Metallothionein protects against isoniazid-induced liver injury through the inhibition of CYP2E1-dependent oxidative and nitrosative impairment in mice
Metallothionein protects against isoniazid-induced liver injury through the inhibition of CYP2E1-dependent oxidative and nitrosative impairment in mice
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DOI：
10.1016/j.fct.2017.01.016
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发表时间：
2017-04-01
影响因子：
4.3
通讯作者：
Peng, Shuang-Qing
中科院分区：
文献类型：
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作者：
Lian, Yong;Zhao, Jing;Peng, Shuang-Qing
异烟肼（INH）代谢过程中肝脏CYP 2 E1介导的氧化应激被认为是INH肝毒性的原因。本研究试图确定金属硫蛋白（MT），半胱氨酸丰富的抗氧化剂是否可以保护对异烟肼诱导的肝损伤，通过使用MT-I/II缺陷小鼠模型（MT-/-小鼠）。MT-/-小鼠和相应的野生型小鼠分别接受0、75、150和300 mg/kg INH灌胃给药15天。结果表明，150和300 mg/kg的INH可引起两种类型小鼠的肝损伤，表现为肝指数增加和肝空泡变性的组织病理学改变。肝组织MDA含量和3-NT表达增加，GSH含量和SOD活性降低，提示氧化应激和亚硝化应激的参与。INH处理上调肝脏CYP 2 E1表达在两种类型的小鼠，肝损伤的严重程度与CYP 2 E1表达的升高一致。比较分析显示MT-/-小鼠的肝空泡变性和氧化及亚硝化应激比野生型小鼠更严重，表明MT对INH肝毒性的肝保护作用。综上所述，这些发现清楚地表明，MT通过改善CYP 2 E1依赖性氧化和亚硝化损伤来保护INH诱导的肝毒性。(C)2017爱思唯尔有限公司版权所有
Oxidative stress mediated by hepatic CYP2E1 during isoniazid (INH) metabolism is considered responsible for INH hepatotoxicity. This study attempts to determine whether metallothionein (MT), a cysteinerich antioxidant can protect against INH-induced liver injury by using a MT-I/lI deficient mouse model (MT-/- mice). MT-/- mice and the corresponding wild-type mice received intragastric administrations of 0, 75, 150 and 300 mg/kg of INH for 15 days. The results showed that 150 and 300 mg/kg of INH induced liver injury in both types of mice, as evidenced by increased liver index and histopathological change of liver vacuolar degeneration. Increased hepatic MDA level and 3-NT expression, and decreased GSH content and SOD activity were also observed in both types of mice, indicating the involvement of oxidative and nitrosative stress. INH treatment upregulated hepatic CYP2E1 expression in both types of mice, and the severity of liver injury was in concert with the elevation of CYP2E1 expression. Comparative analyses revealed liver vacuolar degeneration and oxidative and nitrosative stress were more severe in MT-/- mice than wild-type mice, suggesting the hepatoprotection of MT against INH hepatotoxicity. Taken together, these findings clearly demonstrate that MT protects against INH-induced liver toxicity by ameliorating CYP2E1-dependent oxidative and nitrosative impairment. (C) 2017 Elsevier Ltd. All rights reserved.