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TNF-\u03b1 treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-\u03b1 response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-\u03baB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-\u03b1-induced levels of c-Jun NH<jats:sub>2<\/jats:sub>-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-\u03b1 stimulation. Sensitization to TNF-\u03b1-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-\u03b1 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-\u03b1 toxicity in liver disease.<\/jats:p>","DOI":"10.1152\/ajpgi.00304.2001","type":"journal-article","created":{"date-parts":[[2015,3,3]],"date-time":"2015-03-03T19:55:03Z","timestamp":1425412503000},"page":"G257-G266","source":"Crossref","is-referenced-by-count":65,"title":["Increased cytochrome<i>P<\/i>-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-\u03b1"],"prefix":"10.1152","volume":"282","author":[{"given":"Hailing","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Medicine, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York 10461; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brett E.","family":"Jones","sequence":"additional","affiliation":[{"name":"Department of Medicine, Marion Bessin Liver Research Center, 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