Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1
Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1
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DOI：
10.1016/j.taap.2008.04.020
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发表时间：
2008-09-15
影响因子：
3.8
通讯作者：
Nakajima, Tamie
中科院分区：
文献类型：
--
作者：
Ramdhan, Doni Hikmat;Kamijima, Michihiro;Nakajima, Tamie
细胞色素P450（CYP）2 E1是三氯乙烯（TRI）代谢和肝毒性的主要酶，但后者的分子机制尚未完全阐明。通过比较CYP 2 E1（+/+）和CYP 2 E1（-/-）小鼠的肝毒性，研究CYP 2 E1在TRI-ET诱导肝毒性中的作用及其分子机制。通过吸入将小鼠暴露于0（对照）、1000或2000 ppm的TRI，每天8小时，持续7天，并通过测量血浆丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）活性和组织病理学来评估TRI-hepatocytosis。与cyp 2 e1（-/-）小鼠相比，cyp 2 e1（+/+）小鼠中三氯乙醇和三氯乙酸（TCA）的尿液代谢物显著更高，表明CYP 2 E1是参与这些代谢物形成的主要P450。与血浆ALT和AST活性升高一致，2000 ppm组中的cyp 2 e1（+/+）小鼠显示组织病理学炎症。TRI显著上调了PPAR α，其可能起抑制NF κ B B p50和p65信号传导的作用。此外，TRI-NF-κ B p52 mRNA的表达与ALT活性呈显著正相关，提示p52参与了肝脏炎症反应。综上所述，本研究直接证明CYP 2 E1是参与TRI代谢第一步的主要P450，产生的代谢产物可能具有两种相反的作用：一种诱导肝毒性，另一种保护免受毒性。由CYP 2 E1介导的氧化作用产生的从TRI到水合氯醛的中间代谢产物可能参与前者，而TCA可能参与后者。(C)2008年爱思唯尔公司所有战斗保留。
Cytochrome P450 (CYP) 2E1 was suggested to be the major enzyme involved in trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter Molecular mechanism is not fully understood. The involvement of CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in cyp2e1(+/+) and cyp2e1(-/-) mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of trichloroethanol and trichloroacetic acid (TCA) were considerably greater in cyp2e1(+/+) compared to cyp2e1(-/-) mice, suggesting that CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities, cyp2e1(+/+) mice in the 2000 ppm group showed histopathological inflammation. TRI significantly upregulated PPAR alpha, which might function to inhibit NF kappa B p50 and p65 signalling. In addition, TRI-induced NF kappa B p52 mRNA, and significantly positive correlation between NF kappa B p52 mRNA expression and plasma ALT activity levels were observed, Suggesting the involvement of p52 in liver inflammation. Taken together, the current Study directly demonstrates that CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter. (C) 2008 Elsevier Inc. All Fights reserved.