavelengths that regularly penetrate the atmosphere and reach the earth’s surface. After UV absorption, 7-dehydrocholesterol is converted to previtamin D3 which undergoes an internal isomerization to form vitamin D3. Vitamin D3 is biologically inert and is exported out of the skin into the plasma, where it is bound to a vitamin D-binding transport protein. It can be stored in the fat for later use or—in most higher vertebrates, including amphibians, reptiles, birds, nonhuman primates, and humans—undergoes hydroxylation in the liver to form 25-hydroxyvitamin D3, 25(OH)D3 or calcidiol. This metabolite is the major circulating form used to assess vitamin D status in most terrestrial vertebrates.

When vitamin D is ingested, either as vitamin D2 (ergocalciferol, or ercalciol) or vitamin D3 (cholecalciferol, or calciol), it is incorporated into chylomicra, and about 80% in humans is absorbed into the lymphatic system and directed to the liver (Holick, 1999).

25(OH)D, although the major circulating form of vitamin D, is biologically inert at normal physiologic concentrations and undergoes 1 a-hydroxylation in the kidney to form 1,25-dihydroxyvitamin D, 1,25(OH)2D. 1,25(OH)2D is considered the principal biologically functioning form of vitamin D, responsible for maintaining calcium and phosphorus homeostasis and normal bone metabolism. Specific nuclear receptors for 1,25(OH)2D3, known as vitamin D receptors (VDRs), have been identified in the tissues of rodents, birds, nonhuman primates, and humans. It is suspected that there are also nuclear vitamin D receptors in lower vertebrates, including amphibians and reptiles (Holick, 1996).

1,25(OH)2D interacts with its target-tissue nuclear VDR and in birds, rodents, and humans combines with retinoic acid X receptor to form a heterodimeric complex. This

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

heterodimeric complex then sits on vitamin D-responsive elements in the genomic DNA to alter transcriptional activity and modulate calcium metabolism (Holick, 1989; Darwish et al., 1993). In the small intestine, 1,25(OH)2D enhances intestinal calcium transport along its entire length. However, the region of highest efficiency for vitamin D-mediated calcium transport is the duodenum. In bone, 1,25(OH)2D interacts with osteoblasts to induce production of osteocalcin, osteonectin, osteopontin, and alkaline phosphatase (Lian et al., 1987; Darwish et al., 1993). It also stimulates the expression of the osteoclast differentiation factor in osteoblasts that, in turn, signals preosteoclasts to become mature (Holick, 1999). Thus, 1,25(OH)2D3 indirectly increases the number of mature osteoclasts, which increase mobilization of calcium stores from the bone.

MEASURES OF VITAMIN D ACTIVITY

The World Health Organization has defined an international unit (IU) of vitamin D activity as that provided by 0.025 µg (65.0 pmol) of crystalline cholecalciferol (Norman, 1998). The US Pharmacopeia (USP; Rockville, MD) makes available a USP Reference Standard which provides 1 IU of vitamin D activity per 0.025 µg (or 40 IU·µg-1).

VITAMIN D DEFICIENCY

A deficiency of vitamin D in humans, rodents, birds, and nonhuman primates results in a decrease in intestinal calcium absorption. The decrease leads to a decline in plasma ionized calcium (detected by the calcium sensor in the parathyroid glands), which results in an increase in the production of parathyroid hormone (PTH) (Darwish et al., 1993). PTH has several effects on calcium and phosphorus metabolism. It interacts with osteoblasts to induce osteoclast differentiation factor, which stimulates preosteoclasts to become mature (Holick, 1999); this ultimately results in an increased number of osteoclasts and increased bone mineral mobilization. PTH enhances reabsorption of mobilized calcium in the distal renal convoluted tubules and increases loss of mobilized phosphate into the ultrafiltrate; this loss results in phosphaturia. PTH also stimulates the renal production of 1,25(OH)2D, which, in turn, enhances intestinal calcium absorption (Darwish et al., 1993).

Chronic vitamin D deficiency results in mineralization defects in the skeleton. During growth, before skeletal epiphyseal plates have closed, vitamin D deficiency can lead to marked epiphyseal plate hypertrophy, producing bulges at the ends of the long bones and at the costachondral junctions in the rib cage. In adults, after the epiphyseal plates have closed, vitamin D deficiency results in a more subtle defect known as osteomalacia. Although the osteoblasts function normally and lay down collagenous bone matrix, the deficiency of vitamin D results in an inadequate calcium x phosphate product, preventing normal mineralization of the soft osteoid and leading to an increased risk of bone fracture. Vitamin D deficiency and consequent secondary hyperparathyroidism also result in increased mobilization of precious calcium stores from the adult skeleton, thereby inducing and exacerbating osteoporosis. Chronic vitamin D deficiency with low calcium intake ultimately results in hypocalcemia; this can lead to severe spasms of skeletal muscle, with tetany, laryngospasms, and death.

There are numerous reports of rickets or osteomalacia in captive nonhuman primates (Vickers, 1968; Miller, 1973; Fiennes, 1974; Ullrey, 1986; Allen et al., 1995; Morrisey et al., 1995; Meehan et al., 1996). The syndrome has been called simian bone disease, woolly monkey disease, and cage paralysis. Signs of deficiency have been reported more frequently in young than in mature primates and in platyrrhines (New World monkeys) than in catarrhines (Old World monkeys and apes). Some have proposed that the difference is a result of higher vitamin D requirements in New World monkeys or a limited ability to use vitamin D2 (Hunt et al., 1966). The suggestion by Freedman et al. (1976) that it is a failure to convert vitamin D2 to vitamin D3 is not consistent with known metabolic pathways (Norman and Collins, 1994; Holick, 1999)

Signs of vitamin D deficiency were seen in a nursing red howler (Alouatta seniculus) infant (Ullrey, 1986) and in three juvenile colobus monkeys (Colobus guereza kikuyuensis) (Morrisey et al., 1995) housed with their mothers in zoo exhibits without sunlight exposure or an artificial UVB source. The infants ate little solid food and depended heavily on mother’s milk for their nutrient intake. Gradually, their activity declined, and they had difficulty in walking, climbing, and grasping their mothers. Physical examination revealed bone pain, bowed long bones, and limb joints that were lax and swollen. Changes visualized with radiography included cupping of the metaphyses, widening of the epiphyseal plates, and thinning of the cortices. Some bones exhibited fibrous osteodystrophy, and fractures were seen in the distal femoral epiphyses. Serum calcium, inorganic phosphorus, and alkaline phosphatase in a severely affected 10-month-old female colobus were 8.1 mg·dl-1, 2.7 mg·dl-1, and 1,293 IU·L-1, respectively. The serum 25(OH)D concentration was less than 10 ng·ml-1.A2-month-old colobus monkey showed mild widening of epiphyseal plates radiographically and had increased serum alkaline phosphatase activity (2,268 IU·L-1) and low 25(OH)D concentration (10 ng·ml-1). After intramuscular injection of ergocalciferol and solar exposure, the radiographic appearance of the skeleton returned to normal, and serum 25(OH)D rose to 19 ng·ml-1. Although milk vitamin D concentrations were not measured, the authors proposed that nonhuman primate milk was low in vitamin

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

D, as is human and cow’s milk, and nursing infants that do not eat substantial amounts of other vitamin D-containing foods are at risk if not exposed to UVB. It is noteworthy that rickets has not been seen after installation of UVB-transparent skylights in the red howler and the colobus zoo exhibits.

DISCRIMINATION BETWEEN VITAMIN D2 AND VITAMIN D3

The major structural difference between vitamin D2 and vitamin D3 is that vitamin D2, which originates from the fungal and plant sterol ergosterol, has a methyl group on carbon 24 and a double bond between carbons 22 and 23. In the 1930s, it was shown that chickens fed vitamin D2 developed rickets (Holick, 1996), and ultimately vitamin D3 was found about 10 times more effective than vitamin D2 in preventing rickets in poultry (Hurwitz et al., 1967). For years, the biologic activities of the two vitamins were assumed equal in domestic mammals. However, studies showed that vitamin D2 is also less active than vitamin D3 in the pig, cow, and horse, but the difference is not as great as in the chicken. The vitamin D-binding and vitamin D-metabolite-binding transport proteins appear to vary among species (Edelstein, 1974; Hay and Watson, 1976a, 1976b, 1977), and Edelstein et al. (1973) speculated that the apparent dissimilarity between New World and Old World monkeys in the biologic activity of vitamins D2 and D3 (Hunt et al., 1967; Lehner et al., 1968) might be due to these differences. The mechanism of discrimination is not entirely understood, but Horst et al. (1988) published data suggesting that there is less absorption of vitamin D2 from the gut and enhanced clearance of 25(OH)D2 and 1,25(OH)2D2 from the blood than is the case for vitamin D3 and its metabolites. Furthermore, there is some evidence that tissue vitamin D receptors do not recognize 1,25(OH)2D2 as well as 1,25(OH)2D3 (Holick, 1996).

There are about 100 species of New World monkeys (platyrrhines) and over 100 species of Old World monkeys and apes. Relatively few species in either group have been studied, and published research findings are inadequate to make generalizations about differences between them. Nevertheless, the evidence that vitamin D2 is less active than vitamin D3 in the New World species that have been studied is convincing. Well-controlled studies comparing the activities of the two vitamin forms in Old World species appear not to have been conducted.

Lehner et al. (1968) fed growing squirrel monkeys (Saimiri sciureus) no vitamin D or vitamin D2 at 1,250, 2,500, 5,000, or 10,000 IU·kg-1 of diet. They grew poorly and exhibited rickets, regardless of treatment. In contrast, when squirrel monkeys were fed vitamin D3 at 1,250, 2,500, 5,000 or 10,000 IU·kg-1 diet, all grew equally well, and no rickets were seen. Hunt et al. (1967) fed adult white-fronted capuchin monkeys (Cebus albifrons) purified diets containing 0.8% calcium, 0.46% phosphorus, vitamin A and D2 at 12,500 and 2,000 IU·kg-1, respectively, for 2 years. The monkeys developed fibrous osteodystrophy, were thin and inactive, and had distorted limbs, kyphosis, and multiple fractures with no evidence of callus formation. When dietary vitamin D2 was replaced by vitamin D3 at 2,000 IU·kg-1 for 5 months, the appearance of the capuchin monkeys improved, and they became more active. Previous fractures became resistant to movement, and callus formation was evident radiographically. Hunt et al. (1967) also fed adult cotton-top tamarins (Saguinus oedipus), white-lipped tamarins (Saguinus nigricollis), and black-chested mustached tamarins (Saguinus mystax) a commercial primate diet containg vitamin D2 at 2,200 IU·kg-1 for 8-12 months and observed deficiency signs that were similar to but less severe than those seen in the capuchins. Healing was initiated by feeding each animal 500 IU of vitamin D3 per week. The researchers reported anecdotally that they had seen fibrous osteodystrophy in squirrel monkeys fed vitamin D2 but not in squirrel monkeys or woolly monkeys (Lagothrix spp.) fed vitamin D3 or exposed to sunlight. Although no information on dietary nutrient concentrations or husbandry was provided, they also stated that thousands of rhesus and other Macaca species (Old World monkeys) had been fed diets containing only vitamin D2 without evidence of metabolic bone disease.

Vickers (1968) observed osteomalacia and rickets in capuchins fed a commercial primate diet containing vitamin D2 and noted that injections of vitamin D (form unspecified) or vitamin D3 at 2,200 IU·kg-1 diet would reverse the disease. Lehner et al. (1968) observed bone lesions in squirrel monkeys that could not be prevented by vitamin D2 at 10,000 IU·kg-1 diet, but the lowest concentration of vitamin D3 tested, 1,250 IU·kg-1 of diet, was effective.

METABOLIC RESISTANCE TO VITAMIN D3 IN CALLITRICHIDS

In 1983, Shinki et al. reported blood concentrations of 25(OH)D3, 1,25(OH)2D3, and 24,25(OH)2D3 in seven adult (five males and two females) marmosets (Callithrix jacchus) that weighed about 300 g. They were fed a commercial diet ostensibly containing vitamin D3 at 9,100 IU·kg-1 (not analyzed) and fruit. In addition, they were given 500 IU of vitamin D3 orally twice a week. Housing was not described. Daily mean feed intake (± SEM) was reported to be 20 ± 5 g, but there was no indication whether this was the intake of DM, whether fruit was included, or whether the mean was derived from daily food intake for the group or for individual animals. Serum calcium concentrations in these marmosets ranged from 7.9-9.9 mg·dl-1, and serum phosphorus ranged from 2.1-4.7 mg·dl-1. Circulating concentrations of 25(OH)D3 were 12.4-204.1 ng·ml-1, with a mean of 94.5 ng·ml-1, about 5 times that in six

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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volunteer men from whom blood samples were taken. The mean 1,25(OH)2D3 concentration of 418.8 pg·ml-1, with a range of 196.1-642.4 pg·ml-1, was about 10 times that in the volunteers. Two marmosets that had serum calcium concentrations of 8.8 and 9.9 mg·dl-1 with serum phosphorus concentrations of 2.1 mg·dl-1 and serum 25(OH)D3 concentrations of 16.5 and 12.4 ng·ml-1 had somewhat increased alkaline phosphatase values, were osteomalacic, and had bone fractures. Serum 24,25(OH)2D3 concentrations ranged from less than 0.2 ng·ml-1 (in the marmosets with fractures) to 8.23 ng·ml-1, but the mean, although numerically higher than the mean in the volunteers, did not differ significantly from it. It should be noted that a later report from the same research group (Yamaguchi et al., 1986) stated that marmosets were housed in pairs in cages and that the very low serum levels of 25(OH)D3 in osteomalacic marmosets were probably due to insufficient intake of food (and of vitamin D) because of interference in food selection by cagemates.

In the same study, six young adult female rhesus monkeys (Macaca mulatta) weighing 4-6 kg were fed a commercial diet containing vitamin D3 at 2,400 IU·kg-1 of diet (not analyzed). The mean serum concentration of 25(OH)D3 (estimated by measuring column heights in Shinki et al. [1983], Figure 1) was 50 ng·ml-1 and of 1,25(OH)2D3 was 96 pg·ml-1. Those were not significantly different from the concentrations in the volunteers, who had a mean 25(OH)D3 concentration (estimated as above) of 17 ng·ml-1 and a mean 1,25(OH)2D3 concentration of 44 pg·ml-1. The mean 24,25(OH)2D3 concentration in the serum of rhesus monkeys was essentially identical with that in the marmosets.

The finding of extremely high serum concentrations of 1,25(OH)2D3 without hypercalcemia in common marmosets was duplicated in emperor tamarins (Saguinus imperator) by Adams et al. (1984).

Another study of the common marmoset (Callithrix jacchus) as an animal model for vitamin D-dependent rickets, type II, was published by Suda et al. (1986). (Apparently this study was republished by Yamaguchi et al. [1986] with slightly different marmoset data.) Seventeen adult marmosets weighing about 300 g were fed a diet containing vitamin D3 at 1,480 IU·kg-1 and were given an additional 1,000 IU of vitamin D3 orally twice a week. On the basis of a mean daily intake of 20 g of diet, vitamin D3 intakes were estimated to be 110 IU·BW100g-1·day-1. Five rhesus monkeys (Macaca mulatta) weighing about 5 kg were fed a diet containing vitamin D3 at 2,400 IU·kg-1. On the basis of a daily diet intake of about 100 g, vitamin D3 intake was estimated to be 5 IU·BW100g-1·day-1. Two of the 17 marmosets were found to have bone fractures and radio-graphic evidence consistent with osteomalacic changes in their bones despite the high vitamin D intake, whereas none of the five rhesus monkeys showed any signs of osteomalacia. The mean (± SEM) serum 25(OH)D3 concentration in the rhesus monkeys was 50 ± 4 ng·ml-1; in the 15 marmosets showing no osteomalacia, it was 478 ± 108 ng·ml-1. The serum level of 1,25(OH)2D3 in the rhesus monkeys was 95 ± 17 pg·ml-1; in the marmosets, it was 491 ± 93 pg·ml-1. The two osteomalacic marmosets had serum calcium concentrations of 8.8 and 9.9 mg·dl-1 and serum inorganic phosphorus concentrations of 2.2 mg·dl-1 compared with means of 8.4 ± 0.2 and 4.5 ± 0.2 mg·dl-1, respectively, in the normal marmosets. Serum 25(OH)D3 and 1,25(OH)2D3 concentrations in the osteomalacic marmosets were 17 and 12 ng·ml-1 and 642 and 524 pg·ml-1, respectively. Two rhesus monkeys were given vitamin D3 at 900 IU·BW100g-1·day-1 for 1 month; it resulted in serum 25(OH)D3 concentrations of 1,352 and 1,651 ng·ml-1 and serum 1,25(OH)2D3 concentrations of 73 and 74 pg·ml-1. In vitro studies with kidney homogenates and intestinal cytosols led these researchers to conclude that 1a-hydroxylase activity is higher in the kidney of the marmoset and 24-hydroxylase activity is higher in the kidney of the rhesus monkey. In addition, there appeared to be fewer 1,25(OH)2D3 receptors and lower activity of the receptor-binding complex in the intestine of the marmoset than in that of the rhesus monkey (see also Takahashi et al., 1985). Whether the differing dietary history of the tissues used in the in vitro tests might have influenced the results was not explored.

