S-Adenosyl-L-methionine and mitochondrial reduced glutathione depletion in alcoholic liver disease.
The pathogenesis of alcohol-induced liver disease is not well understood, and many factors have been described to contribute to the progressive loss of liver functions, including the overgeneration of reactive oxygen species. Mitochondria are specific targets of the toxic effects of ethanol, reflected in the loss of phosphorylative oxidation and defective ATP generation, which underlie one of the hallmarks of the hepatic alterations induced by chronic alcohol intake. Mitochondrial reduced glutathione (GSH), whose primary function is to maintain a competitive functional organelle, becomes depleted by alcohol intake. Furthermore, GSH depletion in hepatocyte mitochondria has been revealed as an important mechanism in the sensitization of liver to alcohol-induced injury. This depletion of the mitochondrial GSH level is determined by an impaired transport of GSH from the cytosol into the mitochondrial matrix owing to a partial inactivation of mitochondrial GSH carrier. The loss of function of this specific mitochondrial transporter is due to the alterations in the physicochemical properties of the inner mitochondrial membrane caused by alcohol. Because of the primary defect in the transport of cytosolic GSH into mitochondria, GSH precursors are inefficient in replenishing the levels of mitochondrial GSH despite significant increase in cytosolic GSH. Supplementation of S-adenosyl-L-methionine (SAM) to rats fed alcohol chronically has been shown to replete the mitochondrial GSH levels because of normalization of the microviscosity of the mitochondrial inner membrane. Because of the instrumental role of GSH in mitochondria in hepatocyte survival against inflammatory cytokines, its repletion by SAM feeding may underlie the potential therapeutic use of this hepatoprotective agent in the treatment of alcohol-induced liver injury.
Fernández-Checa
José C
JC
Liver Unit, Hospital Clinic I Provincial, 08036 Barcelona, Spain. checa@medicina.ub.es
Colell
Anna
A
García-Ruiz
Carmen
C
D000818:Animals; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000172:deficiency* / Q000378:metabolism
D012436:S-Adenosylmethionine; D005978:Glutathione