Vitamin D and genomic stability

1 alpha ,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] has been shown to act on novel target tissues not related to calcium homeostasis. There have been re ports characterizing 1,25(OH) D3 receptors and activities in diverse tissue s such as brain, pancreas, pituitary, skin, muscle, placenta, immune cells and parathyroid. The receptor hormone complex becomes localized in the nucl eus, and undergoes phosphorylation by reacting with a kinase. This form of the receptor then interacts with the Vitamin D responsive element of target gene and modifies the transcription of those genes to develop the action. The modulation of gene transcription results in either the induction or rep ression of specific messenger RNAs (m-RNAs), ultimately resulting in change s in protein expression needed to produce biological responses. Genes for c arbonic anhydrase that are expressed at high levels in osteoclast are known to be involved in bone resorption and Id genes role in osteoblast-osteacla st differentiation reflects the genomic effect of Vitamin D on bones. Genom ic action of vitamin D also explains the biosynthesis of oncogenes, polyami nes, lymphokines and calcium binding proteins. However, there is a possibil ity that some of;he actions of 1,25(OH)(2)D-3 may be mediated by non-genomi c mechanisms and may not require the binding to Vitamin B receptor (VDR). Vitamin D offers a protection from genotoxic effects of Vitamin D deficienc y by increasing the insulin receptor gene expression and BSP (bone sialopro tein), bone-remodeling by decreasing the osteopontin (OPN) m-RNAs, maintain ing the normal epidermal structure and enamel matrix. Gonadal insufficiency in Vitamin B deficiencp was corrected by vitamin mediated direct regulatio n of the expression of aramotase gene. The supportive role of Vitamin D in placental function is also evident by its influence on human placental lact ogen (hpl) gene transcription accompanied by increase hpl m-RNA levels. Fur ther role of Vitamin D is envisaged in identifying cyclin C as an important target for Vitamin D in cell-cycle regulation. Vitamin D at physiological concentratrion inhibiting the peroxidative attac k on membrane lipids. Vitamin D, at a concentration range of 2 x 10(-8)-5 x 10(-8) M, induces apoptosis in most cancer cells, stabilizes chromosomal s tructure and prevents DNA double-strand breaks induced either by endogenous or exogenous factors. Vitamin D is also effective in stimulating DNA synth esis in adult alveolar II cells and provides a novel mechanism of modulatio n of epithelial cell proliferation in the context of rung development and r epair against injury. The regulation of various proto-oncogenes (c-myc, c-f os, c-jun), differentiation inducing properties, antiproliferative effects on keratinocytes and inhibitory effects in several human malignancy ranks V itamin D as a novel hormone that may have physiological and clinical implic ation in the carcinogenic process. (C) 2001 Elsevier Science B.V. All right s reserved.