To put the above observations on vitamin D metabolite concentrations in the serum of captive primates in perspective, it should be noted that 18 free-ranging, wild cotton-top tamarins (Saguinus oedipus) in Colombia had serum 25(OH)D concentrations of 25.5-120 ng·ml-1 with a mean of 76.4 ng·ml-1 (Power et al., 1997). Serum 25(OH)D concentrations in six normal captive cotton-top tamarins consuming diets containing vitamin D3 at 2,500 IU·kg-1 of dry matter were 48-236 ng·ml-1 with a mean of 143.5 ng·ml-1. Serum 25(OH)D concentrations in 24 captive cotton-top tamarins consuming diets containing vitamin D3 at 26,000 IU·kg-1 of dry matter were 11-560 ng·ml-1; two were 11 and 12 ng·ml-1, five ranged from 46 to 60 ng·ml-1, three were between 126 and 176 ng·ml-1, and the remaining 14 were over 224 ng·ml-1. None of the tamarins exhibited bone disease (Ullrey et al., 1999). Analyses of 1,25(OH)2D and 24,25(OH)2D were not performed in the studies of either Power et al. (1997) or Ullrey et al. (1999).

Liberman et al. (1985), using soluble extracts of EpsteinBarr virus-transformed B lymphocytes, found that extracts from a single common marmoset (Callithrix jacchus) had a lower binding affinity for 1,25(OH)2D3 (Kd, 2.2 nM) than did extracts from three normal humans (Kd, 0.27 nM). 1,25(OH)2D3 binding capacity for extracts from the marmoset lymphocytes also were lower (6.9 fmol·mg-1 of protein) than those from human lymphocytes (15.4 fmol·mg-1 of protein). Soluble extracts from herpesvirus papio-trans-

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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formed B lymphocytes from a stump-tailed macaque (Macaca arctoides) had a 1,25(OH)2D3 binding affinity of 0.40 nMand a 1,25(OH)2D3 binding capacity of 14 fmol·mg-1 of protein. The researchers speculated that a defective receptor for 1,25(OH)2D3 could account for target-tissue resistance to this hormone in the common marmoset, but they acknowledged that the type of defect (binding affinity versus capacity) appeared to vary with the cell system analyzed. For example, Chandler et al. (1984) found that LLC-MK2 cells isolated from renal tissue of rhesus monkeys (M. mulatta) had a 1,25(OH)2D3 binding affinity lower by a factor of 30 than LLC-MK2 renal cells from humans.

Gacad and Adams (1992) studied the specificity of steroid binding in B95-8 B-lymphoblastoid cell lines established by Epstein-Barr virus transformation of peripheral blood mononuclear cells from the common marmoset (Callithrix jacchus). The binding of 1,25(OH)2D3 and 25(OH)D3 in extracts of the lymphoblastoid cells was studied in the presence and absence of potentially competitive ligands, including 1,25(OH)2D3, 25(OH)D3,17ß -estradiol, testosterone, and progesterone. Compared with extracts containing the authentic nuclear 1,25(OH)2D3 receptor, extracts of B95-8 cells bound 180% more 1,25(OH)2D3 and 12 times more 25(OH)D3 by weight. The rank order of steroid binding by this intracellular competitive binding component was 25(OH)D3 >1,25(OH)2D3 = estradiol = progesterone = testosterone. The investigators suggested that the higher concentrations of 25(OH)D3 in the serum of some New World primates result from the relative lack of 25(OH)D3-24-hydroxylase activity and are necessary to ensure that there is adequate substrate for maintenance of the increased 1,25(OH)2D3 concentrations that these primates require. Furthermore, they speculated that the elevated 1,25(OH)2D3 concentrations represented an evolutionary adaptation to ancestral diets that included hypercalcemic plants similar to Solanum glaucophyllum, containing high concentrations of 1,25(OH)2D3 glycosides. One means of avoiding life-threatening hypercalcemia would be for the authentic nuclear 1,25(OH)2D3 receptor to coexpress or overexpress an intracellular steroid-binding protein that would intercept such glycosides. Alternatively, the intracellular binding protein might have evolved to protect against non-vitamin D steroid-like compounds. Because the nocturnal Aotus trivirgatus also expresses this protein, but at a much lower level, these workers suggested that the vitamin D so readily supplied via cutaneous photosynthesis during daytime in an equatorial environment also might have contributed to the development of vitamin D-resistant primate phenotypes.

ANIMALS NOT EXPOSED TO NATURAL SUNLIGHT OR UNABLE TO MAKE VITAMIN D IN THEIR SKIN

Diverse terrestrial vertebrate species are never exposed to sunlight, these including some species of bats and some rodents. The rodent species Rattus rattus has 7-dehydrocholesterol in the skin, providing the substrate required for cutaneous photosynthesis of vitamin D; considering this rat’s nocturnal behavior, it is uncertain whether vitamin D requirements are met mostly by photosynthesis or by the diet. Intense skin pigmentation and minimal exposure to sunlight might put some species at substantial risk for vitamin D deficiency. Some nonhuman primate species are nocturnal, and solar UVB exposure is slight. It has not been established how such species obtain their vitamin D supply or, in some cases, whether they require vitamin D.

Naked mole rats spend their entire lives underground and are never exposed to sunlight. Furthermore, vitamin D has not been found in the roots and other foods that they eat (Skinner et al., 1991). There is evidence that naked mole rats have extremely low circulating concentrations of 25(OH)D and 1,25(OH)2D (Buffenstein et al., 1993). Little is known about parathyroid function in these animals, but it appears that their intestine is able to transport calcium adequately in the absence of vitamin D (Pitcher et al., 1992).

A remarkable observation is that cats have extremely low concentrations of 7-dehydrocholesterol in their skin for which Morris (1999) provide convincing evidence of an ineffectiveness in photosynthesizing vitamin D. As a result, vitamin D must be present in their diet to maintain circulating concentrations of 25(OH)D and 1,25(OH)2D in the physiologic ranges needed to satisfy requirements for normal calcium homeostasis and bone metabolism. However, cats are carnivorous, in contrast with most primate species; because tissues of carnivore prey usually contain sufficient vitamin D, there presumably would be little need for cutaneous vitamin D photosynthesis. Whether any nonhuman primate species resembles cats in that regard has not been established.

VITAMIN D REQUIREMENTS

Presumably, if nonhuman primates have little or no exposure to UVB radiation, either from the sun or from artificial sources, they require vitamin D in their diet. Few studies have been conducted to define requirements quantitatively. Lehner et al. (1968) made it clear that the form of vitamin D used in setting the requirement is important when they found that vitamin D3 at 1,250 IU·kg-1 of diet (the lowest concentration studied) was adequate for growing squirrel monkeys (Saimiri sciureus) but that vitamin D2 at 10,000 IU·kg-1 was not. Because the difference in biologic activity between vitamins D2 and D3 has been observed in so many species, estimates of vitamin D requirements will be given here only in terms of vitamin D3.

In a study of vitamin E deficiency, Ausman and Hayes (1974) fed a purified diet for 2 years that furnished vitamin D3 at 1,000 IU·kg-1 to juvenile crab-eating macaques

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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(Macaca fascicularis) and capuchins (Cebus albifrons, apella), Old World and New World monkeys, respectively. Growth was normal, and no bone lesions were observed in any of the monkeys.

Hunt et al. (1967) induced fibrous osteodystrophy in adult white-fronted capuchins (Cebus albifrons) by feeding a purified diet containing vitamin D2 at 2,000 IU·kg-1 for 2 years. When vitamin D3 at 2,000 IU·kg-1 (lowest concentration studied) replaced the vitamin D2 for 5 months, callus formation began and the fractures were stabilized. The previous National Research Council (1978) recommendation for nonhuman primates was vitamin D3 at 2,000 IU·kg-1 of diet (presumably 90% DM), and Flurer and Zucker (1987) reported that this concentration supported serum 25(OH)D concentrations of 30-300 nmol·L-1 (12-120 ng·ml-1) in saddle-back tamarins (Saguinus fuscicollis) and was sufficient to meet their needs.

To establish baseline serum 25(OH)D concentrations for assessing vitamin D status of captive callitrichids, Power et al. (1997) collected blood samples from 18 wild, free-ranging cotton-top tamarins (Saguinus oedipus) in Colombia. They found serum 25(OH)D concentrations of 25.5-120 ng·ml-1 with a mean of 76.4 ng·ml-1. Assuming that cotton-top tamarins that have serum 25(OH)D concentrations in or near that range are adequately nourished with respect to vitamin D, the minimal dietary concentration of vitamin D3 supporting such concentrations in captive cotton-top tamarins with no UVB exposure could be used as an estimate of the minimal dietary requirement. Ullrey et al. (1999) found that a diet containing vitamin D3 at 2,500 IU·kg-1 of DM, fed to six captive cotton-top tamarins with no UVB exposure for 2 years, supported growth, reproduction, and serum 25(OH)D concentrations of 48-236 ng·ml-1 with a mean of 143.5 ng·ml-1, with no evidence of pathologic changes. Lower dietary concentrations of vitamin D3 were not tested.

The growth of common marmosets (Callithrix jacchus) fed purified diets was studied by Tardiff et al. (1998). Power et al. (1999) then tested the ability of adult marmosets on these diets (males and nulliparous and pregnant or lactating multiparous females) to distinguish between water and calcium lactate solutions. According to Power (2000, personal communication), those and related studies involved feeding the purified diets to marmosets for 5 years. The initial dietary vitamin D3 concentration was 3,000 IU·kg-1, and it was used for about 2½ years. Because of concern about suspected vitamin D deficiency in some animals, the dietary vitamin D3 was increased to 9,000 IU·kg-1, although there was no evidence of pathologic changes in most of the marmosets at the lower concentration. No other dietary vitamin D3 concentrations were tested, and no explanation for the variation in response has been provided.

Barnard and Knapka (1993) discussed callitrichid nutrition and summarized much of the research related to callitrichid nutrient requirements and dietary husbandry. They noted that when commercial primate diets were “supplemented” with fruit, preferences for fruit often reduced the intake of more nutritious food and resulted in nutrient imbalances and deficiencies. Ultimately, a highly palatable pelleted diet was formulated that, when fed alone, maintained normal weight in adult Saguinus mystax (Barnard et al., 1988). It was designated the NIH 48 Open Formula Pelleted Diet, and Barnard and Knapka (1993) presented details of its composition. The vitamin premix supplied vitamin D3 at 2,145 IU·kg-1 of diet. The diet contained 10.3% moisture, so the premix added vitamin D3 at about 2,400 IU·kg-1 of dietary DM. Information on vitamin D supplied by the other ingredients was not provided, but on the basis of published analyses, amounts of vitamin D supplied by ingredients other than the vitamin premix would be negligible.

Because few studies were designed to define vitamin D requirements and there are disparate findings, it is not possible to identify a minimal dietary requirement with certainty. For the species that have been studied, it appears that in the absence of solar or artificial UVB exposure, dietary vitamin D3 concentrations of 1,000-3,000 IU·kg-1 DMmeet the needs of most. However, considering our present degree of uncertainty about minimal requirements and safe upper limits of vitamin D3 in the diet, it might be prudent to provide some exposure to natural or artificial UVB radiation. That requires either unimpeded exposure to solar radiation, careful selection of UVB-transparent plastics for windows or skylights, or use of artificial light sources that emit substantial UVB energy at appropriate wavelengths. Ullrey and Bernard (1999) have published information on UVB-transmitting plastics and UVB-emitting artificial lights.

HYPERVITAMINOSIS D

Daily oral doses of 50,000-100,000 IU of Vitamin D3 produced hypervitaminosis D in squirrel monkeys and white-fronted capuchins, whereas similar amounts of vitamin D2 did not (Hunt et al., 1969). The syndrome in squirrel monkeys included hypercalcemia, hyperphosphatemia, uremia, and death in 20-35 days, with no substantial metastatic calcification and minimal nephrocalcinosis. The capuchins died in 52-89 days and exhibited widespread metastatic calcification, including mineralization in the kidneys, aorta, lungs, myocardium, stomach, and various tissue arteries and arterioles. Bone lesions were not seen in either species.

Daily oral doses of 50,000-200,000 IU of vitamin D2 produced hypercalcemia in rhesus monkeys, but no soft-tissue calcification or deaths (Hunt et al., 1972). However, comparable oral doses of vitamin D3 produced marked

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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hypercalcemia, death in 16-160 days, and evidence of nephrocalcinosis at necropsy.

Regular consumption of diets containing vitamin D3 at 6,000-8,200 IU·kg−1 by several New World and Old World primate species has resulted in increased serum 25(OH)D concentrations and speculation about whether such dietary concentrations might be excessive. When rhesus monkeys were fed a commercial primate diet containing vitamin D3 at 6,600 IU·kg−1, serum concentrations of calcium, inorganic phosphorus, and parathormone were normal, but the mean (± SD) serum 25(OH)D concentration was 188 ± 94 ng·ml−1 and was considered high (Arnaud et al., 1985).

Free-ranging rhesus monkeys maintained on Cayo Santiago by the Caribbean Primate Research Center (CPRC) in Puerto Rico were fed a commercial high-protein monkey diet containing vitamin D3 at 8,200 IU·kg−1 to complement wild foods (Vieth et al., 1987). However, monkey density was very high, and the commercial diet made up most of the food consumed (Ullrey, personal observation). Serum from 48 monkeys (six samples from each sex in each of four age classes) that were transferred from Cayo Santiago to the CPRC Sabana Seca Field Station was analyzed for 25(OH)D and 1,25(OH)2D. Group means for 25(OH)D were 143-230 ng·ml−1 and were considered high. Serum concentrations of 1,25(OH)2D were variable (group means, 59-247 pg·ml−1) but were also considered high, and the authors suggested that, if the higher concentrations of this metabolite were sustained in individual monkeys, subtle changes in calcium and phosphorus metabolism might partially explain the calcium pyrophosphate dihydrate crystal deposition arthropathy that was a problem in the colony.

Marx et al. (1989) studied the differences between four species of nonhuman primates in response to vitamin D2 and vitamin D3, including a comparison of serum 25(OH)D concentrations. Consumption of a commercial primate diet containing vitamin D3 at 6,000-6,600 IU·kg−1 resulted in mean 25(OH)D values of 96, 144, 88, and 148 ng·ml−1 in the serum of crab-eating macaques, rhesus macaques, night monkeys, and squirrel monkeys, respectively. After transfer to a diet containing vitamin D3 at 1,500 IU·kg−1 for 5 months, serum 25(OH)D concentrations were 44, 68, 56, and 60 ng·ml−1. There was no hypercalcemia, parathormone suppression, or azotemia in primates fed the commercial diet, which would be suggestive of hypervitaminosis D; but the lack of biochemical and histologic evidence of vitamin D deficiency in monkeys fed diets containing vitamin D3 at 1,500 IU·kg−1 suggested to the researchers that the commercial diet with vitamin D3 at 6,000-6,600 IU·kg−1 was providing more of the vitamin than was needed.

Gray et al. (1982) offered brown lemurs (Lemur fulvus) a commercial primate diet containing vitamin D3 at 6,600 IU·kg−1 plus fresh fruit and a “supplement” containing oats, soy flour, eggs, wheat germ, evaporated milk, sugar, and bananas. Calcium concentrations in the serum from 20 lemurs were 9.6-12.6 mg·dl−1. Serum 25(OH)D3 concentrations were 3.4-94.8 ng·ml−1, and serum 1,25(OH)2D3 concentrations were less than 4 to 220 pg·ml−1. Because the lemurs could make a variety of food choices, it was not possible to relate composition of the diet consumed directly to animals whose biochemical measures appeared to be outside a normal range. Nevertheless, the researchers suggested that some lemurs were hypercalcemic and might have had increased 25(OH)D3 or 1,25(OH)2D3 because of episodic intoxication by vitamin D from the commercial diet. Some animals had low 25(OH)D3 or 1,25(OH)2D3 concentrations, so it is also possible that some lemurs consumed a diet that was low in vitamin D3, although no clinical signs of deficiency were reported.

