Gene-specific effects of inflammatory Cytokines on cytochrome P4502C, 2B6 and 3A4 mRNA levels in human Hepatocytes
Gene-specific effects of inflammatory Cytokines on cytochrome P4502C, 2B6 and 3A4 mRNA levels in human Hepatocytes
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DOI：
10.1124/dmd.107.015511
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发表时间：
2007-09-01
影响因子：
3.9
通讯作者：
Morgan, Edward T.
中科院分区：
文献类型：
--
作者：
Aitken, Alison E.;Morgan, Edward T.
细胞色素P450(P450)在炎症和感染时在肝细胞中表达下调。这种效应在动物模型中得到了广泛的研究，但对人类的反应知之甚少，对于没有诱导剂的反应更是知之甚少。本文主要研究细菌脂多糖(LPS)、白介素6(IL-6)、肿瘤坏死因子-α(TNF)、干扰素-γ(IFN)、转化生长因子-β(TGF)和白介素1-β(IL-1)对人肝细胞中细胞色素P450 2B6和细胞色素P450 2 C基因表达的影响。将这些效应与研究得更好、更丰富的CYP3A4的反应进行了比较。所有细胞因子处理均下调细胞色素P3A4和细胞色素P450 2C8的表达。在肝脏中低水平表达的细胞色素P450 2 C18不受细胞因子治疗的影响。其他的细胞色素P450 2 C和细胞色素P2 2 B6具有细胞因子特异性作用。细胞色素P450 2C9和细胞色素P450 2C19的反应模式几乎相同，均被IL-6和转化生长因子下调，但不受内毒素、肿瘤坏死因子、干扰素或IL-1的显著影响。CYP2B6mRNA只对IL-6和干扰素有反应。IL-6下调所有研究的P450细胞的mRNAs。P450蛋白表达的蛋白质印迹分析在很大程度上支持了mRNA的数据，尽管观察到了一些不一致的情况。我们的结果表明，人类对炎症的CYP2C8、2C9、2C18、2C19、2B6和3A4反应是独立调节的，表明这种精细控制可能对疾病状态下的人类药物反应具有关键影响。
Cytochromes P450 ( P450s) are down-regulated in hepatocytes in response to inflammation and infection. This effect has been extensively studied in animal models, but significantly less is known about responses in humans and even less about responses in the absence of inducing agents. This article focuses on the effects of bacterial lipopolysaccaride (LPS), interleukin-6 (IL-6), tumor necrosis factor-alpha( TNF), interferon gamma (IFN), transforming growth factor-beta (TGF) and interleukin- 1 beta ( IL-1) on expression of CYP2B6 and the CYP2C mRNAs in human hepatocytes. These effects were compared with responses of the better studied and more abundant CYP3A4. CYP3A4 and CYP2C8 were down-regulated by all cytokine treatments. CYP2C18, which is expressed at very low levels in liver, was unaffected by cytokine treatments. The other CYP2Cs and CYP2B6 showed cytokine-specific effects. CYP2C9 and CYP2C19 showed almost identical response patterns, being down-regulated by IL-6 and TGF but not significantly affected by LPS, TNF, IFN, or IL-1. CYP2B6 mRNA responded only to IL-6 and IFN. IL-6 down-regulated the mRNAs of all P450s studied. Western blot analysis of P450 protein expression supported the mRNA data to a large extent, although some inconsistencies were observed. Our results show that human CYP2C8, 2C9, 2C18, 2C19, 2B6, and 3A4 responses to inflammation are independently regulated and indicate that this fine control may have a critical effect on human drug responses in disease states.