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Synergistic Toxic Interactions Between CYP2E1, LPS/TNFα, and JNK/p38 MAP Kinase and Their Implications in Alcohol-Induced Liver Injury

  • Arthur I. Cederbaum
  • Yongke Lu
  • Xiaodong Wang
  • Defeng Wu
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 815)

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.

Keywords

Alcohol liver injury CYP2E1-dependent toxicity Lipopolysaccharide–CYP2E1 interactions Oxidative stress and liver injury CYP2E1-tumor necrosis factor alpha toxicity JNK and p38 mitogen-activated kinases Mitochondrial dysfunction 

Notes

Acknowledgement

Studies from the author’s lab were supported by USPHS grants RO1 AA 018790 and R21 AA 021362 from The National Institute on Alcohol Abuse and Alcoholism.

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Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Arthur I. Cederbaum
    • 1
  • Yongke Lu
    • 1
  • Xiaodong Wang
    • 1
  • Defeng Wu
    • 1
  1. 1.Department of Pharmacology and Systems TherapeuticsMount Sinai School of MedicineNew YorkUSA

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