Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes.
Pregnane X receptor is required for interleukin-6-mediated down-regulation of cytochrome P450 3A4 in human hepatocytes.
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孕烷 X 受体是白细胞介素 6 介导的人肝细胞中细胞色素 P450 3A4 下调所必需的。
DOI：
10.1016/j.toxlet.2010.06.003
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发表时间：
2010-09-01
影响因子：
3.5
通讯作者：
Yan, Bingfang
中科院分区：
文献类型：
--
作者：
Yang, Jian;Hao, Chunshu;Yang, Dongfang;Shi, Deshi;Song, Xiulong;Luan, Xiaofei;Hu, Gang;Yan, Bingfang
关键词：
细胞色素 P450 3A4 (CYP 3A4) 是人体肝脏中最丰富的细胞色素 P450 酶，代谢人体内 60% 以上的处方药物。患有肝硬化等肝脏疾病的患者细胞因子（例如白细胞介素 6）的分泌增加，许多药物的氧化能力下降。在这项研究中，我们提供了分子证据，表明细胞因子分泌直接导致人肝脏氧化生物转化能力下降。 IL-6处理人肝细胞后，CYP3A4的mRNA和蛋白水平表达均降低，CYP3A4酶活性也降低。同时，IL-6对CYP3A4的抑制是在人肝细胞中孕烷X受体(PXR)减少后发生的。 PXR 过表达的细胞（用人 PXR 转染）增加了 CYP3A4 mRNA 水平，并且 PXR 过表达的细胞中 IL-6 对 CYP3A4 的抑制比对照细胞更大。此外，与用相应载体转染的对照细胞相比，PXR敲低（用siPXR构建体转染）降低了CYP3A4 mRNA水平，并且IL-6的抑制较少。总的来说，我们的研究表明 PXR 对于 IL-6 介导的人肝细胞中 CYP3A4 表达的抑制是必需的。
Cytochrome P450 3A4 (CYP 3A4) 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.
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影响因子：
3.5
作者：
CASTELL, JV;GOMEZLECHON, MJ;HEINRICH, PC
通讯作者：
HEINRICH, PC
影响因子：
3.9
作者：
Lindley, C;Hamilton, G;LeCluyse, EL
通讯作者：
LeCluyse, EL
影响因子：
3.8
作者：
Cooper, Beth W.;Cho, Taehyeon M.;Wallace, Andrew D.
通讯作者：
Wallace, Andrew D.
影响因子：
13.5
作者：
CASTELL, JV;GOMEZLECHON, MJ;HEINRICH, PC
通讯作者：
HEINRICH, PC
影响因子：
4.1
作者：
Li, YX;Song, XL;Yan, BF
通讯作者：
Yan, BF