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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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. , 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.  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-
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 (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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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.
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Nutrient Requirements of Nonhuman Primates: Second Revised Edition, 2003 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). REFERENCES Acuff, R.V., S.S. Thedford, N.N. Hidiriglou, A.M. Papas, and T.A. Odom, Jr. 1994. Relative bioavailability of RRR- and all-rac-a-tocopheryl acetate in humans using deuterated compounds. Am. J. Clin. Nutr. 60:397-402. Adams, J.A., M.A. Gacad, G. Keuhn, A.J. Baker, and R.K. Rude. 1984. 1,25 Dihydroxyvitamin D suppresses proliferation and immunoglobin production by normal human peripheral blood mononuclear cells (Abstract). Calcif. Tissue Int. 36:508. Agamanonalis, D.P., E.M. Chester, M. Vixtor, J.A. Kark, J.D. Hines, and J.W. Harris. 1976. 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Representative terms from entire chapter: