Factors involved in hepatic glutathione depletion induced by acute ethanoladministration

Factors implicated in changes of the hepatic glutathione concentration foll owing acute ethanol administration were examined in rats. Adult female rats were treated with either ethanol (4 g/kg, po) or an isocaloric glucose sol ution. The hepatic reduced glutathione (GSH) concentration decreased rapidl y after ethanol intake with a maximum diminution, approximately 50% of the control value, being observed at t = 6 h. The hepatic GSH concentration gra dually increased, and finally rebounded at 24 h after ethanol ingestion. Th e dose of ethanol induced a transient increase in the oxidized glutathione (GSSG) and GSSG/GSH ratio, which was associated with a significant reductio n in GSH rather t han elevation in GSSG. The activity of gamma-glutamylcyst eine synthetase (GCS), the rate-limiting enzyme for glutathione synthesis, and the cysteine concentration in liver were also measured. The GCS activit y was depressed to approximately 80% of the control value at t = 2.5 h foll owed by rapid recovery, but no difference in the hepatic cysteine concentra tion between control and ethanol treated rats was observed for 24 h, sugges ting that the reduction in glutathione synthesis may not play a major role in the significant depletion of this tripeptide in liver. The total glutath ione concentration was measured both in prehepatic and posthepatic inferior vena cava blood. The glutathione concentration in posthepatic blood was ap proximately twice as high as that of prehepatic blood in control rats. Acut e ethanol administration doubled the elevation of glutathione in posthepati c blood measured at t = 2.5 h. The sinusoidal efflux of glutathione estimat ed from the increase in blood glutathione concentration was greater than th e total amount of its depletion in the liver of rats treated with ethanol. The results suggest that in the liver of rats treated acutely with ethanol, glutathione efflux plays the most important role in the reduction of this tripeptide, which would be aggravated by a transient decrease in glutathion e synthesis and by increased consumption in association with its metabolism .