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

AutorColell Riera, Anna ; García-Ruiz, Carmen ; Miranda, Merge; Ardite, Esther; Marí, Montserrat ; Morales, Albert ; Corrales, Fernando J.; Kaplowitz, Neil; Fernández-Checa, José C.
Fecha de publicación1998
EditorW.B. Saunders
CitaciónGastroenterology 115(6): 1541-1551 (1998)
ResumenBackground and Aims: Tumor necrosis factor (TNF)-α 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-α. Methods: Cultured hepatocytes from ethanol-fed (ethanol hepatocytes) or pair-fed (control hepatocytes) rats were exposed to TNF-α, 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-α. The susceptibility to TNF-α, manifested as necrosis rather than apoptosis, was accompanied by a progressive increase in hydrogen peroxide that correlated inversely with cell survival. Nuclear factor κB activation by TNF-α 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-α 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- α. Conclusions: These results indicate that mGSH controls the fate of hepatocytes in response to TNF-α. Its depletion caused by alcohol consumption amplifies the power of TNF-α to generate reactive oxygen species, compromising mitochondrial and cellular functions that culminate in cell death.
URIhttp://hdl.handle.net/10261/111820
Identificadoresissn: 0016-5085
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