Reduction by acetylsalicylic acid of paracetamol-induced hepatic glutathione depletion in rats treated with 4,4'-dichlorobiphenyl, phenobarbitone and pregnenolone-16-alpha-carbonitrile.
The role of enzyme induction in the reduction by acetylsalicylic acid (ASA) of paracetamol-induced hepatic glutathione (GSH) depletion has been studied in rats. Administration of an overdose of paracetamol to control rats resulted in an appreciable decrease of GSH concentration. Pretreatment with the enzyme inducers phenobarbitone, 3-methylcholanthrene (3-MC), pregnenolone-16-alpha-carbonitrile (PCN) and 4,4'-dichlorobiphenyl (4,4'-DCB) significantly potentiated the paracetamol-induced depletion of GSH. Simultaneous administration of an equimolar dose of ASA resulted in a reduction of the paracetamol-induced depletion of GSH in all instances except for those rats that were not pretreated and those given 3-MC. Benorylate, the ASA ester of paracetamol, depressed rat liver GSH to levels comparable to those produced by the combination of paracetamol and ASA. ASA itself caused only minor changes in liver GSH concentrations. The results demonstrate that ASA causes a diminution of paracetamol-induced GSH depletion in rats with phenobarbitone type of enzyme induction. Inhibition of the formation of the reactive metabolite of paracetamol or reduction of the absorption rate of paracetamol seem to be unlikely as mechanisms underlying the ASA-induced effect. An ASA-mediated effect via changes of the hepatic thiol status is proposed.
van Bree
L
L
Department of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Groot
E J
EJ
De Vries
J
J
D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D001241:Aspirin / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D005753:Gastric Mucosa / Q000187:drug effects / Q000201:enzymology; D005978:Glutathione / Q000378:metabolism*; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D010634:Phenobarbital / Q000494:pharmacology; D011078:Polychlorinated Biphenyls / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012459:Salicylates / Q000494:pharmacology
D012459:Salicylates; D011285:Pregnenolone Carbonitrile; D000082:Acetaminophen; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; C029861:4,4'-dichlorobiphenyl; D005978:Glutathione; D001241:Aspirin; D010634:Phenobarbital