Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor |
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Authors: | Anna Colell,Carmen Garcí a-Ruiz,Merce Miranda,Esther Ardite,Montse Marí ,Albert Morales,Fernando Corrales,Neil Kaplowitz,José C. Ferná ndez-Checa |
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Affiliation: | *Liver Unit, Department of Medicine, Hospital Clinic i Provincial and Instituto Investigaciones Biomédicas, Consejo Superior Investigaciones Cientificas, Barcelona, Spain;‡Division of Hepatology and Gene Therapy, Department of Medicine, University of Navarra, Pamplona, Spain;§Center for Liver Disease Research, University of Southern California School of Medicine, Los Angeles, California |
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Abstract: | Background & 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.GASTROENTEROLOGY 1998;115:1541-1551 |
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Keywords: | Abbreviations: ALD, alcoholic liver disease BHT, butylated hydroxytoluene CINC, cytokine-induced neutrophil chemoattractant DCFDA, 2',7'-dichlorofluorescindiacetate DCF, 2',7'-dichlorofluorescein diacetate GSH, glutathione GSH-EE, GSH&ndash ethyl ester GST, glutathione S-transferase HP, (R,S)-3-hydroxy-4-pentenoate MAT, methionine adenosyl transferase NAC, N-acetylcysteine NF-κB, nuclear factor κB ROS, reactive oxygen species SAH, S-adenosyl-homocysteine SAM, S-adenosyl- font-variant: small-caps" >L-methionine TNF-α, tumor necrosis factor α |
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