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Am J Physiol Gastrointest Liver Physiol 282: G257-G266, 2002. First published October 24, 2001; doi:10.1152/ajpgi.00304.2001
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Vol. 282, Issue 2, G257-G266, February 2002

Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-alpha

Hailing Liu1, Brett E. Jones1, Cynthia Bradham2, and Mark J. Czaja1

1 Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461; and 2 Department of Medicine and Department of Biochemistry and Biophysics, Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina 27599

The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-alpha (TNF-alpha )-mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as those that occur with hepatic overexpression of cytochrome P-450 2E1 (CYP2E1) may promote TNF-alpha death. TNF-alpha treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-alpha response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-kappa B transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-alpha -induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-alpha stimulation. Sensitization to TNF-alpha -induced cell death by CYP2E1 overexpression was inhibited by antioxidants or adenoviral expression of a dominant-negative c-Jun. Increased CYP2E1 expression sensitized hepatocytes to TNF-alpha toxicity mediated by c-Jun and overwhelming oxidative stress. The chronic increase in intracellular oxidant stress created by CYP2E1 overexpression may serve as a mechanism by which hepatocytes are sensitized to TNF-alpha toxicity in liver disease.

nuclear factor-kappa B; glutathione; apoptosis; necrosis; c-Jun NH2-terminal kinase


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