In some circumstances, hypervitaminosis D might be less of a threat to nonhuman primates than to other species that are housed with them. Pacas (Cuniculus paca) and agoutis (Dasyprocta aguti) housed in mixed-species exhibits at three zoos died with extensive soft-tissue mineralization, including mineralization of the kidneys, leading to renal failure (Kenny et al., 1993). New World primates shared the exhibits, and zoo personnel reported that dropped primate diets, containing vitamin D3 at 7,000 to 22,000 IU·kg−1, were consumed by the affected animals. Analyses of blood from four moribund pacas revealed reduced packed red-cell volume and increases in serum calcium, inorganic phosphorus, urea nitrogen, and creatinine. Histologic examination of affected paca tissues confirmed extensive mineralization of the kidneys, heart, major blood vessels, stomach, intestinal tract, liver, spleen, and skeletal muscle. Serum vitamin D metabolites were not analyzed, but a provisional diagnosis of vitamin D toxicity was made.

Vitamin E

CHEMISTRY AND MEASURES OF ACTIVITY

Vitamin E is a collective term for compounds that were thought to have the biologic activity of α-tocopherol (Traber, 1999). Eight are found in nature. Four are tocols (tocopherols) with a saturated side chain and variable placement and numbers of methyl groups on the chromanol ring; they are designated α- (methyls on carbons 5, 7, and 8), β- (methyls on carbons 5 and 8), γ- (methyls on carbons 7 and 8), and δ- (methyl on carbon 8) tocopherols. Four are tocotrienols with an unsaturated side chain and comparable placement and numbers of methyl groups on the chromanol ring; they are designated α-, β-, γ-, and δ-tocotrienols. Those eight compounds are synthesized by higher plants and are found principally as free alcohols in lipid-containing fractions of green leaves and seeds. They differ in vitamin E potency based on the rat fetal-resorption assay (Bunyan et al., 1961); because α-tocopherol has been assigned the

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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highest relative potency, it is common to assay only for this isomer rather than to perform the more difficult separation and measurement of all eight natural compounds.

The principal commercially available forms of vitamin E are acetate and hydrogen succinate esters of RRR-α-tocopherol (formerly d-α-tocopherol) and of all-rac-α -tocopherol (formerly d,l-α-tocopherol). RRR-α-tocopherol is usually concentrated from natural sources, but it can be synthesized. All-rac-α-tocopherol is a condensation product of trimethylhydroquinone and racemic isophytol; the process results in a totally synthetic mixture of four 2R-stereoisomers (RRR-, RSR-, RRS-, and RSS-α-tocopherol) and four 2S-stereoisomers (SRR-, SSR-, SRS-, and SSS-α-tocopherol). It is sometimes confused with 2-ambo-α-tocopherol (also labeled d,l-α-tocopherol), a partially synthetic condensation product of trimethylhydroquinone and natural phytol that, as the acetate, served as the vitamin E standard for the international unit (IU) until its distribution was discontinued in 1956 (WHO, 1963). The confusion was of concern to Ames (1979) who claimed that the two synthetic forms differed in their relative potency, on the basis of retrospective examination of fetal-resorption bioassays over the previous 21 years. However, Weiser and Vecchi (1981) concluded from more recent research that the previously established biopotency ratios of 1:1 for all-rac-α-tocopheryl acetate to 2-ambo-α-tocopheryl acetate and 1.36:1 for RRR-α-tocopheryl acetate to 2-ambo-α-tocopheryl acetate were still valid. The US Pharmacopeia and National Formulary (1985) accepted those relationships, although relative plasma concentrations in humans after oral administration of RRR-α-tocopheryl acetate and all-rac-α-tocopheryl acetate suggested that RRR-α-tocopheryl acetate can have 2-3 times the bioavailability of the synthetic form per unit of weight (Acuff et al., 1994; Kiyose et al., 1995, 1997). Nevertheless, use of the traditionally defined IU persists: 1 IU = 1 USP unit = 1 mg of all-rac-α-tocopheryl acetate = 0.74 mg RRR-α-tocopheryl acetate = 0.67 mg RRR-α-tocopherol.

Alternatively, α-tocopherol equivalents (α-TEs) have been used to characterize vitamin E activity in human and animal diets; 1 α-TE was defined as the activity of 1 mg of RRR-α-tocopherol. Other natural compounds that once were thought to provide substantial vitamin E activity are β-tocopherol, γ-tocopherol, α-tocotrienol, and β-tocotrienol. When present and assayed, their contributions to dietary α-TEs were estimated by multiplying their concentrations in milligrams by 0.5, 0.1, 0.3, and 0.05, respectively (National Research Council, 1989). However, these other naturally occurring forms of vitamin E appear not to contribute toward meeting the vitamin E requirements of humans because, although absorbed, they are not converted to α-tocopherol and are recognized poorly by the α-tocopherol transfer protein in the liver. Because the 2S-stereoisomers of synthetic α-tocopherol are not maintained in human plasma or tissues, the relative vitamin E activity of 1 mg of all-rac-α-tocopherol has been set at 50% that of 1 mg of RRR-α-tocopherol (Institute of Medicine, 2000). Whether these quantitative relationships apply to nonhuman primates has not been established.

ABSORPTION, METABOLISM, AND EXCRETION

Absorption of tocopherols from the small intestine depends upon bile and pancreatic secretions, as involved in the typical processes of fat digestion (Traber, 1999). Pancreatic esterases are required for release of free fatty acids from dietary triglycerides and for hydrolytic cleavage of tocopheryl esters. Bile acids, monoglycerides, and free fatty acids form mixed micelles in the gut, in which the tocopherols dissolve. Chylomicrons—incorporating triglycerides, free and esterified cholesterol, phospholipids, and apolipoproteins—are synthesized in intestinal mucosal cells. Tocopherols enter the mucosal cells by an unknown mechanism and are incorporated into the chylomicrons, which are secreted into the mesenteric lymphatics and later enter the blood.

Although the efficiency of vitamin E absorption is relatively low in humans (about 15-45%) (Blomstrand and Forsgren, 1968), there appears to be no discrimination against different forms of vitamin E in the gut. During later chylomicron catabolism in the circulation, some of the absorbed forms of vitamin E are transferred to plasma lipoproteins, but much appears to remain with the chylomicron remnants taken up by the liver parenchyma. During catabolism of chylomicron remnants in the liver, RRR-α-tocopherol can be preferentially transferred (compared with other isomers) by α-tocopherol transfer protein in the hepatocytic cytosol to very-low-density lipoproteins (VLDLs) (Hosomi et al., 1997). VLDLs are later secreted by the liver into the plasma. In the circulation, VLDL-bound tocopherols are transferred nonspecifically to various plasma lipoproteins. Traber et al. (1990) demonstrated the preferential association of RRR-α-tocopherol with VLDLs in the livers of cynomolgus monkeys by feeding various deuterated tocopherols and finding that RRR-α-tocopherol was about 80% of the VLDL-bound tocopherol in hepatic perfusate. After secretion of VLDLs into plasma, lipolysis by lipoprotein lipase and hepatic tryglyceride lipase results in transfer and preferential enrichment of plasma lipoproteins with RRR-α-tocopherol. That is consistent with observations that RRR-α-tocopherol is the primary form of vitamin E circulating in plasma in the species that have been studied.

Tocopherols circulate in the body as components of several plasma lipoproteins, and no specific vitamin E-transport protein has been identified in the plasma. In the plasma of African green monkeys (Carr et al., 1993), the molar ratio of α-tocopherol to high-density lipoprotein

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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(HDL) was greater than that of α-tocopherol to low-density lipoprotein (LDL), or to VLDL and LDL combined, and α-tocopherol was associated with the protein component of the HDL particle. However, vitamin E is readily transferred to other lipoproteins in a process catalyzed by phospholipid transfer protein in human plasma. HDLs can play an important role in delivering vitamin E to circulating blood cells. LDLs appear to be important in supplying vitamin E to peripheral tissues, where it is rapidly exchanged with cell membranes.

Vitamin E turnover rates vary among tissues. Erythrocytes, liver, and spleen are in rapid equilibrium with the plasma α-tocopherol pool. The heart, muscle, and spinal cord have slower turnover rates and the brain is slowest of all.

More than 90% of the human body α-tocopherol pool has been found in adipose tissue, and over 90% of that is in fat droplets, not in cell membranes (Traber and Kayden, 1987). The turnover rate of this pool is quite low, and the relative bioavailability of α-tocopherol in human adipose tissue compared with that in other tissues is controversial (Traber, 1999).

The primary oxidation product of α-tocopherol is α-tocopheryl quinone, which, after reduction to the hydroquinone, can be conjugated to yield a glucuronate. The glucuronate can be excreted in the bile or can be degraded to α-tocopheronic acid in the kidneys and excreted in urine (Drevon, 1991), with possible further oxidation to dimers, trimers, or other adducts (Kamal-Eldin and Appleqvist, 1996). Vitamin E isomers that are not preferentially used, such as γ-tocopherol and some of the isomers in synthetic racemic mixtures, are probably excreted in bile.

BIOLOGIC FUNCTIONS

Vitamin E functions as a chain-breaking antioxidant in biologic membranes. It is a potent peroxyl-radical scavenger that prevents free-radical damage to polyunsaturated fatty acids (PUFAs) in membrane phospholipids and plasma lipoproteins. Lipid hydroperoxides, oxidized to peroxyl radicals (ROO·), react much faster with vitamin E in its reduced state (vit E-OH) than with PUFAs to form the corresponding hydroperoxide (ROOH) and a tocopheroxyl radical (vit E-O·). The tocopheroxyl radical formed in the cell membrane emerges from the lipid bilayer into the aqueous medium, where hydrogen donors, such as vitamin C or glutathione, react with the tocopheroxyl radical to return it to its reduced state (vit E-OH). Thus, the antioxidant function of oxidized vitamin E can be restored if aqueous antioxidants are present in sufficient amounts (Halpner et al., 1998a, 1998b).

The relative order of peroxyl radical scavenging reactivity of α-, β-, γ-, and δ-tocopherol (100, 60, 25, and 27, respectively) is similar to their relative biologic activities (1.5, 0.75, 0.15, and 0.05 IU·mg−1, respectively) as determined by the rat fetal-resorption assay. However, the biologic activities of vitamin E isomers appear not to reside exclusively in their ability to function as antioxidants. For example, α-tocotrienol has antioxidant activity that is at least equivalent to that of α-tocopherol but has only about one-third of its ability to prevent fetal resorption. It has been suggested that α-tocopherol’s activity is associated with unique structural features that interact preferentially with stereospecific cellular ligands, such as the hepatic protein α-TTP. Some forms of vitamin E modulate the activity of enzymes (such as suppression of arachidonic acid metabolism via inhibition of phospholipase A2 by α-tocopherol), and γ-tocotrienol enhances degradation of an enzyme (3-hydroxy-3-methyl glutaryl coenzyme A reductase) that regulates rates of cholesterol biosynthesis (Traber, 1999).

VITAMIN E DEFICIENCY

Vitamin E status depends not only on vitamin E forms and concentrations in the diet, but also on dietary concentrations of PUFA, nutritional history, concentrations of other antioxidants, and the presence of xenobiotics and some clinical abnormalities, such as malabsorption (Machlin, 1991). Indeed, vitamin E deficiency was observed in Saguinus labiatus and Callithrix jacchus (Baskin et al., 1983; Chalmers et al., 1983) in association with malabsorption, but Gutteridge et al. (1986) found no increase in vitamin E deficiency among marmosets with wasting syndrome.

Mason and Telford (1947) were among the first to observe signs of vitamin E deficiency in monkeys (Macaca mulatta) fed diets containing 4% lard and 0.57% cod liver oil. After 5 months, the animals developed muscular dystrophy and brownish intracellular pigmentation in several organs and tissues, including striated and smooth muscle. During the late 1950s and into the late 1960s, several investigators conducted studies of vitamin E deficiency in rhesus monkeys. A profound deficiency state—characterized by anemia, muscular dystrophy, and increased urinary excretion of creatine and allantoin—was reported after 167-391 days (Dinning and Day, 1957; Marvin et al., 1960; Porter et al., 1962; Fitch et al., 1980; Fitch and Dinning, 1963). Fitch et al. (1965) showed that the anemia was cured by α-tocopherol in doses approximating 0.378 mg·BWkg−1·d−1. Remissions of shorter duration could also be achieved by coenzyme Q10 and hexohydrocoenzyme Q4, although their potencies with respect to curing the anemia were markedly lower (Dinning et al., 1962; Farley et al., 1967). It was demonstrated that the anemia was due both to ineffective erythropoiesis, because of defective α-amino-levulinic acid synthesis (Porter and Fitch, 1966), and to hemolysis and shortened red-cell life span as measured by chromium-51 labeling (Fitch 1968a,b). The ineffective

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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erythropoiesis was characterized by the presence of multi-nucleated red-cell precursors in both bone marrow and peripheral-blood smears (Porter and Fitch, 1966; Ausman and Hayes, 1974; Fitch et al., 1980). The hemolytic anemia occurred nearly at the end stage and was initially normocytic and then macrocytic, with insufficient reticulocytosis to ameliorate the anemia. Severe anemia was characterized by segmented erythrocytes in the blood and evidence of localized folate deficiency in bone marrow (Ausman and Hayes, 1974). In addition to those observations, Morris et al. (1966) reported defective cholesterol metabolism in vitamin E-deficient monkeys—a finding that was later supported by Mickel et al. (1975).

The initial experimental diets used by the above investigators were rich in animal-based saturated fat but contained small amounts of plant or fish oils to provide essential fatty acids. Bieri and Evarts (1972) showed that RRR-α-tocopherol at 5 mg·kg−1 of diet was insufficient to return plasma α-tocopherol concentrations to normal in monkeys experimentally depleted for periods of 20-60 days, whereas 10 mg·kg−1 of diet re-established baseline plasma α-tocopherol concentrations of 12-14 mg·L−1. They calculated that the -tocopherol requirement was 0.72 mg·g−1 of linoleic acid in the diet.

Fitch and Dinning (1963) showed in the rhesus monkey and Horwitt et al. (1972) in humans that the vitamin E requirement depends on concentrations of PUFAs in the diet. In a series of long-term experiments, both cebus monkeys (Cebus albifrons) and cynomolgus monkeys (Macaca fascicularis) were fed experimental diets containing 22% by weight of either coconut oil or stripped safflower oil (Ausman and Hayes, 1974; Hayes, 1974a,b; Mickel et al., 1975). Neither species fed the diet that was nearly devoid of PUFAs developed signs of vitamin E deficiency within a 2-year period. In contrast, cebus monkeys fed the diet containing stripped safflower oil developed classic signs of vitamin E deficiency within 12 months (lethargy, weakness, muscular dystrophy, hemolytic anemia, jaundice, splenomegaly, hemosiderosis, and lipofuscin and ceroid pigments in various organs), as well as evidence of peroxidation of retinal lipids in the macula of the eye (Hayes 1974b). Cynomolgus monkeys developed the same signs after 24 months. That moderate to large amounts of PUFAs will hasten the development of vitamin E deficiency also has been observed in common marmosets (McIntosh et al., 1987; Ghebremeskel et al., 1991), African green monkeys (Parks et al., 1987, 1990), and cynomolgus monkeys (Kaasgaard et al., 1992; Thomas et al., 1994; Thomas and Rudel, 1996). Finally, in a series of experiments examining immune function in cynomolgus monkeys fed marine- and plant-derived n-3 fatty acids it was possible to ensure adequate vitamin E status by adjusting dietary tocopherol content in relation to fatty acids, according to the formula of Muggli (1989). Thus, vitamin E requirements of nonhuman primates appear to vary (in part) in relation to dietary concentrations of 18:2 and 18:3 fatty acids.

