Acute ethanol pretreatment increases FAS-mediated liver injury in mice: Role of oxidative stress and CYP2E1-dependent and -independent pathways
Acute ethanol pretreatment increases FAS-mediated liver injury in mice: Role of oxidative stress and CYP2E1-dependent and -independent pathways
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DOI：
10.1016/j.freeradbiomed.2006.12.023
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发表时间：
2007-04-01
影响因子：
7.4
通讯作者：
Cederbaum, Arthur I.
中科院分区：
文献类型：
--
作者：
Wang, Xiaodong;Cederbaum, Arthur I.
本研究评估了急性乙醇预处理是否增强Fas介导的肝损伤，以及氧化应激和CYP 2 E1是否在任何增强的肝毒性中发挥作用。与生理盐水对照组或单独用Jo 2或乙醇处理的小鼠相比，用Jo 2 Fas激动性抗体加乙醇处理的小鼠中转氨酶增加3倍，肝细胞凋亡坏死和肝小叶局灶性坏死更广泛。急性乙醇预处理使CYP 2 E1催化活性和蛋白质增加2倍。有2和2.5倍增加的caspase-8和caspase-3的活性和1.6倍增加的促凋亡阳性细胞在乔2加急性乙醇组相比，乔2单独组。肿瘤坏死因子-α，丙二醛，4-羟基壬烯醛，蛋白质羰基形成，3-硝基酪氨酸蛋白加合物，诱导型一氧化氮合酶的水平增加，在乔2加乙醇组。与表达CYP 2 E1的野生型小鼠相比，在CYP 2 E1敲除小鼠中，Jo 2加乙醇的增强的肝毒性和升高的氧化应激和TNF水平较低，但高于盐水对照。用氯化钆（一种诱导型一氧化氮合酶的抑制剂）或抗氧化剂N-乙酰-L-半胱氨酸治疗的小鼠的毒性也有所下降。这些数据表明，急性乙醇预处理能够提高肝细胞凋亡和肝损伤诱导的Jo 2 Fas激动性抗体。肝毒性增强涉及氧化和亚硝化应激增加，似乎是由CYP 2 E1依赖性和非依赖性机制介导的。(c)2007年爱思唯尔公司All rights reserved.
This study evaluated whether acute ethanol pretreatment potentiates Fas-mediated liver injury and if oxidative stress and CYP2E1 play a role in any enhanced hepatotoxicity. There were 3-fold increases of transaminases and more extensive apoptotic necrosis of hepatocytes and focal hemorrhages of the hepatic lobule in mice treated with Jo2 Fas agonistic antibody plus ethanol compared to saline control or to mice treated with Jo2 or ethanol alone. CYP2E1 catalytic activity and protein were increased 2-fold by the acute ethanol pretreatment. There were 2- and 2.5-fold increases of caspase-8 and caspase-3 activity and 1.6-fold increases of apoptotic-positive cells in the Jo2 plus acute ethanol group compared to the Jo2 alone group. Levels of TNF-alpha, malondialdehyde, 4-hydroxynonenal, protein carbonyl formation, 3-nitrotyrosine protein adducts, and inducible nitric oxide synthase were increased in the Jo2 plus ethanol group. The enhanced hepatotoxicity of Jo2 plus ethanol and the elevated oxidative stress and TNF levels were lower in CYP2E1 knockout mice compared to wild-type mice expressing CYP2E1 but higher than saline controls. Toxicity also declined in mice treated with gadolinium chloride, an inhibitor of the inducible nitric oxide synthase or the antioxidant, Nacetyl-L-cysteine. These data indicate that acute ethanol pretreatment is capable of elevating hepatic apoptosis and liver injury induced by Jo2 Fas agonistic antibody. The enhanced hepatotoxicity involves increased oxidative and nitrosative stress, and appears to be mediated by CYP2E1-dependent and also CYP2E1-independent mechanisms. (c) 2007 Elsevier Inc. All rights reserved.