Vitamin D receptors

The vitamin D receptor (VDR/NR1I1) is a member of the superfamily of steroid hormone receptors. It regulates calcium homeostasis, cell proliferation, and differentiation, and exerts immunomodulatory and antimicrobial functions [119]. VDR binds to and mediates the calcemic effects of calcitriol (la,25-dihydroxy vitamin D3) after forming an heterodimer with RXR. la,25-dihydroxyvitamin D3 negatively regulates its own synthesis by repressing the 25-hydroxyvitamin D3 la-hydroxylase (CYP27B1) in a cell-type selective event that involves different combinations of multiple VDR response elements [120, 121]. 

VDR has also been demonstrated to be an intestinal receptor for the toxic secondary bile acid LCA [122], Activation of VDR by vitamin D or LCA induces expression of CYP3A4 that can detoxify LCA via phase I hydroxylation [122], Low expression of VDR in hepatocytes [123] and the coexpression of VDR and CYP3 A4 in enterocytes indicate that dietary vitamin D may modulate first-pass drug metabolism in the intestine. The murine multispecific anion transporter Mrp3, which is also expressed in intestine, harbors a VDR response element in its promoter region and is transactivated upon calcitriol and LCA treatment [124], VDR-stimulated Mrp3 expression could thus further contribute to intestinal first-pass drug metabolism. 

VDR also plays an important role in bile acid homeostasis, since ASBT mRNA and promoter activity are increased by calcitriol [132], In addition, VDR negatively interacts with FXR and calcitriol inhibits FXR transactivation in vitro [133]. Thus VDR is an important regulator of drug metabolism and disposition and—due to its high expression in enterocytes—a potent modulator of first-pass drug metabolism in intestine. 

---

In the treatment of diseases where the metaboUtes are not being deUvered to the system, synthetic metaboUtes or active analogues have been successfully adrninistered. Vitamin metaboUtes have been successfully used for treatment of milk fever ia catde, turkey leg weakness, plaque psoriasis, and osteoporosis and renal osteodystrophy ia humans. Many of these clinical studies are outlined ia References 6, 16, 40, 51, and 141. The vitamin D receptor complex is a member of the gene superfamily of transcriptional activators, and 1,25 dihydroxy vitamin D is thus supportive of selective cell differentiation. In addition to mineral homeostasis mediated ia the iatestiae, kidney, and bone, the metaboUte acts on the immune system, P-ceUs of the pancreas (iasulin secretion), cerebellum, and hypothalamus. 

Russell J et al Interaction between calcium and 1,25-dihydroxy-vitamin D3 in the regulation of preproparathyroid hormone and vitamin D receptor mRNA in avian parathyroids. Endocrinology 1993 132 2639. 

Osteoporosis Commonly postmenopausal or In other cases Is more gradual and related to age a small number of cases are due to mutations In the COL lA 1 and COL 1A2 genes and possibly In the vitamin D receptor gene (MIM 166710)... 

Other vitamin D analogs available in the United States include paricalcitol (19-nor-l,25-dihydroxyvitamin D2, Zemplar by Abbott Laboratories, North Chicago, IL) and doxercalciferol (1 -a-hydroxyvitamin D2, Hectoral by Bone Care International, Middleton, WI). Alfacalcidiol (1-a-hydroxyvitamin D3) is only available outside the United States. Paricalcitol has less effect on vitamin D receptors in the intestines, decreasing the effects on... 

Zmuda JM, Cauley JA, Ferrell RE. Molecular epidemiology of vitamin D receptor gene variants. Epidemiol Rev 2000 22 203-217. 

Vitamin D receptor (VDR) 1,25 dihydroxyvitamin-D3 Vitamin D response in patients affected with rickets (96) Susceptibility to osteoporosis (97) and autosomal dominant rickets disease (96)... 

Malloy PJ, Eccleshall TR, Gross C, Van Maldergem L, Bouillon R, Feldman D. Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness. J Clin Invest 1997 99[2] 297-304. 

Lucotte G, Mercier G, Burckel A. The vitamin D receptor FokI start codon polymorphism and bone mineral density in osteoporotic postmenopausal French women. Clin Genet 1999 56[3] 221 224. 

Calcitriol, 1,25-dihydroxyvitamin D3, directly suppresses PTH synthesis and secretion and upregulates vitamin D receptors, which ultimately may reduce parathyroid hyperplasia. The dose depends on the stage of CKD and type of dialysis (Table 76-4). 

Froicu, M. et al., A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases, Mol. Endocrinol. 17, 2386, 2003. 

Zemplar (paricalcitol) injection is a synthetically manufactured selective vitamin D receptor activator (SVDRA) indicated for the prevention and treatment of secondary hyperparathyroidism associated with chronic kidney disease (CKD) stage 5. The U.S. Food Drug Administration (FDA) approved a capsule form of Zemplar for development to satisfy a need for an oral formulation. The objective of study M04-693 was to assess the bioequivalencies of several dosage strengths of paricalcitol capsules under fasting conditions. 

Saint J. Van Tomout JM, Loro ML, Sayre J, Roe TF, Gilsanz V. Vitamin D-receptor gene polymorphisms and bone density in prepubertal American girls of Mexican descent. New England Journal of Medicine 1997 337 7782. 

Adorini L, Penna G, Giarratana N, Uskokovic M Tolerogenic dendritic cells induced by vitamin D receptor ligands enhance regulatory T cells inhibiting allograft rejection and autoimmune diseases. J Cell Biochem 2003 88 227-233. 

Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. 2005. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat 29 21-30. 

Donath, J., Speer, G., Poor, G., Gergely, P., Tabak, A., and Lakatos, P. (2004) Vitamin D receptor, oestrogen receptor-alpha and calcium-sensing receptor genotypes, bone mineral density and biochemical markers in Paget s disease of bone. Rheumatology. 43, 692-695. 

X Receptor alpha and beta, Liver X Receptor alpha and beta, and Vitamin D Receptor, International Union of Pharmacology, LXII. 

Race and genetic factors [e.g., FOKl gene polymorphism of the vitamin D receptor (VDR)]... 

Abrams, S. A., Griffin, I. J., Hawthorne, K. M., Chen, Z., Gunn, S. K., Wilde, M., Darlington, G., Shypailo, R. J., and Ellis, K. J. (2005a). Vitamin D receptor Fokl polymorphisms affect calcium absorption, kinetics, and bone mineralization rates during puberty. JBMR 20, 945-953. 

Ames, S., Ellis, K., Gurm, S., Copeland, K., and Abrams, S. (1999). Vitamin D receptor gene Fokl polymorphism predicts calcium absorption and bone mineral density in children. JBMR 14, 740-746. 

Evidence of an age-related decrease in intestinal responsiveness to vitamin D Relationship between serum 1,25-dihydroxy D3 and intestinal vitamin D receptor concentrations in normal women. J. Clin. Endocrinol. Metab. 75,176-182. 

---