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Articles in PresS, published online ahead of print October 24, 2001
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00304.2001
Submitted on July 9, 2001
Accepted on October 17, 2001
1 Department of Medicine and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
2 Departments of Medicine and Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC, USA
* To whom correspondence should be addressed. E-mail: CZAJA{at}AECOM.YU.EDU, caponigr@aecom.yu.edu.
The mechanisms that underlie hepatocyte sensitization to TNF--mediated cell death remain unclear. Increases in hepatocellular oxidant stress such as occur with hepatic overexpression of cytochrome P450 2E1 (CYP2E1) may promote TNF- death. TNF- treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF- response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of NF-
B transcriptional activity, and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal, and TNF--induced levels of c-Jun N-terminal kinase (JNK) activity, as well as a prolongation of JNK activation after TNF- stimulation. Sensitization to TNF--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- 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- toxicity in liver disease.
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