VITAMIN E REQUIREMENTS

The dependent variables used most often to assess vitamin E status or to define vitamin E requirements are plasma α-tocopherol concentrations, followed by the presence or absence of clinical signs of deficiency. α-Tocopherol concentrations in the plasma of apparently normal nonhuman primates have been reported to be 5-10 mg·L−1 in chimpanzees and orangutans (Ghebremeskel and Williams, 1988; Crissey et al., 1999), 10-11.6 mg·L−1 in gorillas (McGuire et al., 1989; Crissey et al., 1999), 5-8 mg·L−1 in baboons (de La Pena et al., 1972; Slifka et al., 2000), 9-10.6 mg·L−1 in mandrills (Slifka, 1994; Crissey et al., 1999), 12-16 mg·L−1 in rhesus monkeys (Nelson et al., 1981), 5-10.5 mg·L−1 in common marmosets (Charnock et al., 1992; Flurer and Zucker, 1989; Ghebremeskel et al., 1990), and 5 mg·L−1 in Saguinus fuscicollis (Flurer and Zucker, 1989). Six free-ranging black spider monkeys (Ateles paniscus chamek) had a mean plasma α-tocopherol concentration of 3.7 mg·L−1, with a range of 2.3-4.8 mg·L−1 (Karesh et al., 1998). Animals made experimentally deficient or exhibiting frank malabsorption or other illnesses that potentially affect vitamin E status had plasma α-tocopherol concentrations ranging from undetectable to 1 mg·L−1 (Ausman and Hayes, 1974; Fitch et al., 1980; Baskin et al., 1983; Chalmers et al., 1983; McIntosh et al., 1987; McGuire et al., 1989). In studies in which plasma concentrations of both α- and γ-tocopherol were determined, γ-tocopherol concentrations were generally no more than 10% of α-tocopherol concentrations (Slifka, 1994, 2000; Crissey et al., 1999)

Aside from prevention of the classical signs of deficiency, vitamin E has been used as a supplement to help prevent a variety of chronic diseases. Marmosets given neurotoxin to induce Parkinson’s disease appeared to derive no benefit from the intramuscular injection of α-tocopherol at 1,000 mg·BWkg−1 (Perry et al., 1987), although such an injection proved beneficial in mice (Perry et al., 1985). Verlangieri and Bush (1992) were able to show that 79 mg of d-α-tocopherol per day was beneficial in prevention and reversal of aortic stenosis in long-term atherogenic studies in the cynomolgus monkey. In a series of investigations of the rhesus monkey as a model of age-related macular degeneration (ARM) in humans (Crabtree et al., 1996a, 1996b, 1997), vitamin E concentrations in the peripheral neural retina correlated with concentrations of retinal protein, plasma α-tocopherol, and dietary vitamin E. The lowest concentration of vitamin E found in the retina of rhesus monkeys was in the foveal crest, which is where ARM begins in humans.

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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More recently, immune function has been used as a dependent variable to help to determine proper vitamin E nutriture. In a rat model, Bendich et al. (1986) showed that vitamin E concentrations required for optimal T- and B-lymphocyte responses to mitogens were greater than 50 mg·kg-1 of diet, whereas 7.5 mg·kg-1 and 15 mg·kg-1 of diet were sufficient for normal rates of growth and prevention of red-cell hemolysis, respectively. In a randomized, double-blind, placebo-controlled intervention study in healthy elderly human subjects fed a placebo or vitamin E at 60, 200 or 800 mg·d-1 for 235 days, Meydani et al. (1997) were able to demonstrate that at least 200 mg·d-1 were needed to enhance in vivo indexes of T-cell-mediated function. That dosage is about 10-12 times higher than the 15-19 mg·d-1 currently recommended for adult humans (Institute of Medicine, 2000). A careful examination of the immune response, as reflected in a dose-response experiment with vitamin E, has not been conducted in nonhuman primates.

A number of studies have provided evidence that vitamin E metabolism or requirements might vary among species. The New World monkey Cebus albifrons appeared to develop vitamin E deficiency twice as fast as an Old World species Macaca fascicularis when the two species were fed identical diets (Ausman and Hayes, 1974). The cause of the greater sensitivity of the cebus monkey than the cynomolgus monkey to vitamin E deficiency in this study was not established. Ghebremeskel et al. (1990) observed that common marmosets exhibit higher erythrocyte hemolysis and lower plasma a-tocopherol:cholesterol ratios compared to humans at equivalent plasma a-tocopherol concentrations of 10 mg·L-1. Some karyotypes of owl monkeys (Aotus trivirgatus) developed a hemolytic anemia and cardiomyopathy that were ameliorated with intramuscular vitamin E and selenium injections (Sehgal et al., 1980; Beland et al., 1981; Meydani et al., 1983). Further investigations into the mechanism of this apparent vitamin E-deficiency anemia indicated that susceptible Aotus had no change in activity of the glutathione peroxidase system (Brady et al., 1982; Meydani et al., 1982). However, they did have decreased concentrations of PUFAs and increased cholesterol concentrations in their erythrocytes, leading to a markedly increased free-cholesterol:phospholipid ratio in red-cell membranes (Walsh et al., 1982). That presumably made the erythrocytes more susceptible to hemolysis. Susceptible Aotus monkeys suffered from chronic enteritis and inflammatory bowel disease (Meydani, 1983), which might have led to decreased absorption of PUFA, vitamin E, and cholesterol and later abnormal cholesterol metabolism and decreased cholesterol esterification (Mickel et al., 1975). The anemia observed in some Aotus might also be secondary to genetically determined dietary allergies and an associated malabsorption.

Table 7-1 is a summary of individual studies in which nonhuman primates were fed one or more diets in an attempt to assess vitamin E requirements. Studies in which only a deficiency was produced without an estimation of requirements are omitted. Vitamin E requirements are reported or calculated as a-tocopherol both in mg·kg-1 dietary DMand in mg·BWkg-1·d-1.

For the Old World macaques and African green monkeys fed diets that did not contain large amounts of n-3 fatty acids (fish oils), minimal dietary requirements were variously estimated to be 3.2, 5-10, 12, less than 50, less than 60, or 87 mg·kg-1 of DM. Dinning and Day (1957) showed that 333 mg·kg-1 of dietary DMwas more than enough to cure vitamin E-deficiency anemia. In the short term, with one exception, a-tocopherol at 50 mg·kg-1 dietary DM appears to be a reasonable estimate of the requirement on the basis of published data. In relation to body weight, the vitamin E requirement appears to be about 3.0 mg·BWkg-1·d-1.

The New World monkeys that have been studied include Cebus albifrons and Callithrix jacchus. The minimal dietary requirements of the former were estimated to be about 3.0 mg·kg-1 of DMand of the latter 4-48 mg·kg-1 of DM. When fish oils were included in the diet, vitamin E requirements appeared to be greater than 95 mg·kg-1 of DMbut certainly less than the one dose of 1,600 mg·kg-1 of DMthat was used. In relation to body mass, Cebus albifrons appeared to require -tocopherol at least at 0.165 mg·BWkg-1·d-1, and Callithrix jacchus at 0.4-4.7 mg·BWkg-1·d-1. When fish oils were added to the diet, the estimate increased to something less than 14 mg·BWkg-1·d-1.

All the above estimates should be used with caution because of uncertainty about the relative biologic activity per unit of weight of all-rac-a-tocopherol vs RRR-a-tocopherol and because the forms of tocopherol used in some of the published studies were not identified. In addition, many observations in other animals have shown that vitamin E requirements for support of optimal immune function are higher than for prevention of clinical signs of deficiency.

Vitamin K

Vitamin K is the collective name for compounds with a 2-methyl-1,4-napthoquinone nucleus and a lipophilic side chain (attached at carbon 3) that have antihemorrhagic activity. The principal active compound in higher plants is phytylmenaquinone (phylloquinone, or vitamin K1) with a 20-carbon phytyl side chain. Prenylmenaquinones (menaquinones, or vitamin K2) are compounds with polyisoprenyl side chains of varied length, generically designated menaquinone-n (MK-n). Those produced by bacteria have side chains with seven to 13 unsaturated isoprenyl units and are designated menaquinone-7 to menaquinone-13 (MK-7 to MK-13). The synthetic provitamin menadione (formerly known as vitamin K3) has no side chain but can be alkylated

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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TABLE 7-1 Survey of Data Used to Estimate Vitamin E Requirement

 

Estimated Requirement

 

Species

Age and Body Weight

Daily DM Consumption

Type of Diet

Nutrient Levels Studied

Criteria Used to Estimate Requirement

mg·kg−1 of dietary DM

mg (or IU)·BWkg-1·d-1

Reference

Macaca mulatta

Young 2 kg

Assumed 30 g·BWkg1·d−1

Purified

0 (+ suppl) or 20 mg·d−1

Dose needed for anemia remission, number days of remissions

<10 mg·0.03 kg−1 = <333 mg of α-tocopherol

<10 mg of αtocopherol

Dinning and Day, 1957

Macaca mulatta

Immature 1.5-2.5 kg

Assumed 30 g·BWkg1·d−1

Purified

0 (+ suppl) or 34 mg·d−1

Dose needed to keep urinary creatine:creatinine ratio below 1

2.6 mg·0.03 kg−1 = 87 mg of d,lα-tocopherol

2.6 of mg d,l-αtocopherol

Fitch and Dinning, 1963

Macaca mulatta

Young 1.3-1.8 kg

Assumed 30 g·BWkg1·d−1

Purified

0 (+ suppl) or 34 mg·d−1

Dose needed for anemia remission, number days of remission

0.378 mg·0.03 kg−1 = 12.6 mg of l-α-tocopherol

0.378 ± 0.108 mg of l-α-tocopherol

Fitch et al., 1965

Macaca mulatta

4.5 and 4.0 kg

170 g (ME at 3.48 kcal·g−1 of DM)

Purified

0, 5, and 10 mg·kg−1 of diet

Plasma vitamin E concentrations

>5 mg and <10 mg of d-α-tocopherol

>0.4 mg <0.75 mg of d-α-tocopherol

Bieri and Evarts, 1972

Cebus albifrons

14 mos 1.4-1.8 kg

86 g (ME at 185 kcal·BWkg−1)

Purified

Trace vs 100 mg·kg−1 of diet

Dose needed for anemia remission, number days of remission

3.0 mg of α-tocopherol

0.165 ± 0.02 mg of α-tocopherol

Ausman and Hayes, 1974

Macaca fascicularis

14 mos 2.2 kg

67 g (ME at 105 kcal·BWkg−1)

Purified

Trace vs 100 mg·kg−1 of diet

Curing anemia

3.2 mg

0.10 mg

Ausman and Hayes, 1974

Callithrix jacchus

80-90% mature 306-344 g

Assumed 32 g

Purified

4 or 48 mg·kg−1 of diet

Plasma α-tocopherol concentrations, ability to reduce peroxidative hemolysis

>4 mg to <48 mg of d-αtocopherol

Calc: (>4 mg) (0.032 g of diet) = 0.128 mg·0.325 kg−1 = >0.4 mg; (<48 mg) (0.032 g) = 1.536 mg· 0.325 kg−1 = <4.7 mg

McIntosh, 1987

Callithrix jacchus

400 ± 20 g

31 g

Purified (+ fish oils)

2.94 mg per monkey

Plasma concentrations and erythrocyte hemolysis

>95 mg

<7.4 mg

Ghebremeskel et al., 1990

Callithrix jacchus

Adult 392 g

31 and 33 g

Purified (+ fish oils)

2.94 mg and 52.7 mg per monkey

Hydrogen peroxide-induced hemolysis—64% (high) vs 2% (normal)

>95 mg <1,600 mg

>7.4 mg <134 mg

Ghebremeskel et al., 1991

Callithrix jacchus

Young, 9-12 mos 295-330 g

Assumed 32 g

Purified

130 IU·kg−1 of diet

Plasma tocopherol concentrations

<130 IU of α-tocopherol

Calc: (130 IU)(0.032 kg of diet) = 4.16 IU·0.33 kg−1 = <12.6 IU

Charnock et al., 1992

Macaca fascicularis

N.A.

Assumed 30 g·BWkg−1·d−1

Purified

60 or 270 mg·kg−1 of diet

Liver α-tocopherol, lipofuscin pigments, enzymes, and TBRS

<60 mg >270 mg if ω-3 fatty acids present

N.A.

Kaasgaard et al., 1992a

Cercopithecus aethiops

Adult

30 g·BWkg−1·d−1 (ME at 90 kcal·BWkg−1·d−1)

Purified

Vitamin E at 30-50 mg·kg−1 of diet

Plasma concentrations

<50 mg

N.A.

Carr et al., 1993a

aReport did not identify minimal vitamin E requirements, but data provide an upper boundary of need based on criteria used.

in the liver of rats and chicks to form menaquinone-4 (MK-4) (Olson, R.E., 1999).

Vitamin K is the cofactor for γ-glutamyl carboxylase, a microsomal enzyme responsible for the posttranslational carboxylation of glutamyl residues (producing γ-carboxy-glutamic acid, Gla) in seven coagulation proenzymes (clotting factors II, VII, IX, and X and proteins C, S, and Z) and in intracellular protein Gas 6 (growth-arrest-specific factor, homologous to protein S), matrix Gla protein, and bone Gla protein (osteocalcin) (Hauschka et al., 1989; Liu et al., 1996; Ferland, 1998).

It is now apparent that vitamin K is important not only in blood coagulation but also in bone metabolism. Matrix Gla protein is found in the organic matrix of bone, dentin,

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

and cartilage but does not bind with hydroxyapatite. Osteocalcin appears to be derived from osteoblasts, is one of the most abundant noncollagenous proteins in bone, and binds to hydroxyapatite. Synthesis of those two proteins in cultured osteosarcoma cells was regulated by 1,25-dihydroxy-vitamin D3, and there is evidence that matrix Gla protein inhibits growth-plate mineralization, whereas osteocalcin can stimulate bone remodeling and mobilization of bone calcium (Olson, 1999).

Metta and Gopalan (1963) attempted to produce a vitamin K deficiency in Macaca mulatta by feeding a vitamin K-deficient diet (vitamin K [expressed as menadione] at 0.06 μg·g−1 of diet) and by administering antibiotics to limit intestinal production of vitamin K by bacteria. No alterations in clotting were observed, so it was assumed that this amount of dietary vitamin K was adequate. Hill et al. (1964) conducted similar experiments, but clotting times increased over a 270-d period. Administration of vitamin K [as the tetrasodium salt of 2-methyl-1,4-naptho-hydroquinone diphosphate] at 0.1 g·BWkg−1·d−1 was sufficient to normalize clotting times. Two decades later, Suttie (1985), on the basis of data in Griminger (1971), reported that M. mulatta required vitamin K (form not specified) at 2 μg·BWkg−1·d−1; this was equivalent to vitamin K at 0.06 mg·kg−1 of diet. That dietary concentration may be compared with about 3 and 12 mg·kg1 found in two commercial monkey diets (Lab Diet® and Harlan®, respectively). The vitamin K concentrations in the two commercial diets seem more than adequate.

Because vitamin K deficiency produced by medical use of warfarin has sometimes been associated with negative effects on bone mass, Binkley et al. (2000) assessed the skeletal status of healthy adult (7-18 years) rhesus macaques during long-term warfarin administration. Bone mass of the total body, lumbar spine, and distal and central radius was determined by dual energy X-ray absorptiometry (DEXA) at baseline and after 6, 12, and 18 months. At these times, serum total and bone-specific alkaline phosphatase concentrations, total and percent unbound osteocalcin concentrations, and urinary calcium:creatinine ratios also were measured. Warfarin administration produced an elevation in serum undercarboxylated osteocalcin but did not alter markers of skeletal turnover or calcium excretion, nor was bone mineral density altered at any measured site. The authors concluded that long-term warfarin administration did not have adverse skeletal consequences in healthy primates with high intakes of vitamin K, calcium, and vitamin D.

Infant humans are more likely to develop vitamin K deficiency than are adults, and this possibility should be considered in infant nonhuman primates. The special sensitivity of the young is associated with poor placental transfer of lipids, limited ability of the liver of the newborn to synthesize prothrombin, low concentrations of vitamin K in breast milk, and sterility of the infant gut at birth, which limits microbial synthesis of menaquinones.

Setting a minimal dietary requirement for vitamin K is difficult because of uncertainty about the quantity and availability of the menaquinones produced by intestinal bacteria. Intestinally active antibiotics can severely limit gut synthesis of menaquinones and increase the importance of vitamin K in the diet. Clotting times, as a means of assessing vitamin K status, are neither particularly precise nor sensitive. Vitamin K deficiency differentially affects the degree of γ-carboxylation of each of its dependent proteins, and there are changes in carboxylation long before changes in clotting time become clinically apparent (Hodges et al., 1993; Sokoll et al., 1997). The presence of des-γ-carboxyprothrombin in the plasma has been used as an early and sensitive indicator of vitamin K deficiency in humans. In healthy people, plasma concentrations should be zero. In people with vitamin K deficiency or liver disease, des-γ-carboxyprothrombin values can reach 30% of total prothrombin levels.

