Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-alpha.
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-kappaB 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 NH(2)-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.
Liu
Hailing
H
Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461, USA.
Jones
Brett E
BE
Bradham
Cynthia
C
Czaja
Mark J
MJ
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002460:Cell Line; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology* / Q000201:enzymology; D048031:JNK Mitogen-Activated Protein Kinases; D008107:Liver Diseases / Q000378:metabolism / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D000970:Antineoplastic Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019392:Cytochrome P-450 CYP2E1; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D005978:Glutathione