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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