干扰素-γ通过猪的孕烷X受体调节细胞色素3A29。

IFN-γ regulates cytochrome 3A29 through pregnane X receptor in pigs.

Li Xiaowen, Hu Xiuzhong, Jin Xiue, Zhou Xiaoqiao, Wang Xiliang, Shi Deshi, Bi Dingren

State Key Laboratory of Agricultural Microbiology, College of Veterinary Medicine, Huazhong Agricultural University , Wuhan , PR China .

Xenobiotica. 2015 May;45(5):373-9. doi: 10.3109/00498254.2014.985761. Epub 2014 Nov 21.

Abstract

The expression and the activity of cytochromes P450 (CYPs) can be elevated by the activation of nuclear receptors. The pregnane X receptor (PXR, or nuclear receptor NR1I2) is a ligand-activated transcription factor that mediates responses to diverse xenobiotics and endogenous chemicals. Here we investigated the regulatory role of PXR in IFN-γ-mediated CYP3A29 expression in pig liver microsomes, primary porcine hepatocytes, and a cultured hepatocyte cell line. 2. IFN-γ significantly up-regulated CYP3A29 and PXR expressions at mRNA and protein levels in a dose-dependent manner. IFN-γ treatment significantly increased the metabolism of nifedipine. PXR and IFN-γ treatments significantly enhanced the activity of CYP3A29 promoter and the upstream region from -1473 to -1021 of CYP3A29 might be PXR-binding site. Moreover, the IFN-γ-induced CYP3A29 expression was blocked by PXR knockdown, whereas CYP3A29 mRNA and protein expression levels were dramatically elevated by PXR overexpression. 3. The regulatory effect of IFN-γ on CYP3A29 expression is mediated via PXR.

摘要

细胞色素P450（CYPs）的表达和活性可通过核受体的激活而升高。孕烷X受体（PXR，或核受体NR1I2）是一种配体激活的转录因子，介导对多种外源性物质和内源性化学物质的反应。在此，我们研究了PXR在猪肝脏微粒体、原代猪肝细胞和一种培养的肝细胞系中IFN-γ介导的CYP3A29表达中的调节作用。2. IFN-γ以剂量依赖的方式显著上调了CYP3A29和PXR在mRNA和蛋白质水平的表达。IFN-γ处理显著增加了硝苯地平的代谢。PXR和IFN-γ处理显著增强了CYP3A29启动子的活性，CYP3A29从-1473至-1021的上游区域可能是PXR结合位点。此外，PXR敲低可阻断IFN-γ诱导的CYP3A29表达，而PXR过表达则使CYP3A29 mRNA和蛋白质表达水平显著升高。3. IFN-γ对CYP3A29表达的调节作用是通过PXR介导的。