Pharmacological Uses of Vitamin D

Multiple sclerosis is less common among people living at high altitude, where UV exposure is greater. Patients with multiple sclerosis have poor vitamin D status and low bone density, although this could be a result of the disease rather than a cause. Calcitriol prevents the development of experimental autoimmune encephalomyelitis in mice, a widely accepted model of multiple sclerosis, and it has been suggested that vitamin D supplements may protect genetically susceptible people from developing the disease (Hayes et al., 1997; Hayes, 2000).

A number of studies have shown that there is a north-south gradient in the incidence of type I diabetes mellitus and that children who are given vitamin

D supplements are less at risk of developing the disease. It is not known how vitamin D protects against the development of diabetes, but it may be by modulation of the differentiation of lymphocytes involved in the autoimmune destruction of pancreatic f-islet cells. The protective dose is above current reference intakes and indeed may be above the tolerable upper intake of 25 ^g per day for infants (Harris, 2002).

The calcitriol molecule shows considerable conformational flexibility, and different conformations are required for binding to the plasma vitamin D binding protein (Section 3.2.7), nuclear receptors (Section 3.3.1), and cell surface receptors (Section 3.3.2; Norman et al., 1996; 2001a; 2001b). Because of the roles of vitamin D in regulating cell proliferation and differentiation (Section 3.3.6), there is considerable interest in the development of analogs of calcitriol that have little or no hypercalcemic action, for the treatment of psoriasis and some cancers. Such compounds include calcipotriol (1a,27-dihydroxycholecalciferol), 19-nor-calcidiol, doxercalciferol, 22-oxacalcitriol, and alfacacidiol (Brown, 1998, 2001; Guyton et al., 2001).

FURTHER READING

Beckerman P and Silver J (1999) Vitamin D and the parathyroid. American Journal of

Medical Science 317,363-9. Boyan BD, Sylvia VL, Dean DD, and Schwartz Z (2001) 24,25-(OH)(2)D(3) regulates cartilage and bone via autocrine and endocrine mechanisms. Steroids 66, 363-74. Bronner F and Pansu D (1999) Nutritional aspects of calcium absorption. Journal of Nutrition 129, 9-12.

Brown AJ (2001) Therapeutic uses of vitamin D analogues. American Journal of Kidney Disease 38, S3-S19.

Brown AJ, Dusso A, and Slatopolsky E (1999) Vitamin D. American Journal of Physiology 277, F157-75.

Casteels K, Bouillon R, Waer M, and Mathieu C (1995) Immunomodulatory effects of 1,25-dihydroxyvitamin D3. Current Opinion in Nephrology and Hypertension 4, 31318.

Chatterjee M (2001) Vitamin D and genomic stability. Mutation Research 475, 69-87. Christakos S, Raval-Pandya M, Wernyj RP, and Yang W (1996) Genomic mechanisms involved in the pleiotropic actions of 1,25-dihydroxyvitamin D3. Biochemical Journal 316, 361-71.

DeLuca HF and Zierold C (1998) Mechanisms and functions of vitamin D. Nutrition

Reviews 56, S4-S10; discussion S54-S75. GennariC (2001) Calcium and vitamin D nutrition and bone disease of the elderly. Public

Health Nutrition 4, 547-59. Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh JC, Remus LS, Selznick SH, and Whitfield GK (1997) The vitamin D hormone and its nuclear receptor: molecular actions and disease states. Journal of Endocrinology 154(Suppl.) S57-S73.

Holick MF (1996) Vitamin D and bone health. Journal of Nutrition 126, 1159S-64S.

Jones G, Strugnell SA, and DeLuca HF (1998) Current understanding of the molecular actions of vitamin D. Physiological Reviews 78, 1193-1231.

MawerEB and Davies M (2001) Vitamin D nutrition and bone disease in adults. Reviews of Endocrine and Metabolic Disorders 2, 153-64.

Narvaez CJ, Zinser G, and Welsh J (2001) Functions of 1alpha,25-dihydroxyvitamin D(3) in mammary gland: from normal development to breast cancer. Steroids 66, 301-8.

Norman AW, Henry HL, Bishop JE, Song XD, Bula C, and Okamura WH (2001) Different shapes of the steroid hormone 1alpha,25(OH)(2)-vitamin D(3) act as agonists for two different receptors in the vitamin D endocrine system to mediate genomic and rapid responses. Steroids 66, 147-58.

Norman AW, Ishizuka S, and Okamura WH (2001) Ligands for the vitamin D endocrine system: different shapes function as agonists and antagonists for genomic and rapid response receptors or as aligand for the plasma vitamin D binding protein. Journal of Steroid Biochemistry and Molecular Biology 76, 49-59.

Omdahl JL, Bobrovnikova EA, Choe S, Dwivedi PP, and May BK (2001) Overview of regulatory cytochrome P450 enzymes of the vitamin D pathway. Steroids 66, 381-9.

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Pike JW (1994) Vitamin D receptors and the mechanism of action of 1,25-dihy-droxyvitamin D3. In Vitamin Receptors: Vitamins as Ligands in Cell Communication, K Dakshinamurti (ed.), pp. 59-77. Cambridge, UK: Cambridge University Press.

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St-Arnaud R (1999) Targeted inactivation of vitamin D hydroxylases in mice. Bone 25, 127-9.

Various authors (1997) Symposium on nutritional aspects of bone. Proceedings of the Nutrition Society 56, 903-87.

Webb AR and Holick MF (1988) The role of sunlight in the cutaneous production of vitamin D3. Annual Reviews of Nutrition 8, 375-99.

White P and Cooke N (2000) The multifunctional properties and characteristics of vitamin D-binding protein. Trends in Endocrinology and Metabolism 11,320-7.

Wikvall K (2001) Cytochrome P450 enzymes in the bioactivation of vitamin D to its hormonal form (review). International Journal of Molecular Medicine 7, 201-9.

Wood RJ and Fleet JC (1998) The genetics of osteoporosis: vitamin D receptor polymorphisms. Annual Reviews of Nutrition 18, 233-58.

Yamada S, Yamamoto K, Masuno H, and Choi M (2001) Three-dimensional structure-function relationship of vitamin D and vitamin D receptor model. Steroids 66,177-87.

References cited in the text are listed in the Bibliography.

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