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Gastroenterology. 1998 Dec;115(6):1541-51.

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

Author information

1
Liver Unit, Department of Medicine, Hospital Clinic i Provincial and Instituto Investigaciones Biomédicas, Consejo Superior Investigaciones Cientificas, Barcelona, Spain.

Abstract

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.

PMID:
9834283
DOI:
10.1016/s0016-5085(98)70034-4
[Indexed for MEDLINE]

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