Forms of vitamin K commonly incorporated into nonhuman-primate diets include the water-soluble derivatives menadione dimethylpyrimidinol bisulfite (MPB), menadione sodium bisulfite (MSB), and menadione sodium bisulfite complex (MSBC). Vitamins K1 and K2 and menadione also have been used, but they are fat-soluble, so it is difficult to distribute them uniformly in dry feeds. The vitamin K activities of the three water-soluble forms are related to their molecular proportions of menadione, which are 46%, 52%, and 33% for MPB, MSB, and MSBC, respectively. Moisture, alkalinity, and contact with trace minerals and choline chloride can impair their stability. Coelho (1991) reported that MPB and MSBC can lose up to 80% of their activity after 3 months in vitamin-trace mineral premixes containing choline. However, when choline was not included in the premixes, declines in vitamin K activity were much smaller. Microencapsulation of vitamin K compounds also has improved their stability.

WATER-SOLUBLE VITAMINS

Thiamin

Thiamin, as the coenzyme thiamin pyrophosphate, functions in oxidative decarboxylation of α-ketoacids. The vitamin is critical for decarboxylation of pyruvate in preparation for its entry into the tricarboxylic acid cycle. The coenzyme also is involved in the decarboxylation of α-ketoglutarate and the α-ketoacids resulting from metabolism of branched-chain amino acids. And it functions in transketolase reactions and may play a role in neurotransmission and nerve conduction (Rindi, 1996; Tanphaichitr, 1999).

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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Thiamin is added to diets as the salt of chloride-hydro-chloride (usually called thiamin hydrochloride) or as the mononitrate. Those forms are stable under dry and acidic conditions, but thiamin is destroyed under alkaline conditions, especially when accompanied by heat. It also is destroyed by X-rays, γ-rays, UV irradiation, and sulfites (Rindi, 1996; Tanphaichitr, 1999).

Thiamin status can be influenced by its bioavailability in food, the presence of antithiamin factors, and dietary concentrations of folate and protein (Tanphaichitr, 1999). Thiaminase I (found in several microorganisms and certain plants, raw fresh-water fish, shellfish, and marine fish) and thiaminase II (found in several microorganisms) are thermolabile antithiamin factors that destroy the vitamin activity of thiamin during food storage or preparation, prior to ingestion or during food passage through the gastrointestinal tract. Thermostable antithiamin factors have been found in plants and a few animal tissues. Those in plants are related to ortho- and para-polyphenolic compounds, such as caffeic acid, chlorogenic acid, and tannic acid. In the presence of oxygen, active quinones are generated that interact with thiamin to produce thiamin disulfide and other less active or inactive compounds. Ascorbic acid and other reducing agents tend to inhibit this process. The bioavailability of thiamin in foods also may be reduced by divalent cations, such as Ca2+ and Mg2+, which tend to augment the precipitation of thiamin by tannins. Ascorbic acid, tartaric acid, and citric acid will inhibit this precipitation, apparently by sequestering these cations. Subjects with a folate or protein deficiency exhibit a reduction in thiamin absorption that can be reversed by folate and protein supplementation.

Thiamin deficiency has been produced in rhesus monkeys (Macaca mulatta) by Lebond and Chaulin-Serviniere (1942), Waisman and McCall (1944), Rinehart et al. (1948,1949a), Blank et al. (1975), Witt and Goldman-Rakic (1983a), and Cogan et al. (1985). Deficiency signs include weight loss, anorexia, apathy, weakness, ophthalmoplegia, loss of reflexes, paralysis, incoordination, convulsions, cardiac failure, and death. Thiamin-deficient animals also exhibit behavioral abnormalities and memory loss (Witt and Goldman-Rakic, 1983b).

Observations of pathologic conditions have focused on the myocardium and the nervous system. Focal necrosis of myocardial fibers is a relatively constant finding and has been associated with electrocardiographic abnormalities. Degeneration of the fibers in the myocardial conduction system also has been seen (Waisman and McCall, 1944; Rinehart and Greenberg, 1949a). Both peripheral nerve (Lebond and Chaulin-Serviniere, 1942) and central nervous system degeneration similar to Wernick’s encephalopathy (Rinehart et al., 1949; Blank et al., 1975; Witt and Goldman-Rakic, 1983a, 1983b) have been described in rhesus monkeys. Wernick’s encephalopathy is a disease often associated with chronic alcoholism in humans.

Waisman and McCall (1944) found that rhesus monkeys weighing about 3 kg and consuming 100-200 g of food per day required thiamin at 15 μg·BWkg−1·d−1 to prevent deficiency signs and support maintenance. Optimal growth was obtained at 25-30 μg·BWkg−1·d−1, whereas borderline deficiency signs appeared in animals receiving less than 10 μg·BWkg−1·d−1.

Rinehart et al. (1948) described an anemia associated with reduced erythropoiesis in thiamin deficiency. They estimated the thiamin requirement by observing the time necessary to replete thiamin-deficient rhesus monkeys weighing 1.7-5.0 kg after administration of a single small thiamin dose separate from food. The researchers concluded that the thiamin requirement was about 15.5 μg·BWkg−1·d−1.

Thiamin-deficient rhesus monkeys have reduced blood transketolase activity (Mesulam et al., 1977), an accepted end point for assessing thiamin status (Rindi, 1996). However, measurements of transketolase activity have not been applied to studies of the quantitative thiamin requirement.

The quantitative requirement for thiamin has not been studied in nonhuman primates other than rhesus monkeys. However, the thiamin requirement of nonhuman primates is estimated to be 1.1 mg·kg−1 of dietary DM, primarily on the basis of the report of Waisman and McCall (1944). That estimate was based on the use of purified diets, and the biologic availability of thiamin in natural ingredients and the destruction of thiamin during feed processing or storage were not taken into account. These studies are summarized in Table 7-2.

Riboflavin

Riboflavin is a precursor of the coenzymes flavine adenine mononucleotide (FMN) and flavine adenine dinucleotide (FAD). Those coenzymes and their associated enzymes catalyze oxidation-reduction reactions and are important in the metabolism of carbohydrates, fats, and proteins. The enzymes function in the transfer of electrons in oxidation-reduction reactions (Rivlin, 1996). A riboflavin coenzyme also plays a role in the conversion of pyridoxine to pyridoxamine phosphate, which acts as a coenzyme in the conversion of tryptophan to niacin. Thus, riboflavin may be involved indirectly in the biosynthesis of niacin from tryptophan (Cooperman and Lopez, 1991; McCormack, 1999).

Riboflavin is added to animal feeds in the form of the crystalline vitamin. The biologic availability to humans of riboflavin in natural foods is estimated to be about 95% (Institute of Medicine, 1998).

Riboflavin deficiency has been induced and studied in rhesus monkeys (Macaca mulatta) by Day et al. (1935),

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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TABLE 7-2 Estimates of Thiamin Requirement

Species

Age

Body Weight

Daily Air-Dry Diet Consumption

Type of Diet

Thiamin Levels Studied

Criteria

Estimated Requirement

Reference

Macaca mulatta

Not specified

3 kg

100-200 g

Purified

10-100 µg·d-1

No deficiency signs, maintained weight

15 µg·BWkg-1·d-1 for maintenance

Waisman and McCall, 1944

Macaca mulatta

Not specified

3 kg

100-200 g

Purified

10-100 µg·d-1

Growth

25-30 µg·BWkg-1·d-1

Waisman and McCall, 1944

Macaca mulatta

Not specified

1.7-5.0 kg

 

Purified

Not specified

Dose divided by time to replete deficient monkeys

15.5 µg·BWkg-1·d-1 for maintenance

Rinehart et al., 1948

Waisman (1944), Cooperman et al. (1945), and Greenberg and Moon (1963). The signs of deficiency in rhesus monkeys include growth failure, “freckled” dermatitis, incoordination, faulty grasping reflexes, impaired vision, scanty hair coat, reduced red-cell count, anemia, leukopenia, fatty liver, blindness, and eventual death. The dermatitis begins as small, dry, red spots about the face and progresses to dark scabs over the entire body. The severe anorexia seen in thiamin deficiency has not been observed.

There are two reports on the riboflavin requirement of macaques. The riboflavin concentration required to cure deficiency signs and allow excretion in the urine of animals weighing 3-4 kg was 25-30 µg·BWkg-1·d-1 (total intake, 90 µg) (Cooperman et al., 1945). In another investigation, the requirement of monkeys weighing 3 to 4 kg was estimated to be 41 µg·BWkg-1·d-1; this estimate was based on the difference in urinary excretion of riboflavin between animals receiving sufficient riboflavin and those fed a deficient diet for 5 weeks (Greenberg, 1970).

Mann et al. (1952) and Mann (1968) described riboflavin deficiency in capuchin monkeys (Cebus albifrons). Weight loss, dermatitis, alopecia, ataxia, and sudden death were the reported signs. Severe anemia did not develop in capuchin monkeys, although seen consistently in rhesus monkeys. The concentration of plasma riboflavin was considered a good indicator of riboflavin status. A riboflavin intake of 50-55 µg·BWkg-1·d-1 was required to restore maximal growth rate in deficient animals. That represented a daily supplement of 30-40 µg of riboflavin in a basal diet furnishing 10-15 µg·BWkg-1·d-1 (Mann et al., 1952). Although the weights of the animals were not specified, monkeys used in similar studies in the same report, but not involved in the requirement study, weighed 0.9-1.4 kg and consumed 40-60 g of diet per day.

Foy et al. (1964, 1972) and Foy and Kondi (1984) described riboflavin deficiency in the baboon (Papio anubis) as characterized by weight loss, apathy, severe dermatitis, anemia, gingivitis, diarrhea, and adrenal cortical hemorrhage. The dermatitis progressed to nodular lesions that formed mud-pack-like masses on the face, arms, legs, and feet. The lesions extended into the lower third of the esophagus (Foy and Kondi, 1984). An increased concentration of xanthurenic acid, but not of anthranilic acid (both are metabolites of tryptophan), was found in the urine of riboflavin-deficient baboons by Foy et al. (1964). Increased anthranilic acid but unchanged concentrations of xanthurenic acid in the urine were reported by Verjee (1971). No explanation for the different findings was offered. An erythroid aphasia characterized by a fall in marrow erythroid activity leading to reduced hemoglobin, packed-cell volume, and total blood volume was reported in baboons made riboflavin-deficient. A reversal of the albumin:globulin ratio also was observed (Foy et al., 1964, 1968; Foy and Kondi, 1968).

The signs of riboflavin deficiency in the baboon were reversed with a therapeutic dose of about 10-50 mg of riboflavin per animal per day for 3-7 days (Foy and Kondi, 1968). No attempt was made to see whether the same effect could be achieved with smaller doses.

There are insufficient data to show whether different species of primates have similar or different riboflavin requirements. The estimated riboflavin requirement of nonhuman primates has been set at 1.7 mg·kg-1 of dietary DM. That requirement is based on studies with purified diets fed to rhesus and capuchin monkeys, summarized in Table 7-3.

Pantothenic Acid

Pantothenic acid is a part of coenzyme A, which is involved in metabolic acetylation reactions. Coenzyme A serves as a cofactor in the tricarboxylic acid cycle, in fatty-acid synthesis and degradation, and in the formation of acetylcholine in nervous tissue (Plesofsky-Vig, 1996, 1999). Biologic availability of pantothenic acid in the average American human diet is estimated to be about 50% (Tarr et al., 1981; Institute of Medicine, 1998). The supplemental form usually added to diets is D-calcium pantothenate, equivalent in activity to 85% pantothenic acid.

McCall et al. (1946) reported that pantothenic acid deficiency in rhesus monkeys (Macaca mulatta) resulted in lack of growth, anemia, loss of hair, and ataxia. Only partial

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

TABLE 7-3 Estimates of Riboflavin Requirement

Species

Age

Body Weight

Daily Air-Dry Diet Consumption

Type of Diet

Riboflavin Levels Studied

Criteria

Estimated Requirement

Reference

Macaca mulatta

Not specified

3.3 kg

100 g

Purified

40-90 µg·d-1

Reverse deficiency signs, allow riboflavin excretion in urine

90 µg·d-1 or 25-30 µg· BWkg-1·d-1

Cooperman et al., 1945

Macaca mulatta

Not specified

3.0-4.0 kg

Not specified

Not specified, probably purified

0 and 1.0 mg·d-1

Difference in urinary riboflavin excretion between animals receiving sufficient and no riboflavin

41 µg·BWkg-1·d-1

Greenberg, 1970

Cebus albifrons

Young adult

Not specified; probably 9001,400 g

40-60 g

Purified

20-70 µg·d-1

Weight gain of deficient animals

50-55 µg·d-1 or 30-40 µg·BWkg-1·d-1

Mann et al., 1952

improvement was noted with oral administration of D-calcium pantothenate at 1-3 mg·BWkg-1·d-1. Complete recovery was noted when supplements of both calcium pantothenate and liver powder were included in the diet, so a simultaneous deficiency of nutrients other than pantothenic acid is likely to have occurred. Greenberg (1970), citing unpublished studies, reported a dramatic response to 3 mg of calcium pantothenate per animal per day. Those are the only studies describing pantothenic acid deficiency in nonhuman primates.

Semipurified diets with calcium pantothenate at about 22-23 mg·kg-1 DM(equivalent to pantothenic acid at 1920 mg·kg-1 DM) have been fed to rhesus monkeys (Kark et al., 1974) and to squirrel monkeys (Rasmussen et al., 1979) without signs of deficiency. These latter studies do not provide the basis for estimating minimum pantothenic acid requirements, and the concentrations used exceed the minimum pantothenic acid requirements reported for other species in the National Research Council nutrient requirement series.

Niacin

Niacin (also known as nicotinic acid) is a component of the coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), which play a part in metabolic oxidation-reduction and dehydrogenase reactions, serving as electron receptors or hydrogen donors (Jacob and Swenside, 1996; Cervantes-Laurean et al., 1999). Although niacin is widely distributed in natural foodstuffs, it is bound and largely unavailable in grains, such as wheat and corn (Jacob and Swenside, 1996). Niacin supplements are commonly added to diets as nicotinic acid or nicotinamide.

Estimating the niacin requirement is complicated by the ability of many mammals to synthesize niacin from a dietary excess of the amino acid tryptophan. That ability has been identified in some primate species (Tappan et al., 1952; Banerjee and Basak, 1957). Thus, to some extent the niacin requirement is related to the tryptophan supply in the diet. Deficiencies of a number of other nutrients—including vitamin B6, riboflavin, iron, and copper—can inhibit the conversion of tryptophan to niacin (van Eys, 1991).

Niacin deficiency has been studied in rhesus monkeys (Macaca mulatta) by Tappan et al. (1952), Belavady et al. (1968), and Belavady and Rao (1973). The deficiency syndrome was characterized by weight loss, alopecia, anemia, skin hyperpigmentation, anorexia, chronic gastritis, and diarrhea. Declines in serum albumin and blood pyridine nucleotide concentrations and development of chronic atrophic gastritis and atrophic necrotizing enterocolitis were also observed.

Tappan et al. (1952) reported that deficiency signs in rhesus monkeys weighing 1.4-3.2 kg and fed purified diets containing 7% protein from casein were ameliorated by weekly administration of 10-35 mg of niacin (equivalent to about 0.7-1.8 mg·BWkg-1·d-1)or 1-4g of D,L-tryptophan. A weekly dose of 5 mg of niacin was not adequate to reverse deficiency signs, and 30-35 mg of niacin per week was more effective than 10 mg. Intermediate dosages were not tested. Belavady et al. (1968) reported that niacin deficiency in rhesus monkeys was reversed by giving animals 25 mg of niacin per day in the first week and 10 mg per day for 3 more weeks; lower dosages were not tested. The animals weighed 6.0-11.0 kg. Belavaday and Rao (1973) induced niacin deficiency by supplementing the diet of rhesus monkeys with 1.5 g of leucine (a niacin antagonist) per day. That resulted in reduced synthesis of nicotinamide

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

nucleotides in erythrocytes, weight loss, and alopecia, which were reversed by injection of 40 mg of niacin.

Data are insufficient to estimate niacin requirements of nonhuman primates with confidence. It is probable that the dietary niacin requirement of rhesus monkeys with minimal synthesis from tryptophan is 16-56 mg·kg-1 of DM.

