Mitochondrial glutathione depletion in alcoholic liver disease.
Alcoholic liver disease (ALD) is one the most serious consequences of chronic alcohol abuse. Liver cirrhosis, the culmination of the illness, is one of the leading causes of death in Western countries. Mitochondria are a target of ethanol intoxication mainly due to the toxic effects of acetaldehyde, a byproduct of ethanol metabolism. Morphological and functional changes in mitochondria are one of the key hallmarks of chronic ethanol exposure in both chronic alcoholics and experimental models of alcoholism. The functional changes observed in mitochondria from ethanol-treated animals are translated in an overall decrease in ATP levels resulting from a lower rate of ATP synthesis as a consequence of impaired processing at the translational level of some components of oxidative phosphorylation encoded by mitochondrial DNA genome. Mitochondrial glutathione (GSH) plays a critical role in the maintenance of cell functions and viability and in mitochondrial physiology by metabolism of oxygen free radicals generated in the respiratory chain. GSH in mitochondria originates from cytosol by a transport system which translocates GSH into the matrix. This transport system is impaired in chronic ethanol-fed rats, which translates in a selective and significant depletion of the mitochondrial GSH content resulting in the development of an increased susceptibility to oxidant stress. Using the intragastric infusion model of experimental ALD in rats, the profound and selective mitochondrial GSH depletion precedes the onset of alcoholic liver disease, mitochondrial lipid peroxidation, and progression of liver damage.(ABSTRACT TRUNCATED AT 250 WORDS)
Fernández-Checa
J C
JC
Division of Gastrointestinal and Liver Diseases, University of Southern California School of Medicine, Los Angeles.
Hirano
T
T
Tsukamoto
H
H
Kaplowitz
N
N
D000435:Alcoholic Intoxication / Q000503:physiopathology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D000431:Ethanol / Q000494:pharmacology; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism* / Q000502:physiology; D010085:Oxidative Phosphorylation / Q000187:drug effects
D000431:Ethanol; D005978:Glutathione