维生素D受体变异对下游靶基因转录调控的研究进展

Progress in effects of VDR variant mediated transcriptional regulation on its downstream target gene

维生素D3是人体必需的一种维生素,属于类固醇激素,在体内的主要活性形式为1,25(OH)2VD3(简称VD3),在体内具有重要的生物学功用,其所有作用的实现都是通过维生素D受体(VDR)来介导的。VDR与VD3结合后,可以调控下游一系列靶基因的转录,发挥其调节钙磷代谢、调控细胞生长分化等作用;另外VDR还在药物代谢、转运、以及药物疗效中起关键作用。VD3的抗肿瘤机制之一也是当今日益受到重视的化学性保护作用:VD3通过VDR诱导了药物代谢酶CYP450,对内外源性物质尤其是一些前致癌物进行代谢分解继而排出体外的能力加强从而起到抗肿瘤的作用;由此VDR基因变异所产生的蛋白数量或质量的改变也就预示了其在临床上将产生深远影响。

1,25-（OH）2D3 is an essential vitamin that belongs to steroid hormone,the principal recognized biological effect of 1,25-（OH）2D3,is to maintain calcium/phosphate ion homeostasis ,regulate cell growth or differentiation and prevent rickets/osteomalacia; through its combined actions on classical endocrine target tissues including intestine,bone,and kidney,liganding of the vitamin D receptor （VDR） with1,25-（OH）2D3 mediates the effects of the 1,25-dihydroxyvitamin D3 hormone to alter a series of target gene transcription of downstream. In addition,VDR may play an important role in drug metabolism,transportation and therapeutic effect. Mounting epidemiological and experimental evidence also implicates 1,25-（OH）2D3 as an epithelialcell anti-cancer and chemopreventative agent. The 1,25-（OH）2D3 ligand and several synthetic vitamin D analogs are known to possess potent anti-proliferative,prodifferentiation,and/or cell cycle arrest activities in epithelial cells,whereas 1,25-（OH）2D3 likely afford some degree of chemoprotection,another mechanism that could contribute to the antitumor activity of 1,25-（OH）2D3 in certain cell types is induction of drug-metabolizing enzyme proteins to initiate enzymatic detoxification of dietary xenobiotics and deleterious endobiotic compounds. This article reviews the function of VDR on transcriptional regulation to drug-metabolizing enzyme and its relationship between gene polymorphisms and some diseases.