Vitamin B6

Vitamin B6 occurs as pyridoxine, pyridoxal, and pyridoxamine. These compounds function metabolically as the coenzymes pyridoxal phosphate and pyridoxamine phosphate. The vitamin B6 coenzymes are important cofactors in amino acid metabolism and in glycogen and lipid metabolism. Vitamin B6 coenzymes also can be involved in the synthesis of niacin from tryptophan (Leklem, 1996, 1999). The bioavailability of vitamin B6 in a mixed human diet is about 75% (Tarr et al., 1981). That in foods used for laboratory animals has been reported to be as low as 40-60% under some conditions (Baker, 1995). Supplemental vitamin B6 is usually added to feeds as pyridoxine hydrochloride, with a vitamin B6 potency of 92%.

Vitamin B6 deficiency has been produced in rhesus monkeys (Macaca mulatta) by a number of investigators, beginning with McCall et al. (1946), who described the resulting syndrome as consisting of weight loss, hypochromic anemia, and ataxia. Clinical improvement was noted in 2 weeks after provision of 1 mg of pyridoxine per day to 1.5- to 2-kg monkeys. Others have confirmed those clinical signs and modified the description of the deficiency to include widespread arteriosclerosis, leukopenia, anemia, liver cirrhosis, decreased plasma albumin, and increased plasma globulin, dental caries, and neural degeneration of the cerebral cortex (Rinehart and Greenberg, 1949a, 1951, 1956; Greenberg et al., 1952; Poppen et al., 1952; Mushett and Emerson, 1956; Victor and Adams, 1956; Greenberg et al., 1958; Greenberg, 1964; Wizgird et al., 1965). Arteriosclerosis involving many tissues and organs, anemia, leukopenia, alopecia, and dermatitis are the most frequently reported signs.

The interrelationship between essential fatty acids and vitamin B6 has been investigated because it was thought that vitamin B6 might be required for the conversion of linoleic acid to arachidonic acid. In turn, a deficiency of arachidonic acid might be responsible for atherosclerosis in primates. The vascular lesions of animals with a combined deficiency of essential fatty acids and vitamin B6 were no more severe than those seen in animals with simple vitamin B6 deficiency. The fatty acid patterns in plasma and erythrocytes of control and vitamin B6-deficient animals were similar and unlike those of animals deficient in essential fatty acids. The conclusion was that no metabolic interrelationship exists between the two nutrients (Greenberg and Moon, 1959, 1961; Greenberg 1964), although the role of vitamin B6 in lipid metabolism remains controversial (Leklem, 1999).

Arteriosclerosis develops in vitamin B6-deficient cynomolgus monkeys (Macaca fascicularis) and rhesus monkeys (Kuzuya. 1993). At least partial regression of the lesions occurs upon refeeding vitamin B6 (Yamada et al., 1965).

Vitamin B6 requirements were investigated in several studies, which are summarized in Table 7-4.

Rinehart and Greenberg (1956) tested graded levels of pyridoxine hydrochloride and measured growth of rhesus monkeys weighing 1.3-3.0 kg. They concluded that the requirement was 62 µg·BWkg-1·d-1 for optimal growth. But Emerson et al. (1960) fed pyridoxine hydrochloride at 50-2,000 µg·d-1 to rhesus monkeys weighing 4.1 kg. Ataxia and alopecia persisted in animals receiving 500 µg·d-1 or less, and higher dosages were required to alleviate deficiency signs. A dosage of 1.0-2.0 mg·d-1 (244-488 µg·BWkg-1·d-1) was required for optimal growth. Specific reasons for the difference in observed requirements reported by these investigators are not apparent, but the low requirement reported by Rinehart and Greenberg (1956) was observed in animals fed diets that were lower in protein than those fed by Emerson et al. (1960). In a number of studies of vitamin B6 deficiency, administration of 3.5 mg of vitamin B6 two times per week or 1.0 mg·d-1 has been sufficient to prevent signs of deficiency (Rinehart and Greenberg, 1949b, 1956; Poppen et al., 1952; Victor and Adams, 1956; Wizgard et al., 1965).

Mann (1968) described a vitamin B6 deficiency in capuchin monkeys (Cebus albifrons) that consisted of weight loss, profound hypochromic microcytic anemia, hair loss, dermatitis (especially about the hands and toes), and, rarely, convulsions. The livers were mildly fatty, but no cirrhosis was observed. In contrast with vitamin B6 deficiency in rhesus monkeys, cardiovascular changes and arteriosclerosis were not observed. A minimal therapeutic dose of vitamin B6 at 50-100 µg·BWkg-1·d-1 was required to promote optimal weight gain. Although it was not summarized in tabular form, inspection of a graph of hematocrit vs pyridoxine dose suggests that a level of about 175-200 µg·BWkg-1·d-1 was required for an optimal hematocrit response (Mann, 1969).

Vitamin B6 deficiency also has been produced in male baboons (Papio anubis) weighing 7-15 kg. The deficient animals became apathetic and anorexic and had occasional bloody diarrhea for a day or two. Some animals’ genitalia remained juvenile. Nervous tremors were sometimes observed. The baboons died after 6-8 months unless they were given pyridoxine parenterally. Some animals were kept on intermittent pyridoxine administration to sustain a concentration of serum pyridoxine known to be compatible with life. After 2 or more years of chronic deprivation, fatty degeneration of the liver was seen with hyperplastic nodules similar to premalignant or neoplastic lesions,

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

TABLE 7-4 Estimates of Vitamin B6 Requirement

Species

Age

Body Weight

Daily AirDry Diet Consumption

Type of Diet

Vitamin B6 Levels Studied

Criteria

Estimated Requirement

Reference

Macaca mulatta

Immature

1.3-3.0 kg

Not specified

Purified

50-1,000 µg·d-1

Growth of depleted animals

62 µg·BWkg-1·d-1

Rinehart and Greenberg, 1956

Macaca mulatta

Not specified

4.1 kg

60-170 g

Purified fat 220%

Pyridoxine HCl at 0.5-2.0

Growth of depleted animals

1.0-2.0 mg·d-1 or 0.24-0.49 mg·BWkg-1·d-1

Emerson et al., 1960 mg·d-1

 

1.0 mg·d-1 required to prevent all deficiency signs; 2.0 mg·d-1 supported faster growth

 

Cebus albifrons

Not specified

900-1,500 g

Not Specified

Purified

0-1,100 µg· BWkg-1· d-1

Weight gain and hematocrit recovery in depleted animals

50-100 µg·BWkg-1·d-1 for growth; 175-200 µg·BWkg-1·d-1 for optimum hematocrit

Mann, 1968

Papio hamadryas

Adolescent males

7-15 kg

Probably 190-378 g

Purified

1.11 mg·d-1

Control animals exhibit no deficiency signs.

 

Foy et al., 1974

although the baboons had received no carcinogenic substance. Serum vitamin B6 concentrations dropped from 200-350 ng·ml-1 to 5-10 ng·ml-1 (Foy et al., 1970; Foy et al., 1974). The urine of pyridoxine-deficient baboons had increased concentrations of the tryptophan metabolites xanthurenic acid, kynurenine, and 3-hydroxykynurenine (Foy et al., 1974; Verjee, 1971).

Control baboons in the investigations of Foy et al. (1974) received a daily oral supplement of 1.0 mg of pyridoxine hydrochloride and an additional 0.11 mg from ingredients in the diet. That dosage level was equivalent to 74-158 µg·BWkg-1·d-1, or about 3.1 mg·kg-1 of dietary DM, and apparently exceeded the requirement.

A syndrome similar to vitamin B6 deficiency has been observed after chronic administration of isoniazid, a drug used for prevention of and treatment for tuberculosis. Although evidence of an induced B6 deficiency was equivocal, urinary vitamin B6 was increased when the drug was administered to humans (Levy et al., 1967). Manning and Clarkson (1971) did not observe a decrease in vitamin B6 concentrations in the serum of rhesus monkeys receiving isoniazid when fed a diet containing vitamin B6at 21 mg·kg-1. That is a high dietary intake of vitamin B6 and suggests that supplemental vitamin B6 should be considered for primates receiving this drug even though the pathogenesis of the syndrome induced by isoniazid is not understood.

The dietary vitamin B6 requirement has been estimated to be 4.4 mg·kg-1 of DM. The preponderance of evidence suggests that that level is adequate to meet the needs of rhesus and capuchin monkeys. However, if the details of the study by Emerson et al. (1960) were correctly reported, the dietary requirement under some conditions could be as high as 9.6 mg·kg-1 of DM.

Biotin

Biotin serves as a cofactor in carboxylation and decarboxylation reactions. It is concerned with introduction of bicarbonate, as a carbonyl group, into metabolic steps involved in gluconeogenesis, fatty acid synthesis, and amino acid metabolism (Mock, 1996, 1999). Substantial amounts of biotin can be synthesized by the microbial flora in the intestinal tract. Signs of biotin deficiency have been produced experimentally by feeding raw egg white. Raw egg white contains the protein avidin, which binds biotin and prevents its absorption (Bonjour, 1991). Biotin is widely distributed in natural feedstuffs. However, the biologic availability of biotin in wheat, wheat byproducts, barley, and oats is low (Frigg, 1976; Anderson et al., 1978).

Biotin deficiency has been produced in rhesus monkeys (Macaca mulatta) by feeding deficient diets and by feeding deficient diets containing raw egg white. A more severe deficiency is produced by feeding sulfa drugs (sulfguanidine or sulfasuxidine) to prevent production of biotin by the intestinal microflora (Lease et al., 1937; Waisman and Elvehjem, 1943; Waisman et al., 1945). Animals fed a biotin-deficient purified diet, without egg white or sulfa drugs, showed a gradual loss of fur color followed by loss of fur. These deficiency signs could be reversed or prevented by the daily administration of 20 µg of biotin. Rhesus monkeys receiving 12 µg of biotin daily did not show deficiency signs, whereas those receiving 1.7-9.0 µg per day showed

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

mild signs after an extended time. The monkeys in the study were consuming 200 g of air-dry food per day, so a biotin requirement of 60 g·kg-1 of air-dry diet (2.4 µg·BWkg-1·d-1) was suggested. When a biotin deficiency was produced in animals fed egg white or sulfa drugs, acute dermatitis developed around the hands, face, and feet and was accompanied by watering of the eyes, loss of fur color, and loss of weight (Lease et al., 1937; Waisman et al., 1945). Complete blood profiles of animals receiving sulfa drugs revealed no changes in hemoglobin concentration, red-cell or white-cell numbers, or differential white-cell count. Biotin at 20 µg·d-1 reversed deficiency signs in animals receiving either egg white or sulfa drugs (Waisman et al., 1945).

On the basis of the data of Waisman, biologically available biotin at 110 µg·kg-1 of dietary DMis adequate to prevent deficiency in animals fed egg white or receiving sulfa drugs. That requirement estimate assumes little or no synthesis of the vitamin by intestinal microflora and no biologic availability of biotin in natural feed ingredients.

Folacin

Folacin is the term used to refer to a family of pteroylglutamates or folates. Folic acid, which is sometimes used as an alternative name for folacin, is a pteroylmonoglutamate. In the older primate literature, folic acid is referred to as vitamin M. Folic acid is part of a coenzyme involved in receiving or donating one-carbon fragments in metabolic reactions, in much the same way that pantothenic acid is involved in metabolism of two-carbon acetyl fragments. Folic acid is involved in the metabolism of nucleotides, essential components of DNA and RNA. Folic acid coenzymes also are involved in the synthesis of serine from glycine and the synthesis of methionine from homocystine (Selhub and Rosenberg, 1996; Herbert, 1999).

Folacin in natural ingredients exists as polyglutamate conjugates. Before absorption by humans, folic acid must be released from the polyglutamate by hydrolysis to the monoglutamate form via intestinal conjugases (Selhub and Rosenberg, 1996). Humans have two intestinal conjugases, one on the brush border of intestinal cells and the other an intracellular soluble enzyme. Rhesus monkeys (Macaca mulatta) fed a nonpurified diet containing synthetic folic acid did not have a conjugase on the intestinal-cell brush border (Wang et al., 1985). Other species of monkeys appear not to have been studied in this respect. The lack of a brush-border conjugase in rhesus monkeys might be related to the predominant form of folic acid in the diet. However, complete biologic availability of polyglutamate forms to nonhuman primates in natural dietary ingredients cannot be assumed. Folic acid is the supplemental folacin form usually added to feeds.

Dietary factors can affect folic acid availability. Gyr et al. (1974) reported a decrease in folic acid absorption in patas monkeys (Erythrocebus patas) fed a protein-deficient diet (0% protein). Ethanol also has been shown to inhibit folic acid absorption (Blocker and Thenen, 1987). In humans, the bioavailability of synthetic folic acid consumed with food is estimated to be 85%, whereas the bioavailability of folic acid in natural foods is estimated to be 50%. Folic acid in natural foods is concluded to be about 60% as available as synthetic folic acid (50/85 × 100 = 59%) (Institute of Medicine, 1998).

Folic acid deficiency has been studied in macaques, marmosets, squirrel monkeys, and capuchin monkeys. The most consistent deficiency signs in all species were leukopenia and megaloblastic anemia. The anemia was characterized by lowered hemoglobin and red-cell counts and higher mean corpuscular volumes (Blocker and Thenen, 1987).

Langston et al. (1938) first demonstrated the need for folic acid (then designated vitamin M) in the rhesus (Macaca mulatta) monkey. The deficiency signs in rhesus monkeys were weight loss, anorexia, diarrhea, leukopenia, thrombocytopenia, and megaloblastic anemia (Waisman and Elvehjem, 1943; Cooperman et al., 1946). Folic acid-deficient female rhesus monkeys also had abnormalities of their reproductive system characterized by atresic and cystic ovarian follicles with loss of granulosa cells. Proliferation of the granulosa cells appeared to be associated with interruption of DNA synthesis. The normal cyclic changes in the vaginal and cervical epithelium were impaired, and multiple abnormal cells were seen (Mohanty and Das, 1982). Folic acid deficiency in cynomolgus monkeys (Macaca fascicularis) was similar to that in rhesus monkeys, with megaloblastic anemia and weight loss predominant. Folic acid-depleted animals also had lower concentrations of folic acid in red-cells, plasma, and liver. Urinary excretion of formiminoglutamic acid was increased (Blocker and Thenen, 1987).

Folic acid deficiency in the squirrel monkey (Saimiri sciureus) resulted in weight loss, alopecia, scaly dermatitis, and megaloblastic anemia with profound intramedullary hemolysis in the bone marrow. Deficient animals had reduced plasma and red-cell folic acid and increased urinary formiminoglutamic acid (Rasmussen et al., 1979). The folic acid status of pregnant squirrel monkeys fed a commercial stock diet with and without a folic acid supplement was evaluated (Rasmussen, 1979; Rasmussen et al., 1980). Females supplemented with folic acid had greater maternal weight gain during pregnancy, and infants from supplemented females had higher birth weights. Higher red-cell folic acid concentrations and somewhat lower mean cell volumes were also seen in supplemented animals. Those results indicated that the stock diet, presumably adequate

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

in folic acid for reproduction in other monkey species, was not optimal for reproduction in the squirrel monkey.

Capuchin monkeys (Cebus albifrons) exhibited deficiency signs similar to those of squirrel monkeys (Rasmussen et al., 1980; Thenen et al., 1991), including megaloblastic anemia, leukopenia, increased polymorphonuclear leukocyte lobe counts, and increased urinary formiminoglutamic acid. A wide variability in the severity of deficiency signs in dams and suckling neonates fed folic acid-deficient diets has been reported (Gillet et al., 1987); megaloblastic anemia was the sign most consistently present. Pregnant animals fed folic acid sufficient to support reproduction, but apparently below the requirement, had lowered blood and liver folate concentrations, increased urinary formiminoglutamic acid excretion, and reduced milk folate (Blocker et al., 1989).

Folic acid deficiency in marmosets (Callithrix jacchus) produced the usual deficiency signs (weight loss, alopecia, diarrhea, megaloblastic anemia, leukopenia, and granulocytopenia) and lesions of the oral mucosa, described as bilateral angular cheilosis, in about half the deficient animals (Dreizen and Levy, 1969). The stomatitis seemed to be a result of interference with maturation of the epithelial cells and later ulceration and secondary infection (Dreizen et al., 1970). The folic acid deficiency was prevented by supplementing the test diet with 0.1 mg of folic acid per day for animals consuming 30 g of diet per day.

Signs of folic acid deficiency in the baboon (Papio cynocephalus) were similar to those seen in other primate species, including weight loss, anorexia, gingivitis, diarrhea, severe leukopenia and thrombocytopenia, and sometimes macrocytic anemia. The animals lost weight before becoming anorexic. Abnormalities in the white cells appeared well before the development of anemia (Siddons et al., 1974a).

