title: Mitochondrial oxidative stress and CD95 ligand: a dual mechanism for hepatocyte apoptosis in chronic alcoholism.
abstract: Apoptosis plays an important role in the progression of alcohol-induced liver disease to cirrhosis. Oxidative stress is an early event in the development of apoptosis. The major aim of this study was to study the conditions in which oxidative stress occurs in chronic alcoholism and its relationship with apoptosis of hepatocytes. We have found that oxidative stress is associated with chronic ethanol consumption in humans and in rats, in the former independently of the existence of alcohol-induced liver disease. Ethanol or acetaldehyde induces apoptosis in hepatocytes isolated from alcoholic rats, but not in those from control rats. Inhibition of aldehyde dehydrogenase, but not of cytochrome P450 2E1, prevents ethanol-induced cell death. Ethanol-induced apoptosis is caused by increased reactive oxygen species (ROS) driven by increased availability of the reduced form of nicotinamide-adenine dinucleotide (NADH) owing to mitochondrial acetaldehyde metabolism and it is prevented by blocking the opening of mitochondrial permeability transition (MPT) pores with cyclosporine A. Inhibition of nitric oxide (NO) synthase or addition of antioxidant vitamins C and E completely prevented ethanol-induced apoptosis. Mitochondrial oxidative stress, which occurs during chronic alcoholism, renders hepatocytes susceptible to apoptosis. On the other hand, the CD95 ligand expression was up-regulated by acetaldehyde. In conclusion, ethanol induces apoptosis via 2 different pathways: MPT and up-regulation of the expression of CD95-Fas ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabolism, is a common trigger of both mechanisms.
authors: Departamento de Fisiología, Facultad de Medicina, Universitat de València, Valencia, Spain.
authors: Juan B
authors: JB
authors: Miñana
authors: Luis
authors: L
authors: Gómez-Cambronero
authors: Ana
authors: A
authors: Lloret
authors: Federico V
authors: FV
authors: Pallardó
authors: Juan
authors: J
authors: Del Olmo
authors: Amparo
authors: A
authors: Escudero
authors: José M
authors: JM
authors: Rodrigo
authors: Antonio
authors: A
authors: Pellíin
authors: Juan R
authors: JR
authors: Viña
authors: José
authors: J
authors: Viña
authors: Juan
authors: J
authors: Sastre
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology; D000437:Alcoholism / Q000378:metabolism* / Q000473:pathology; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D053222:Fas Ligand Protein; D005215:Fasting / Q000502:physiology; D019803:Glutathione Disulfide / Q000097:blood; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D010545:Peroxides / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D002492:Central Nervous System Depressants; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D010545:Peroxides; D017382:Reactive Oxygen Species; D009243:NAD; D009569:Nitric Oxide; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D000444:Aldehyde Dehydrogenase; D000079:Acetaldehyde; D019803:Glutathione Disulfide