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RESEARCH PRODUCT

The Relationship between Alcohol–induced Apoptosis and Oxidative Stress in the Liver

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This chapter discusses the relationship of apoptosis and oxidative stress induced by alcohol in the liver. Oxidative stress is involved in the pathogenesis and progression of alcohol-induced liver disease. Chronic alcoholism always causes oxidative stress independently of the presence of liver disease. Two key mechanisms are responsible for it: (1) the mitochondrial respiratory chain and (2) cytochrome P450 2El activity. Increased production of reactive oxygen species at complexes I and III together with NADH overproduction would be the major cause for mitochondrial oxidative stress in chronic alcoholism. Reactive Oxygen Species (ROS) cause oxidative damage, which may lead to cell death by necrosis, but also triggers and regulates the apoptosis signaling pathways. A dual mechanism seems to be involved in the ethanol-induced apoptosis: NADH-driven mitochondrial oxidative stress and CD95-mediated apoptosis triggered by the CD95 ligand. The overproduction of ROS by mitochondria, driven by acetaldehyde metabo- lism, is a common trigger of both mechanisms. Repetitive treatment with concentrations of ethanol or acetaldehyde compatible to those reported in plasma of alcoholic subjects causes apoptosis in hepatocytes from alcoholic rats, but not in those from control rats. Mitochondrial oxidative stress renders hepatocytes susceptible to ethanol- or acetaldehyde-induced mitochondrial permeability transition and apoptosis.