Pathogenesis of alcoholic liver disease with particular emphasis on oxidative stress

Abstract

Oxidative stress is well recognized to be a key step in the pathogenesis of ethanol‐associated liver injury. Ethanol administration induces an increase in lipid peroxidation either by enhancing the production of oxygen reactive species and/or by decreasing the level of endogenous antioxidants. Numerous experimental studies have emphasized the role of the ethanol‐inducible cytochrome P450 in the microsomes and the molybdo‐flavoenzyme xanthine oxidase in the cytosol. This review shows the putative role of ethanol‐induced disturbances in iron metabolism in relation to iron as a pro‐oxidant factor. Ethanol administration also affects the mitochondrial free radical generation. Many previous studies suggest a role for active oxygens in ethanol‐induced mitochondrial dysfunction in hepatocytes. Recent studies in our laboratory in the Department of Internal Medicine, Keio University, using a confocal laser scanning microscopic system strongly suggest that active oxidants generated during ethanol metabolism produce mitochondrial membrane permeability transition in isolated and cultured hepatocytes. In addition, acetaldehyde, ethanol consumption‐associated endotoxaemia and subsequent release of inflammatory mediators may cause hepatocyte injury via both oxyradical‐dependent and ‐independent mechanisms. These cytotoxic processes may lead to lethal hepatocyte injury. Investigations further implicate the endogenous glutathione—glutathione peroxidase system and catalase as important antioxidants and cytoprotective machinery in the hepatocytes exposed to ethanol.