Department of Preventive Medicine, School of Environmental Science and Public Health, Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325035, PR China.
Biochem Pharmacol. 2014 Aug 15;90(4):425-31. doi: 10.1016/j.bcp.2014.06.016. Epub 2014 Jun 21.
The CYP2C subfamily of cytochrome P450 enzymes is an important class of drug metabolizing enzymes in human liver. CYP2C9 is the most abundant member of the human CYP2C subfamily in liver and metabolizes ~15% of the therapeutic drugs as well as other xenobiotics and endogenous compounds. A number of nuclear receptors including xenobiotic-sensing receptors such as the constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR) as well as liver enriched receptors hepatic nuclear factor 4α (HNF4α) and the estrogen receptor α (ERα) regulate CYP2C9 expression. Here, we show that Med25, a variable component of Mediator complex, enhanced ligand dependent ERα-mediated transcriptional activation of CYP2C9 promoter and interacts with activated ERα by 17β-estradiol through its C-terminal LXXLL motif. In conclusion, Med25 is identified as a new coactivator of ERα that is required for ERα-mediated regulation of CYP2C9 expression.
细胞色素 P450 酶的 CYP2C 亚家族是人类肝脏中重要的一类药物代谢酶。CYP2C9 是人类 CYP2C 亚家族中肝脏中最丰富的成员，代谢约 15%的治疗药物以及其他外源性化合物和内源性化合物。许多核受体，包括外源性感知受体，如组成型雄烷受体 (CAR)、孕烷 X 受体 (PXR) 和糖皮质激素受体 (GR)，以及富含肝脏的受体肝核因子 4α (HNF4α) 和雌激素受体 α (ERα)，调节 CYP2C9 的表达。在这里，我们表明 Mediator 复合物的可变成分 Med25 增强了配体依赖性 ERα 介导的 CYP2C9 启动子转录激活，并通过其 C 端 LXXLL 基序与激活的 ERα相互作用。总之，Med25 被鉴定为 ERα 的一种新的共激活因子，是 ERα 介导的 CYP2C9 表达调控所必需的。
