Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor

Gastroenterology. 1998 Dec;115(6):1541-51. doi: 10.1016/s0016-5085(98)70034-4.


Background & aims: Tumor necrosis factor (TNF)-alpha induces cell injury by generating oxidative stress from mitochondria. The purpose of this study was to determine the effect of ethanol on the sensitization of hepatocytes to TNF-alpha.

Methods: Cultured hepatocytes from ethanol-fed (ethanol hepatocytes) or pair-fed (control hepatocytes) rats were exposed to TNF-alpha, and the extent of oxidative stress, gene expression, and viability were evaluated.

Results: Ethanol hepatocytes, which develop a selective deficiency of mitochondrial glutathione (mGSH), showed marked susceptibility to TNF-alpha. The susceptibility to TNF-alpha, manifested as necrosis rather than apoptosis, was accompanied by a progressive increase in hydrogen peroxide that correlated inversely with cell survival. Nuclear factor kappaB activation by TNF-alpha was significantly greater in ethanol hepatocytes than in control hepatocytes, an effect paralleled by the expression of cytokine-induced neutrophil chemoattractant. Similar sensitization of normal hepatocytes to TNF-alpha was obtained by depleting the mitochondrial pool of GSH with 3-hydroxyl-4-pentenoate. Restoration of mGSH by S-adenosyl-L-methionine or by GSH-ethyl ester prevented the increased susceptibility of ethanol hepatocytes to TNF-alpha.

Conclusions: These results indicate that mGSH controls the fate of hepatocytes in response to TNF-alpha. Its depletion caused by alcohol consumption amplifies the power of TNF-alpha to generate reactive oxygen species, compromising mitochondrial and cellular functions that culminate in cell death.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Ethanol / metabolism*
  • Glutathione / metabolism*
  • Liver / cytology*
  • Liver / drug effects
  • Liver / physiology*
  • Male
  • Mitochondria / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • S-Adenosylmethionine / pharmacology
  • Time Factors
  • Tumor Necrosis Factor-alpha / physiology*


  • Tumor Necrosis Factor-alpha
  • Ethanol
  • S-Adenosylmethionine
  • Glutathione