Vitamin D and genomic stability.

1alpha,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 reports characterizing 1,25(OH)(2)D(3) receptors and activities in diverse tissues such as brain, pancreas, pituitary, skin, muscle, placenta, immune cells and parathyroid. The receptor hormone complex becomes localized in the nucleus, 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 repression of specific messenger RNAs (m-RNAs), ultimately resulting in changes in protein expression needed to produce biological responses. Genes for carbonic anhydrase that are expressed at high levels in osteoclast are known to be involved in bone resorption and Id genes role in osteoblast-osteoclast differentiation reflects the genomic effect of Vitamin D on bones. Genomic action of Vitamin D also explains the biosynthesis of oncogenes, polyamines, lymphokines and calcium binding proteins. However, there is a possibility that some of the actions of 1,25(OH)(2)D(3) may be mediated by non-genomic mechanisms and may not require the binding to Vitamin D receptor (VDR). Vitamin D offers a protection from genotoxic effects of Vitamin D deficiency by increasing the insulin receptor gene expression and BSP (bone sialoprotein), bone-remodeling by decreasing the osteopontin (OPN) m-RNAs, maintaining the normal epidermal structure and enamel matrix. Gonadal insufficiency in Vitamin D deficiency was corrected by vitamin mediated direct regulation of the expression of aramotase gene. The supportive role of Vitamin D in placental function is also evident by its influence on human placental lactogen (hpl) gene transcription accompanied by increase hpl m-RNA levels. Further 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 concentration has been found to protect cell proteins and membranes against oxidative stress by inhibiting the peroxidative attack on membrane lipids. Vitamin D, at a concentration range of 2x10(-8)-5x10(-8)M, induces apoptosis in most cancer cells, stabilizes chromosomal structure and prevents DNA double-strand breaks induced either by endogenous or exogenous factors. Vitamin D is also effective in stimulating DNA synthesis in adult alveolar II cells and provides a novel mechanism of modulation of epithelial cell proliferation in the context of lung development and repair against injury. The regulation of various proto-oncogenes (c-myc, c-fos, c-jun), differentiation inducing properties, antiproliferative effects on keratinocytes and inhibitory effects in several human malignancy ranks Vitamin D as a novel hormone that may have physiological and clinical implication in the carcinogenic process.