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. (18th October 2011)

• Record Type: Journal Article
• Authors: Cederbaum, Arthur I.; Yang, Lili; Wang, Xiaodong; Wu, Defeng
• Other Names: Kharbanda Kusum Academic Editor.
• Is Part Of: International journal of hepatology. Volume 2012(2012)
• Publication Date: 2011-10-18
• Subjects: Hepatology -- Periodicals; Liver Diseases; Gastroenterology; Hepatology; Electronic journals; Periodicals; Periodicals; Fulltext; Internet Resources; Periodicals; 616.3
• DOI: 10.1155/2012/582790
• Languages: English
• ISSNs: 2090-3448

Abstract

Abstract : 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 TNF α 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 TNF α 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/TNF α -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 TNF α .