CYP2E1 Sensitizes the Liver to LPS- and TNF α-Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of ASK-1 and JNK Mitogen-Activated Kinases.
CYP2E1 Sensitizes the Liver to LPS- and TNF α-Induced Toxicity via Elevated Oxidative and Nitrosative Stress and Activation of ASK-1 and JNK Mitogen-Activated Kinases.
复制标题
DOI：
10.1155/2012/582790
复制
发表时间：
2012
影响因子：
1.8
通讯作者：
Wu D
中科院分区：
文献类型：
--
作者：
Cederbaum AI;Yang L;Wang X;Wu D
酒精导致细胞损伤的机制尚不清楚。一个主要的机制是脂质过氧化和氧化应激在酒精中毒中的作用。许多途径被认为在酒精如何诱导氧化应激中发挥作用。酒精促进脂多糖和肿瘤坏死因子α的产生以及酒精对细胞色素P450的诱导作用已经引起了人们的广泛关注。这两条道路并不是相互排斥的；然而，它们之间的互动并没有得到广泛的评估。由诱导产生的氧化应激增加了肝细胞对脂多糖和肿瘤坏死因子α毒性的敏感性，而氧化剂、诱导型一氧化氮合酶、p38和JNKMAP的激活以及线粒体功能障碍是这种由细胞色素P450-E1LPS/肿瘤坏死因子α增强的肝毒性的下游介质。本文将对这两种危险因素在促进肝损伤中的相互作用及其机制进行综述，包括丝裂原激活的激酶ASK-1的激活。通过ASK-1/JNK依赖的机制，在表达CYP2E1的HepG2细胞中减少胞浆或线粒体硫氧还蛋白会导致细胞活力的丧失和氧化应激的增加。我们假设乙醇诱导细胞色素P450_2和肿瘤坏死因子α发生类似的相互作用。
The mechanisms by which alcohol causes cell injury are not clear. A major mechanism is the role of lipid peroxidation and oxidative stress in alcohol toxicity. Many pathways have been suggested to play a role in how alcohol induces oxidative stress. Considerable attention has been given to alcohol elevated production of lipopolysaccharide (LPS) and TNFα and to alcohol induction of CYP2E1. These two pathways are not exclusive of each other; however, interactions between them, have not been extensively evaluated. Increased oxidative stress from induction of CYP2E1 sensitizes hepatocytes to LPS and TNFα toxicity and oxidants, activation of inducible nitric oxide synthase and p38 and JNK MAP kinases, and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNFα-potentiated hepatotoxicity. This paper will summarize studies showing potentiated interactions between these two risk factors in promoting liver injury and the mechanisms involved including activation of the mitogen-activated kinase kinase kinase ASK-1. Decreasing either cytosolic or mitochondrial thioredoxin in HepG2 cells expressing CYP2E1 causes loss of cell viability and elevated oxidative stress via an ASK-1/JNK-dependent mechanism. We hypothesize that similar interactions occur as a result of ethanol induction of CYP2E1 and TNFα.