The nuclear vitamin D receptor: From clinical radioreceptor assay of the vitamin D hormone to genomics, proteomics and a novel ligand

Vitamin D is bioactivated in kidney to its hormonal form, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3), functioning to prevent rickets/osteomalacia by Stimulating small intestinal calcium absorption. Plasma 1,25(OH)(2)D-3 is depressed in patients with chronic renal failure and elevated in subjects with calcium urolithiasis, but normal in osteoporosis. The chromosomal gene encoding the nuclear vitamin D receptor (VDR) contains two common polymorphisms that influence VDR functional activity, which encompasses 1,25(OH)(2)D-3-ligand-dependent heterodimerization with retinoid X receptor (RXR) and recruitment of cell-specific coactivators for enhancement of target gene transcription. A newly discovered ligand for VDR is lithocholic acid (LCA), a secondary bile acid that is a causative agent in colon cancer promoted by high fat diets. LCA activates the VDR-RXR complex in colon to stimulate the transcription of cytochrome P-450 3A4, which detoxifies LCA. This process is potentiated by 1,25(OH)(2)D-3 binding to VDR, explaining mechanistically the epidemiologic finding that vitamin D prevents colon cancer.