The proposed association between low folate status, hyperhomocyst(e)inemia, and vascular dysfunction has led to research with nonhuman primate models. A diet-induced hyperhomocyst(e)inemia in cynomolgus monkeys resulted in decreased blood flow to the leg when platelets were activated by intraarterial infusion of collagen (Lentz et al., 1996). Supplementation of atherosclerotic cynomolgus monkeys with 5 mg folic acid, 400 µg vitamin B12, and 20 mg vitamin B6 daily reduced plasma homocyst(e)ine concentrations but plasma cholesterol remained elevated, and normal vascular function was not restored (Lentz et al., 1997).

Folic acid requirements have been studied in a number of primate species, but the conclusions have not been consistent, because different measures were used as end points in assessing folic acid status. Findings from these studies are summarized in Table 7-5. The minimal folic acid requirement for growing rhesus monkeys has been estimated to be 30-60 µg·BWkg-1·d-1 (Cooperman et al., 1946; Day and Trotter, 1947, 1948). The requirement for squirrel monkeys for weight maintenance, based on regression analysis, was estimated to be 28 µg·BWkg-1·d-1. That was furnished by folic acid at about 0.3 mg·kg-1 of air-dry diet. However, the data suggest that 0.55 mg·kg-1 of air-dry diet was needed to ensure maximal growth. To maintain normal hematologic measures and cytologic features in bone marrow, the requirement was more than 75 µg·BWkg-1·d-1, which was furnished by folic acid at 0.84 mg·kg-1 of air-dry diet (Rasmussen et al., 1979). A higher dietary concentration was required to support reproduction in squirrel monkeys. Rasmussen et al. (1979) and Rasmussen (1980) reported that a stock diet containing folic acid at 1.4 mg·kg-1 of air-dry diet did not support optimal reproduction and was improved by supplementation with crystalline folic acid; this concentration was equivalent to folic acid at 3.0 mg·kg-1 of air-dry diet. Biologic availability of folic acid in natural ingredients is poorly understood, so these authors suggested a total folic acid requirement of 450 µg·BWkg-1·d-1,onthe basis of 25% availability of food forms. Capuchin monkeys appear to have a folic acid requirement for growth and normal hematologic status of 45-75 µg·BWkg-1·d-1;this requirement is similar to that of squirrel monkeys and could be met by providing folic acid at 0.84 mg·kg-1 of air-dry diet (Rasmussen et al., 1980).

The folic acid requirement of rhesus monkeys has been estimated to be 1.5 mg·kg-1 of dietary DM, on the basis of the data discussed above. The folic acid requirement of squirrel monkeys and capuchin monkeys is estimated to be 1.5 mg·kg-1 of dietary DMfor growth and 3.3 mg·kg-1 dietary DMfor reproduction. Data are insufficient for setting quantitative requirements of other species. The above requirement estimates take no account of the reduced biologic availability of folic acid in natural diets (Institute of Medicine, 1998). If all dietary folic acid is from natural ingredients, it is suggested that the requirements be increased to 2.55 and 5.61 mg·kg-1 dietary DMfor growth and reproduction, respectively.

Vitamin B12

Vitamin B12, also known as cobalamin, contains cobalt. The two active cofactor forms are adenosylcobalamin and methylcobalamin. The two mammalian enzymes for which vitamin B12 is a coenzyme are methylmalonyl-CoA mutase and methionine synthase. The vitamin is part of a metabolic enzyme system that removes the methyl group from folacin, regenerating that vitamin. Vitamin B12 also is involved in the formation of methionine from homocysteine and in nucleic acid metabolism. It is found only in animal products and microorganisms. Vegetables and grains contain no vitamin B12 (Herbert, 1996; Weir and Scott, 1999). Microorganisms in the rumen synthesize vitamin B12 if the cobalt supply is adequate. Thus, ruminants have a nutritional requirement for cobalt but not for vitamin B12 itself. It is

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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TABLE 7-5 Estimates of Folacin Requirement

Species

Age

Body Weight

Daily AirDry Diet Consumption

Type of Diet

Folacin Concentrations Studied

Criteria

Estimated Requirement

Reference

Macaca mulatta

Young, immature

2-3 kg

About 88 g for 2.0 to 2.5 kg monkeys

Casein, rice, wheat, mineral mix, vitamin mix

30-150 µg·d-1

Prevent anemia and leukopenia

60-100 µg·d-1

Day and Totter, 1947

Macaca mulatta

Young, immature

2.1-2.9 kg

About 88 g

Casein, rice, wheat, mineral mix, vitamin mix

N/A

Additional unpublished data indicated 100 µg daily dose required. Basal diet furnished 19 µg·d-1 (Day and Totter, 1947).

119 µg·d-1

Day and Totter, 1948

Saimiri sciureus

12-38 months

440-710 g

Not specified

Purified

0-0.84 mg·kg-1 air-dry diet.

Growth and normal hematologic status

75 µg·BWkg-1·d-1 furnished by 0.84 mg·kg-1 of air-dry diet. Liver folic acid concentrations low compared with other colony animals.

Rasmussen et al., 1979

Saimiri sciureus

Breeding adults

665 g

Not specified

Natural ingredients

1.43 mg·kg-1 air-dry diet compared with supplementation with 80 µg·d-1 5 days·week-1

Hematologic status, folate status, maternal weight gain during pregnancy, infant birth weight

3.0 mg·kg-1 of air dry matter

Rasmussen et al., 1980, Rasmusen, 1979

Cebus albifrons

3 years

1,570-2,170 g

 

Purified

0-1.05 mg·kg-1 of air-dry diet

Growth and normal hematologic status

45-75 µg·kg-1

Rasmussen et al., 1992

not known how nonhuman primates, consuming only plant material, obtain this vitamin, but it is possible that vitamin B12 is synthesized by microorganisms in the gastrointestinal tract (Uphill et al., 1977). Primates that practice coprophagy may obtain vitamin B12 from ingested feces (Oxnard, 1989). Little is known about the biologic availability of vitamin B12 in natural food ingredients (Baker, 1995). Supplemental vitamin B12 is usually added to animal feeds as cyanocobalamin.

The signs of vitamin B12 deficiency in humans are megaloblastic anemia and progressive demyelination and neuropathy (Herbert, 1996). A frank deficiency of vitamin B12 was produced under controlled conditions in rhesus monkeys (Macaca mulatta) by feeding a purified diet containing soy protein rather than casein to avoid potential contamination by vitamin B12 in the latter. During the first 12-18 months, serum concentrations of B12 dropped to 5-10% of initial values. Liver vitamin B12 concentrations were less than 5% of those in supplemented animals. Methlymalonic acid concentrations in the urine, a biochemical indicator of deficiency, increased in deficient animals but not in supplemented controls. In spite of the apparent depletion of vitamin B12 stores, no other manifestations of deficiency were seen (Kark et al., 1974). The studies were then extended. Monkeys fed the deficient diet for a total of 33-45 months exhibited additional deficiency signs, including visual impairment that gradually progressed to blindness, spastic paralysis of the hind limbs and tail, general weakness, apathy, and death. At necropsy, degeneration of nervous tissue was evident, with eventual destruction of the myelin sheath and loss of axons (Agamanolis et al., 1976, 1978; Chester et al., 1980). The degeneration of central nervous tissue was similar to “subacute combined degeneration,” one of the clinical diseases seen in human vitamin B12 deficiency. Even in the most severe cases of vitamin B12 deficiency, no signs of anemia or any other blood disorders were observed.

Chronic deficiency of vitamin B12 in nonhuman primates under somewhat less controlled conditions has also been described. Blood concentrations of vitamin B12 in newly

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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captured rhesus monkeys (Macaca mulatta), patas monkeys (Erythrocebus patas), baboons (Papio anubis), and owl monkeys (Aotus trivirgatus) decreased over time in captivity. During captivity, the primates were fed a vegetarian stock diet consisting of potatoes, bread, carrots, root vegetables, and green vegetables supplemented with ascorbic acid and halibut liver oil (Oxnard, 1964). A condition called “cage paralysis” in captive monkeys is similar to “subacute degeneration” of the spinal cord in humans and might be due to vitamin B12 deficiency. Animals with cage paralysis had lowered serum vitamin B12 concentrations, degeneration of the spinal cord, and patchy demyelination of peripheral nerves (Oxnard and Smith, 1966; Torres et al., 1971). Visual impairment with histologic changes in the visual pathway also were described (Hind, 1970).

Manifestations of vitamin B12 deficiency seem to be similar in rhesus and patas monkeys (Oxnard et al., 1970; Torres et al., 1971; Hind, 1970). In controlled deficiency studies in baboons (Papio cynocephalus), serum and liver vitamin B12 decreased to very low concentrations, and urinary excretion of methylmalonic acid increased after a loading dose of valine. Growth of the deficient animals decreased in the second year. No frank deficiency signs were seen, perhaps because the study was only 24 months long (Siddons, 1974b; Verjee et al., 1975). Siddons and Jacob (1975) found that vitamin B12 concentrations in baboon tissues were highest in the liver, followed by the pituitary, kidney, heart, spleen, and pancreas. The main site of vitamin B12 absorption appeared to be the distal half of the small intestine. Satisfactory body stores were maintained by dietary intakes of 1 to 2 µg per day. Because gastric intrinsic factor is considered important for absorption of vitamin B12, cobalamin absorption was measured in normal baboons and after total gastrectomy (Green et al., 1982). Cobalamin absorption was diminished but not completely abolished by gastrectomy. Provision of intrinsic factor enhanced absorption of orally administered cyanocobalamin, but physiologically significant amounts of cobalamin were still absorbed in its absence. Evidence also was obtained that the form of cobalamin excreted in the bile was more readily absorbed than oral cyanocobalamin, or bile itself may have enhanced cobalamin absorption. The absorption of cobalamin in bile was enhanced further by provision of gastric intrinsic factor, and these studies suggest that the enterohepatic circulation of cobalamin may be an important vitamin B12 conservation measure.

Kark et al. (1974) injected 20 µg of vitamin B12 every 14 days into control animals that weighed about 4.4 kg at the beginning of the study but eventually weighed about 10 kg. All measures of vitamin B12 status were normal. Siddon (1974b), working with baboons fed purified diets, supplemented control animals with vitamin B12 at 1 µg·d-1 for 9 months and 2 µg·d-1 for the next 15 months. The 2-µg dosage promoted a slightly higher body weight gain and a more satisfactory serum vitamin B12 concentration. The baboons weighed about 7.5 kg at the beginning of the study and about 12.3 kg at the beginning of the second year. Wilson and Pitney (1955) found that rhesus monkeys required more than 2 µg but less than 10 µg daily to maintain serum concentrations of vitamin B12. The weights of the animals were not given.

The requirement of nonhuman primates for vitamin B12 has been estimated to be 11 µg·kg-1 of dietary DM; this is adequate to prevent deficiency signs and should provide a reasonably normal serum concentration.

Vitamin C

Vitamin C, also known as ascorbic acid or ascorbate, is required as a cofactor in numerous enzymatic reactions. Some of them concern the hydroxylation of proline or lysine, steps in the formation of collagen. Other metabolic reactions involving ascorbic acid are carnitine biosynthesis, catecholamine synthesis, peptide amidation, and tyrosine metabolism (Levine et al., 1996; Jacob, 1999). Vitamin C enhances the absorption of nonheme iron and decreases copper absorption (Moser and Bendich, 1991). It is added to primate diets in the form of ascorbic acid or L-ascorbyl-2-polyphosphate. L-ascorbyl-2-polyphosphate is a form of ascorbic acid that is less susceptible to oxidation and yet is biologically available to nonhuman primates. Presumably, the phosphate ester is hydrolyzed by intestinal phosphatase before absorption (Machlin et al., 1979). Another form, L-ascorbyl-2-sulfate, although resistant to oxidation and used in fish diets, has no vitamin C activity in primates (Machlin et al., 1976; Kotze and Menne, 1978).

Many mammals have the ability to synthesize ascorbic acid from glucose, but most primates, including humans, lack gulonolactone oxidase, the enzyme required for ascorbic acid synthesis. Many, perhaps most, prosimians possess this enzyme and presumably do not require a dietary source of vitamin C. Fifteen species of prosimians—including sifakas (Propithecus verreauxi), pottos (Perodicticus potto), and a number of species of lemurs, bushbabies, and lorises—have substantial liver concentrations of gulonolactone oxidase; these species might be able to synthesize ascorbic acid (Elliot et al., 1966; Nakajima et al., 1969; Pollock and Mullen, 1987). However, the enzyme is not found in the liver of western tarsiers (Tarsius bancanus), so perhaps prosimians are not all alike in their ability to synthesize this vitamin (Pullock and Mullin, 1987). Confirmatory studies in which diets devoid of vitamin C have been fed to prosimians for extended periods have not been conducted. The ability to synthesize vitamin C is clearly lacking in all other higher primates that have been studied to date.

Effects of vitamin C deficiency in the macaque species include weakness, lethargy, anorexia, weight loss, and mus-

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

cle and joint pain. As the deficiency progresses, other signs appear, including gingival hemorrhage, loose teeth, subperiosteal hemorrhage, normocytic anemia, reduced serum iron concentrations, leukopenia, joint soreness, epiphyseal fractures with loss of bone substance, and exophthalmos (Tomlinson, 1942; Shaw et al., 1945; Greenberg and Rinehart, 1954; Banerjee and Bal, 1959a, 1959b; Ratterree et al., 1990; Eisele et al., 1992; Line et al., 1992). The signs of vitamin C deficiency are collectively called “scurvy,” and deficient animals are called “scorbutic.” Scorbutic rhesus monkeys excrete increased amounts of p-hydroxyphenyl compounds and keto acids in the urine when given test loads of tyrosine or phenylalanine, indicating abnormalities in tyrosine metabolism (Salmon and May, 1950; Rohatgi et al., 1958). Scorbutic animals have increased blood concentrations of glycoproteins and mucoproteins (Bandyopadhyay and Banerjee, 1964). Blood concentrations of nonprotein nitrogen and creatinine also are increased, and urine contains increased concentrations of nonprotein nitrogen and creatine (Rohatgi et al., 1958).

Gingival bleeding and fibrous gingival hyperplasia were reported in African green monkeys (Cercopithecus aethiops) deficient in vitamin C (De Klerk et al., 1973). Hydroxyproline concentrations were decreased in the gingiva, and synthesis of hydroxproline almost stopped in deficient animals; that suggests the lesions were caused by an inability to synthesize normal collagen (Ostergaard and Loe, 1975).

Squirrel monkeys (Saimiri sciureus) fed a vitamin C-deficient diet developed a characteristic subperiosteal hematoma, which progressed to a large swelling over the parietal area of the head (a cephalhematoma). In animals that were given ascorbic acid and recovered, the skull calcified, and this resulted in cranial hyperostosis. Cephalhematomas seem to be the primary diagnostic feature of vitamin C deficiency in squirrel monkeys (Lehner et al., 1968; Blackwell et al., 1974; Demary et al., 1978; Kessler et al., 1980).

Cephalhematomas are also seen in vitamin C deficiency in capuchin monkeys (Cebus apella) (Borda et al., 1996). However, capuchin monkeys also can exhibit all the traditional signs of scurvy, including weakness, joint tenderness, and extensive hemorrhages of the head, arms, and legs. Oral lesions develop, including necrosis of the gums, destruction of alveolar bone, and sloughing of the teeth (Shaw, 1949).

The common marmoset (Callithrix jacchus) has been shown to require a dietary source of vitamin C. Spontaneous physical mobility was decreased in deficient animals, and feed intake was reduced. Mean red-cell volume, packed red-cell volume, and red-cell counts decreased by about 10% overall, but hemoglobin concentration increased slightly. Vitamin C-deficient marmosets were generally free of clinical signs for 10 weeks, then suddenly became seriously ill, and many died within a few days despite therapeutic treatment with ascorbic acid. The disease was prevented by dietary vitamin C (Flurer et al., 1987). Extensive hemorrhages and loss of density about the periodontal ligament were seen, but the type of gingivitis seen in the rhesus monkey was not a prominent feature in the common marmoset (Driezen et al., 1969).

The white-lipped tamarin (Saguinus fuscicollis) and the common marmoset (Callithrix jacchus) appear to differ in their metabolism of vitamin C. When fed a diet ostensibly containing ascorbic acid at 2,000 mg·kg-1, the serum ascorbate concentration of the tamarins was about one-fifth that of the common marmosets (Flurer and Zucker, 1987). Stress appeared to increase the rate of ascorbic acid metabolism in both marmosets and tamarins, and there is some evidence that the difference in blood ascorbate concentrations was due to differences in susceptibility to stress between the two species (Flurer et al., 1990). It should be noted that the concentration of ascorbic acid in the diet at the time of feeding was not determined, and the stated concentration of 2,000 mg·kg-1 was based on the amount of vitamin C added before pelleting (Flurer and Schweigert, 1990).

