Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice
Effect of Lipopolysaccharide on the Xenobiotic-Induced Expression and Activity of Hepatic Cytochrome P450 in Mice
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DOI：
10.1248/bpb.35.473
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发表时间：
2012-04-01
影响因子：
2
通讯作者：
Kugawa, Fumihiko
中科院分区：
文献类型：
--
作者：
Moriya, Nozomu;Kataoka, Hiromi;Kugawa, Fumihiko
炎症反应可改变细胞色素P450（CYP）的表达水平和功能。Cyp基因的表达受几种核受体的激活调节，包括雄烷X受体（PXR）、组成型雄烷受体（CAR）和芳烃受体（AhR）。这些受体可以被包括药物在内的外源性物质激活。在这里，为了研究炎症过程中外源性诱导的CYP 1A 1的波动，我们检测了脂多糖（LPS）处理对小鼠中外源性激活的核受体诱导的编码肝CYP的mRNA水平的影响。检测了Cyp基因的mRNA诱导和Cyp蛋白的代谢活性。LPS处理导致Cyp 3a 11、2c 29、2c 55和1a 2的mRNA诱导表达显著降低，但Cyp 2b 10没有。为了评估睾酮的酶活性，在有或没有LPS给药的情况下，在用异源生物素双烯醇酮-16 α-甲腈（PCN）处理的小鼠中测量了CYP 3A介导的睾酮6 β-羟基化和硝苯地平在肝微粒体中的固有清除率（克林特）。两种方法均显示，LPS处理后，PCN诱导的CYP 3A活性显著下降，且这种下降与Cyp 3a 11 mRNA水平相关。此外，我们发现，白细胞介素（IL）-1 β和肿瘤坏死因子（TNF）α的mRNA与LPS加外源性物质治疗后增加。我们的研究结果表明，LPS治疗减少了PXR和AhR介导的，可能是CAR介导的Cyp基因表达，并进一步表明，这些减少依赖于肝脏中的炎性细胞因子。
Infection-associated inflammation can alter the expression levels and functions of cytochrome P450s (CYPs). Cyp gene expression is regulated by the activation of several nuclear receptors, including pregnane X receptor (PXR), constitutive androstane receptor (CAR), and aryl hydrocarbon receptor (AhR). These receptors can be activated by xenobiotics, including medicines. Here, to study the xenobiotic-induced fluctuations in CYP during inflammation, we examined the effect of lipopolysaccharide (LPS) treatment on the level of mRNAs encoding hepatic CYPs induced by xenobiotic-activated nuclear receptors, in mice. Both the mRNA induction of Cyp genes and the metabolic activities of CYP proteins were examined. LPS treatment caused a significant decrease in the induced expression of the mRNAs for Cyp3a11, 2c29, 2c55, and 1a2, but not for Cyp2b10. To assess the CYP enzymatic activities, CYP3A-mediated testosterone 6 beta-hydroxylation and the intrinsic clearance (CLint) of nifedipine in liver microsomes were measured in mice treated with the xenobiotic pregnenolone-16alpha-carbonitrile (PCN) with or without LPS administration. Both assays revealed that the CYP3A activity, which was induced by PCN, declined significantly after LPS treatment, and this decline correlated with the Cyp3a11 mRNA level. In addition, we found that the mRNAs for interleukin (IL)-1 beta and tumor necrosis factor (TNF) alpha were increased after treatment with LPS plus xenobiotics. Our findings demonstrated that LPS treatment reduces the PXR- and AhR-mediated, and possibly CAR-mediated Cyp gene expression and further suggest that these decreases are dependent on inflammatory cytokines in the liver.