Effect of salicylates and phenobarbital on hepatic glutathione in the rat.
Phenobarbital and salicylates were shown to have opposite effects on hepatic glutathione. Phenobarbital increased glutathione concentration by approximately 20 to 30%. This increase occurred within 48 hr and could be attributed almost exclusively to an increase in bound glutathione. No changes in ATP, substrate amino acids for glutathione synthesis or the level of gamma-glutamylcysteine synthetase, the rate limiting enzymatic step in glutathione synthesis, were found with phenobarbital. Phenobarbital, which induces hepatic proteins that bind glutathione, increased bound glutathione but did not affect unbound glutathione. Therefore, the concentration of the latter probably regulates glutathione synthesis. Salicylates (aspirin and sodium salicylate) were found to deplete hepatic glutathione in both saline- and phenobarbital-treated rats. Maximum depletion (approximately 40%) was seen 4 to 6 hr after salicylate administration and returned toward the control level by 12 hr. The salicylate effect was not related to a change in gamma-glutamylcysteine synthetase, gamma-glutamyl transpeptidase or the concentrations of free hepatic glycine, glutamate, cysteine and methionine. An increase in concentration of glutathione both in vivo in plasma from salicylate-treated rats and in vitro in buffer from the incubation of liver slices with salicylate suggests that glutathione leakage from hepatocytes is an important factor in salicylate-induced hepatic glutathione depletion.
D000596:Amino Acids / Q000032:analysis; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D005978:Glutathione / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D008099:Liver / Q000032:analysis* / Q000201:enzymology / Q000378:metabolism; D008297:Male; D010453:Peptide Synthases / Q000032:analysis; D010458:Peptidyl Transferases / Q000032:analysis; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D012459:Salicylates / Q000097:blood / Q000494:pharmacology*; D013997:Time Factors
D000596:Amino Acids; D012459:Salicylates; D010458:Peptidyl Transferases; D010453:Peptide Synthases; D005978:Glutathione; D010634:Phenobarbital