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

Hailing Liu, Brett E. Jones, Cynthia Bradham, Mark J. Czaja

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The mechanisms underlying hepatocyte sensitization to tumor necrosis factor-α (TNF-α)-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-α death. TNF-α treatment of hepatocyte cell lines with differential CYP2E1 expression demonstrated that overexpression of CYP2E1 converted the hepatocyte TNF-α response from proliferation to apoptotic and necrotic cell death. Death occurred despite the presence of increased levels of nuclear factor-κB transcriptional activity and was associated with increased lipid peroxidation and GSH depletion. CYP2E1-overexpressing hepatocytes had increased basal and TNF-α-induced levels of c-Jun NH2-terminal kinase (JNK) activity, as well as prolonged JNK activation after TNF-α stimulation. Sensitization to TNF-α-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-α 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-α toxicity in liver disease.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume282
Issue number2 45-2
StatePublished - 2002

Fingerprint

Cytochrome P-450 Enzyme System
Hepatocytes
Cell Death
Tumor Necrosis Factor-alpha
JNK Mitogen-Activated Protein Kinases
Oxidants
Lipid Peroxidation
Liver Diseases
Oxidative Stress
Antioxidants
Cell Line
Liver

Keywords

  • Apoptosis
  • c-Jun NH-terminal kinase
  • Glutathione
  • Necrosis
  • Nuclear factor-κB

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology

Cite this

Increased cytochrome P-450 2E1 expression sensitizes hepatocytes to c-Jun-mediated cell death from TNF-α. / Liu, Hailing; Jones, Brett E.; Bradham, Cynthia; Czaja, Mark J.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 282, No. 2 45-2, 2002.

Research output: Contribution to journalArticle

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