Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China.
Toxicol Lett. 2010 Sep 1;197(3):219-26. doi: 10.1016/j.toxlet.2010.06.003. Epub 2010 Jun 9.
Cytochrome P450 3A4 (CYP3A4) is the most abundant cytochrome P450 enzyme in human liver and metabolizes more than 60% of prescribed drugs in human body. Patients with liver conditions such as cirrhosis show increased secretion of cytokines (e.g., interleukin-6) and decreased capacity of oxidation of many drugs. In this study, we provided molecular evidence that cytokine secretion directly contributed to the decreased capacity of oxidative biotransformation in human liver. After human hepatocytes were treated with IL-6, the expression of CYP3A4 decreased at both mRNA and protein levels, so did the CYP3A4 enzymatic activity. Meanwhile, the repression of CYP3A4 by IL-6 occurred after the decrease of pregnane X receptor (PXR) in human hepatocytes. The PXR-overexpressed cells (transfected with human PXR) increased the CYP3A4 mRNA level, and the repression of CYP3A4 by IL-6 was greater in the PXR-overexpressed cells than in the control cells. Further, PXR knockdown (transfected with siPXR construct) decreased the CYP3A4 mRNA level with less repression by IL-6 than in the control cells transfected with corresponding vector. Collectively, our study suggests that PXR is necessary for IL-6-mediated repression of the CYP3A4 expression in human hepatocytes.
细胞色素 P450 3A4（CYP3A4）是人类肝脏中含量最丰富的细胞色素 P450 酶，代谢人体中超过 60%的处方药。患有肝硬化等肝脏疾病的患者会增加细胞因子（如白细胞介素-6）的分泌，并降低许多药物的氧化能力。在这项研究中，我们提供了分子证据，表明细胞因子的分泌直接导致人肝中氧化生物转化能力的降低。在人原代肝细胞中用白细胞介素-6 处理后，CYP3A4 的表达在 mRNA 和蛋白水平上均下降，CYP3A4 酶活性也随之下降。同时，白细胞介素-6 对 CYP3A4 的抑制作用发生在人原代肝细胞中 pregnane X 受体（PXR）下降之后。过表达 PXR 的细胞（转染人 PXR）增加了 CYP3A4 mRNA 水平，白细胞介素-6 对 PXR 过表达细胞中 CYP3A4 的抑制作用大于对照细胞。此外，PXR 敲低（转染 siPXR 构建体）降低了 CYP3A4 mRNA 水平，且白细胞介素-6 的抑制作用低于对照细胞转染相应载体。总之，我们的研究表明，PXR 是白细胞介素-6 介导的人原代肝细胞中 CYP3A4 表达抑制所必需的。
