University of Arizona Cancer Center, University of Arizona, Tucson, AZ, USA.
Cancer Res. 2013 Apr 15;73(8):2563-73. doi: 10.1158/0008-5472.CAN-12-4134. Epub 2013 Feb 19.
Vitamin D is a well-studied agent for cancer chemoprevention and treatment. Its chief circulating metabolite, 25-hydroxyvitamin D, is converted into the active hormone 1,25-dihydroxyvitamin D (1,25D) by the cytochrome P450 enzyme CYP27B1 in kidney and other tissues. 1,25D is then deactivated by CYP24A1 and ultimately catabolized. Colorectal carcinoma cells express CYP27B1 and CYP24A1 that locally regulate 1,25D with potential implications for its impact on carcinogenesis. While 1,25D inhibits cancer growth, the effects of polymorphic variations in genes encoding proteins involved in 1,25D homeostasis are poorly understood. Using an RXR-VDR mammalian two-hybrid (M2H) biologic assay system, we measured vitamin D metabolite uptake and activation of the vitamin D receptor (VDR) pathway in colon cancer cells that expressed one of five CYP27B1 single-nucleotide polymorphisms (SNP) or four CYP24A1 SNPs. Compared with the wild-type control, four of five CYP27B1 SNPs reduced enzymatic activity, whereas one (V166L) increased activity. For CYP24A1, all tested SNPs reduced enzyme activity. Quantitative real-time PCR analyses supported the results of M2H experiments. The observed SNP-directed variation in CYP functionality indicated that vitamin D homeostasis is complex and may be influenced by genetic factors. A comprehensive understanding of 1,25D metabolism may allow for a more personalized approach toward treating vitamin D-related disorders and evaluating risk for carcinogenesis.
维生素 D 是一种经过充分研究的癌症化学预防和治疗药物。其主要循环代谢物 25-羟维生素 D 通过肾脏和其他组织中的细胞色素 P450 酶 CYP27B1 转化为活性激素 1,25-二羟维生素 D（1,25D）。1,25D 然后被 CYP24A1 失活，并最终被分解代谢。结直肠癌细胞表达 CYP27B1 和 CYP24A1，可局部调节 1,25D，这可能对其对癌变的影响有潜在意义。虽然 1,25D 抑制癌症生长，但编码参与 1,25D 动态平衡的蛋白质的基因多态性变异的影响仍知之甚少。使用 RXR-VDR 哺乳动物双杂交（M2H）生物测定系统，我们测量了在表达五种 CYP27B1 单核苷酸多态性（SNP）之一或四种 CYP24A1 SNP 的结肠癌细胞中维生素 D 代谢物摄取和维生素 D 受体（VDR）途径的激活。与野生型对照相比，五种 CYP27B1 SNP 中的四种降低了酶活性，而一种（V166L）增加了活性。对于 CYP24A1，所有测试的 SNP 都降低了酶活性。定量实时 PCR 分析支持 M2H 实验的结果。观察到的 SNP 指导的 CYP 功能变化表明，维生素 D 动态平衡很复杂，可能受到遗传因素的影响。对 1,25D 代谢的全面了解可能允许采取更个性化的方法来治疗与维生素 D 相关的疾病，并评估致癌风险。