There are wide ranges in the estimated ascorbic acid requirements of nonhuman primates. Table 7-6 summarizes the studies in which requirements were estimated. Day (1944) estimated that rhesus monkeys weighing less than 4 kg required 2.0 mg or less per day to prevent signs of scurvy; this estimate was based on calculation of vitamin C intakes from a number of published studies and was based primarly on the amount of orange juice required to prevent scurvy. Solv’ena et al. (1966) reported that a dose of 4 mg of vitamin C per animal per day protected monkeys weighing up to 4.3 kg from scurvy, but it did not prevent a drop in vitamin C concentrations in leukocytes and whole blood. Blood ascorbate is thought to reflect recent intake of ascorbic acid, whereas leukocyte ascorbate is a measure of the body’s reserve (Moser and Bendich, 1991; Turnbull et al., 1980). Machlin et al. (1976) administered vitamin Cat5mg·BWkg-1·d-1 to rhesus monkeys and observed a slow decline of blood ascorbate from 1.3 mg·dl-1 to 0.3-0.4 mg·dl-1. Increasing the ascorbic acid intake to 10 mg·BWkg-1·d-1 stopped the decline and prevented all signs of scurvy. Blood ascorbate levels fell to 0.3-0.4 mg·dl-1 in animals fed a natural diet furnishing ascorbic acid at less than 1.0 mg·BWkg-1·d-1, to render them deficient, but deficiency signs were mild and appeared only sporadically. More persistent signs were observed only when the animals were placed on a more deficient liquid purified diet. Working with cynomolgus monkeys, Tillotson and O’Connor (1980) found that adult and young monkeys required ascorbic acid at 3 and 6 mg·BWkg-1·d-1, respectively, to sustain blood concentrations of vitamin C. At that intake, leukocyte ascorbate concentrations, a measure of total body ascorbate, were minimal, indicating that the tissues were

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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TABLE 7-6 Estimates of Ascorbic Acid Requirement

Species

Age

Body Weight

Daily AirDry Diet Consumption

Type of Diet

Ascorbic Acid Concentrations Studied

Criteria

Estimated Requirement

Reference

Macaca mulatta

Not specified

2.0-4.0 kg

Not specified

Not specified

0.25-3.0 mg·d-1

Protection from scurvy

=2 mg·d-1

Day, 1944; calculated from data of Harden and Zilva, 1920; Greenberg et al., 1936; Langston et al., 1938; Fraser, 1942

Macaca mulatta

Not specified

Up to 4.3 kg

Not specified

Not specified

4 mg·d-1 for 2 months

Protected against scurvy; leukocyte and whole-blood ascorbic acid decreased

 

Solov’eve et al., 1966

Macaca mulatta

Not specified

10 kg deficient animal

Purified diet

Not specified

50, 100 and 250 mg·d-1

Clinical scurvy, weight, and plasma ascorbate

50 mg·d-1 cured clinical scurvy; 250 mg·d-1 required for normal plasma ascorbate

Bucci et al., 1975;

Baker et al., 1975

Macaca mulatta

Young

3.5-8.0 kg

Not specified

Autoclaved natural diet, purified liquid diet

0, 5, and 10 mg·BWkg-1·d-1

Prevent blood ascorbic acid decrease

10 mg·BWkg-1 ·d-1; blood ascorbate decreased with 5 mg·BWkg-1·d-1, but this level prevented deficiency signs

Machlin et al., 1976

Macaca fascicularis

Young (2½-3 yr) and (at least 7 yr)

3.8-3.9 kg and 4.26.9 kg

Not specified

Liquid purified diet

0-6 mg·BWkg-1 ·d-1 of young, 0-3 mg·BWkg-1 ·d-1 of adult adult

Plasma and whole blood ascorbic acid

6 mg·BWkg-1·d-1 in young, 3 mg· BWkg-1·d-1 in adult

Tillotson and O’Connor, 1980

Macaca fascicularis

4-5 yr.

3.0 kg deficient animals

90-110 g

Purified diet

130 mg·kg-1 of diet followed by three daily injections of 50 mg of ascorbate

Periodontal health, weight loss, whole-blood ascorbate

130 mg·kg-1 of diet prevented deficiency signs; injections needed to reverse weight loss; whole-blood ascorbate remained low

Alvares et al., 1981

Cercopithecus aethiops

Not specified

1.5-6.8 kg

Not specified

Not specified, but diet included apples and bananas

10, 20, and 30 mg·d-1 plus 730 mg of ascorbic acid from fruit

Serum ascorbate

27-50 mg·d-1; includes ascorbic acid from fruit

DeKlerk et al., 1973

Callithrix jacchus

3-5 yr

400 g

16 g

Natural ingredient diet

250, 500, 2,000, and 4,000 mg·kg-1 of diet

Serum ascorbic acid above kidney threshold

500 mg·kg-1 of diet or 20 mg·BWkg-1·d-1 (2,000 mg·kg-1 diet produced near saturation of serum with ascorbate)

Flurer et al., 1987

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

not saturated. Bucci et al. (1975) and Baker et al. (1975) studied the amounts of ascorbic acid required by 10-kg monkeys to reverse the deficiency; 50 mg·d-1 (equivalent to 5 mg·BWkg-1·d-1) were sufficient to reverse the deficiency signs, but plasma ascorbate concentrations remained low. Plasma ascorbate concentrations were increased by ascorbic acid at 250 mg·d-1 (equivalent to 25 mg·BWkg-1·d-1). The above data suggest that the ascorbic acid requirement for macaques is about 1.0 mg·BWkg-1·d-1 to prevent deficiency signs and between 5 and 10 mg·BWkg-1·d-1 to maintain blood concentrations of ascorbic acid.

Alveres et al. (1981) studied the effect of subclinical ascorbate deficiency on periodontal health. They fed a recovery diet containing ascorbic acid at 130 mg·kg-1 to cynomolgus monkeys previously fed an ascorbate-free diet for 9 weeks. During the first 3 weeks of the recovery phase, the animals continued to lose weight and were given injections of 50 mg of ascorbic acid per day for 3 days. The animals then began to gain weight, and they weighed nearly the same as the control animals by the end of the study. After 16 weeks, the animals exhibited no clinical signs of ascorbic acid deficiency, but whole-blood ascorbate remained low compared with that in control animals fed a diet containing 2,000 mg·kg-1. The results suggested that ascorbic acid at 130 mg·kg-1 of diet was required to prevent deficiency signs but might have been insufficient to build body stores. Neither spontaneous gingivitis nor periodontitis was evident, but animals fed ascorbic acid at 130 mg·kg-1 of diet were more susceptible to experimentally induced plaque-associated periodontitis.

DeKlerk et al. (1973) found that fruit, estimated to furnish 7-30 mg of ascorbic acid per day, was not sufficient to prevent vitamin C deficiency or to maintain a satisfactory serum concentration of vitamin C in African green monkeys weighing 1.5-6.8 kg. However, animals receiving fruit and 20 mg of ascorbic acid per day were able to maintain satisfactory serum concentrations, and deficiency signs were alleviated. When stress was introduced, serum ascorbate decreased; this suggested that stressed animals have an increased vitamin C requirement.

It has been suggested that some callitrichids have higher requirements for vitamin C than some other primate species. On the basis of the concentration of ascorbic acid needed to maintain blood ascorbate above the kidney threshold, Flurer et al. (1987) concluded that the common marmoset required ascorbic acid at 20 mg·BWkg-1·d-1 or a dietary level of 500 mg·kg-1. That concentration ensured that a small amount of ascorbic acid was excreted in the urine. Serum ascorbic acid concentrations were much higher in marmosets fed 2,000 mg·kg-1 of diet.

A dietary level of ascorbic acid at 55-110 mg·kg-1 of DMhas appeared to prevent signs of deficiency in all species except possibly some marmosets and tamarins. A concentration of 275 mg·kg-1 of dietary DMmight be required to maintain “normal” blood concentrations of ascorbic acid in captive primates, although few blood ascorbate concentrations in free-ranging primates have been reported. Some tamarins and marmosets appear to have higher requirements. Stressed animals have lower blood ascorbic acid concentrations than unstressed animals. That has been observed in rhesus monkeys (Baker et al., 1975), African green monkeys (DeKlerk et al., 1973), and tamarins (Flurer et al., 1990). It is conceivable that stressed animals need more vitamin C. As much dietary ascorbic acid as 560 mg·kg-1 of DMmay be required for small amounts of urinary ascorbate excretion.

It should be noted that few dietary studies with nonhuman primates used a stable form of vitamin C, such as L-ascorbyl-2-polyphosphate. Because of the susceptibility of crystalline ascorbic acid to oxidation, the amounts of vitamin C actually consumed in studies of vitamin C requirements might have been less than expected. As a consequence, estimated vitamin C requirements might be exaggerated. There is no question that crystalline ascorbic acid can be lost from the diet during preparation, storage, or feeding. With respect to the latter, ascorbic acid loss also occurs as a consequence of soaking the feed to render it more palatable.

Few analyses of natural foods consumed by nonhuman primates have been conducted, and it is not rational to conclude that dietary vitamin C requirements greatly exceed the amounts available in the wild. However, a wild fruit (Terminalia ferdinandiana) was found in Australia that was said to have fifty times the vitamin C content of oranges (Brand et al., 1982). Whether this finding has relevance to the vitamin C needs of nonhuman primates has not been established.

One of the metabolites of excess dietary ascorbic acid is oxalic acid. Baboons fed a diet containing ascorbic acid at 25 g·kg-1 for 20 months had no histologic evidence of oxalate crystals in soft tissues or visible oxalate calculi in the kidneys or bladder (Du Bruyn et al., 1977). It appears that in the baboon, at least, high dietary concentrations of ascorbic acid are not pathogenic.

Choline

Choline is essential for the normal function of all cells and ensures the structural integrity and signaling functions of cell membranes (Zeisel, 1999). It directly affects neuro-transmission via acetylcholine and is a major source of labile methyl groups for the synthesis of metabolites via transmethylation. In this latter role, the metabolism of choline, methionine, and methylfolate is closely interrelated. Most choline in the body is found in phospholipids, such as phosphotidylcholine and sphingomyelin. Because an endogenous pathway for synthesis of choline has been identified, choline has not been considered an essential

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

nutrient for humans. However, signs of choline deficiency have been described when dietary choline concentrations are low and supplies of other methyl donors, such as methionine, are inadequate. Choline usually is added to the diet as choline chloride or choline bitartrate. Choline chloride is quite hydrophilic and often is added as a liquid containing 70% choline (Chan, 1991).

Many factors influence the choline requirement. Rats fed low-protein diets or diets containing suboptimal amounts of methionine require choline supplementation, whereas rats fed diets containing 0.8% methionine show no requirement for choline (National Research Council, 1995a).

The evidence of choline need in normal primate diets is not clear. Wilgram et al. (1958) fed a diet devoid of choline to both rhesus monkeys (Macaca mulatta) and capuchin monkeys (Cebus spp.) (four animals of each species) for over a year. The diet contained about 0.16% methionine and 18% fat. Although the protein concentration of the diet was unspecified, it appeared to be 13-14%. When the diet was supplemented with 0.3% choline chloride, weight gains were greater, and one female had a baby and successfully nursed it. After a year, liver biopsies were taken by laparotomy. Liver lipid concentrations were 12-22% in unsupplemented animals and 6-9% in animals that were choline-supplemented. Liver phospholipids were lower and liver cholesterol was higher in unsupplemented animals. Histologic examination of the livers from animals fed the choline-free diet revealed lipid droplets throughout the liver, but no cirrhosis. The livers of the choline-supplemented animals were normal.

The production of fatty livers in rhesus monkeys fed a choline-free diet was confirmed, and one death from liver disease was described by Cueto et al. (1967). Patek et al. (1975) also observed cirrhosis of the liver in a rhesus monkey fed a low-protein, low-choline diet.

Studies with a low-choline diet were extended; diets were modified to contain less protein and 2% cholesterol (Wilgram, 1959; Gaisford and Zuidema, 1965; Ruebner et al., 1969; Rutherford et al., 1969). The diet was said to contain 5% protein, but the formulation indicates about 9% protein. In any event, it produced liver cirrhosis in capuchin and rhesus monkeys. It was suggested that the increased dietary cholesterol might have made the animals more susceptible to liver cirrhosis (Patek et al., 1975). Whether supplemental choline would prevent or reverse the cirrhosis seen with the low-choline, high-cholesterol diet was not tested.

In an attempt to produce choline deficiency in baboons (Papio doguera), a high-fat, low-protein diet that had been shown to produce severe choline deficiency in rats was fed (Hoffbauer and Zaki, 1965). The baboons developed mildly fatty livers after 2 months, but the degree of fat accumulation remained unchanged after 5 months. A control diet with added choline was not fed. The lesions were reversed when the animals were returned to a normal diet. The results suggest that the requirement of the adult baboon for choline, if there is one, is substantially lower than that of the rat. It should be noted that Lieber et al. (1994) were able to prevent fatty liver and fibrosis caused by ethanol ingestion when the diet of baboons was supplemented with phosphatidylcholine.

No studies have clearly established a dietary choline requirement for nonhuman primates independent of other dietary modifications. It does seem clear that a fatty liver, and occasionally cirrhosis, will result from feeding a low-protein, methionine-deficient, low-choline diet. The effect of supplemental methionine has not been investigated, but the fatty liver observed after feeding such a diet can be prevented by supplementation with 0.3% choline chloride (furnishing about 0.23% choline) (Wilgram et al., 1958). Kark et al. (1974) fed a semipurified diet containing 0.1% choline chloride (about 0.075% choline) without producing deficiency signs.

Carnitine

Carnitine is a required vitamin for some insects, but it is not generally recognized as an essential nutrient for mammals. Metabolically, carnitine functions in the transport of fatty acids into the mitochondria (Borum, 1991). There is no evidence that nonhuman primates require carnitine. Carnitine is found only in animal products, so presumably the control diets fed by Kark et al. (1974) and Agamanolis et al. (1976) to rhesus monkeys (Macaca mulatta) for 45 months contained no carnitine. The animals showed no signs of a deficiency disease, so it seems unlikely that there is a substantial carnitine requirement.

Inositol

Inositol has occasionally been considered a vitamin, primarily on the basis of early work that suggested it was a required nutrient for mice. Later research has shown that conventionally reared mice do not require dietary inositol although gnotobiotic or antibiotic-treated mice possibly do (National Research Council, 1995b).

An inositol requirement has not been demonstrated in nonhuman primates, but there has been no attempt to do so. It is not recognized as a required nutrient for humans (Cody, 1991). In obese, insulin-resistant rhesus monkeys (Macaca mulatta), dietary myo-inositol in pharmacologic doses (1.65 g·BWkg-1·d-1) produced a mild decrease in postprandial plasma glucose concentrations without increasing postprandial insulin concentrations (Ortemyer, 1996). However, that relatively small effect of such a large dose cannot be regarded as demonstrating a nutrional requirement.

Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
×

If there is an undemonstrated dietary requirement, it is likely that inositol is present in sufficient concentrations in diets formulated from natural ingredients. Inositol is usually not added to commercial diets, but myo-inositol has been added to semipurified diets at 0.1% (Kark et al., 1974; Ausman et al., 1985).

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Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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Suggested Citation:"7 Vitamins." National Research Council. 2003. Nutrient Requirements of Nonhuman Primates: Second Revised Edition. Washington, DC: The National Academies Press. doi: 10.17226/9826.
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This new release presents the wealth of information gleaned about nonhuman primates nutrition since the previous edition was published in 1978. With expanded coverage of natural dietary habits, gastrointestinal anatomy and physiology, and the nutrient needs of species that have been difficult to maintain in captivity, it explores the impact on nutrition of physiological and life-stage considerations: infancy, weaning, immune function, obesity, aging, and more. The committee also discusses issues of environmental enrichment such as opportunities for foraging.

Based on the world's scientific literature and input from authoritative sources, the book provides best estimates of nutrient requirements. The volume covers requirements for energy: carbohydrates, including the role of dietary fiber; proteins and amino acids; fats and fatty acids; minerals, fat-soluble and water-soluble vitamins; and water. The book also analyzes the composition of important foods and feed ingredients and offers guidelines on feed processing and diet formulation.

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