Glutathione modulates rat and mouse hepatocyte sensitivity to tumor necrosis factor α toxicity

Y. Xu, B. E. Jones, David S. Neufeld, M. J. Czaja

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Background and Aims: Tumor necrosis factor (TNF)-α causes much of the hepatocellular injury and cell death that follows toxin-induced liver damage. The mechanism by which toxic liver injury sensitizes hepatocytes to TNF-α cytotoxicity is unknown. The aim of this study was to determine the role of the antioxidant glutathione in this process. Methods: A rat hepatocyte cell line and primary hepatocytes sensitized to TNF-α toxicity by the addition of actinomycin D were examined for changes in glutathione levels and for the effects of glutathione depletion or supplementation on cell death. The in vivo effects of glutathione depletion were determined in mice treated with galactosamine plus lipopolysaccharide. Results: Treatment of hepatocytes with actinomycin D and TNF-α induced apoptotic cell death without affecting cellular glutathione levels or production of the reactive oxygen intermediate H2O2. Glutathione depletion induced by diethyl maleic acid significantly increased TNF-α-induced cell death even when this agent was administered 2 hours after TNF-α treatment. Hepatocyte cell death was not affected by glutathione supplementation. In mice treated with galactosamine plus lipopolysaccharide, glutathione depletion increased mortality from liver injury from 32% to 72%. Conclusions: TNF-α-induced cytotoxicity in hepatocytes occurs in the absence of glutathione depletion. However, a preexisting reduction in glutathione levels can significantly increase cell death from TNF-α.

Original languageEnglish (US)
Pages (from-to)1229-1237
Number of pages9
JournalGastroenterology
Volume115
Issue number5
DOIs
StatePublished - 1998

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Glutathione
Hepatocytes
Tumor Necrosis Factor-alpha
Cell Death
Galactosamine
Dactinomycin
Lipopolysaccharides
Liver
Wounds and Injuries
Poisons
Antioxidants
Oxygen
Cell Line
Mortality

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Glutathione modulates rat and mouse hepatocyte sensitivity to tumor necrosis factor α toxicity. / Xu, Y.; Jones, B. E.; Neufeld, David S.; Czaja, M. J.

In: Gastroenterology, Vol. 115, No. 5, 1998, p. 1229-1237.

Research output: Contribution to journalArticle

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AU - Czaja, M. J.

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