title: Synergistic toxic interactions between CYP2E1, LPS/TNFα, and JNK/p38 MAP kinase and their implications in alcohol-induced liver injury.
abstract: The mechanisms by which alcohol causes cell injury are not clear. 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, associations and interactions between them, especially in vivo, have not been extensively evaluated. We have shown that increased oxidative stress from induction of CYP2E1 in vivo sensitizes hepatocytes to LPS and TNFα toxicity and that oxidative stress, activation of p38 and JNK MAP kinases, and mitochondrial dysfunction are downstream mediators of this CYP2E1-LPS/TNFα potentiated hepatotoxicity. This Review 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 as a result of CYP2E1-derived reactive oxygen intermediates promoting dissociation of the inhibitory thioredoxin from ASK-1. This activation of ASK-1 is followed by activation of the mitogen-activated kinase kinases MKK3/MKK6 and MKK4/MMK7 and subsequently p38 and JNK MAP kinases. Synergistic toxicity occurs between CYP2E1 and the JNK1 but not the JNK2 isoform as JNK1 knockout mice are completely protected against CYP2E1 plus TNFα toxicity, elevated oxidative stress, and mitochondrial dysfunction. We hypothesize that similar interactions occur as a result of ethanol induction of CYP2E1 and TNFα.
authors.affiliation: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, Box 1603, One Gustave L. Levy Place, New York, NY, 10029, USA, arthur.cederbaum@mssm.edu.
authors.forename: Arthur I
authors.initials: AI
authors.lastname: Cederbaum
authors.forename: Yongke
authors.initials: Y
authors.lastname: Lu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Wang
authors.forename: Defeng
authors.initials: D
authors.lastname: Wu
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008108:Liver Diseases, Alcoholic / Q000209:etiology*; D048848:MAP Kinase Kinase Kinase 5 / Q000502:physiology; D011720:Pyrazoles / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: D008070:Lipopolysaccharides; D011720:Pyrazoles; D014409:Tumor Necrosis Factor-alpha; C031280:pyrazole; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5