Ethanol suppresses hepatic glutathione synthesis in rats in vivo.
Ethanol-induced depletion of hepatic glutathione has been construed as evidence supporting the hypothesis that reactive oxygen intermediates generated during the metabolism of ethanol lead to glutathione oxidation and lipid peroxidation and are responsible for the toxic effects of ethanol. However, the evidence for a pathogenetic role of lipid peroxidation in ethanol-induced liver injury is indirect and a decreased synthesis might well account for the glutathione depletion produced by large doses of ethanol. In order to determine whether a decreased synthesis or an increased consumption of glutathione is responsible for the ethanol-induced glutathione depletion, hepatic glutathione turnover, plasma glutathione and the biliary excretion of glutathione and its disulfide were measured in rats. The administration of 5 g/kg of ethanol p.o. resulted in a decreased incorporation of labeled cysteine and labeled methionine into the hepatic glutathione pool and decreased the hepatic concentration of glutathione from 3.7 +/- 0.1 to 2.7 +/- 0.2 mumol/g. Kinetic analysis of the specific activity-time curves revealed that ethanol decreased significantly the rate of influx of cysteine into the glutathione pool but did not stimulate the rate of consumption of glutathione. Moreover, the plasma concentration of glutathione and the biliary excretion of glutathione disulfide and reduced glutathione decreased after the administration of ethanol, indicating that ethanol does not increase the efflux of glutathione from the liver. Our data demonstrate that a large dose of ethanol does not produce an oxidative stress, which would increase glutathione consumption, but rather impairs glutathione synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D003545:Cysteine / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000096:biosynthesis* / Q000378:metabolism; D019803:Glutathione Disulfide; D007700:Kinetics; D008054:Lipid Peroxides / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors
D008054:Lipid Peroxides; D000431:Ethanol; D005978:Glutathione; D003545:Cysteine; D019803:Glutathione Disulfide