Effects of esterase inhibitors and buthionine sulfoximine on the prevention of acetaminophen hepatotoxicity by N-acetylcysteine.
Mice poisoned with acetaminophen were treated with esterase inhibitors, buthionine sulfoximine, and N-acetyl-L-lysine in experiments designed to explore the mechanism of N-acetylcysteine protection in vivo. Three esterase inhibitors, phenylmethylsulfonyl fluoride, bis-(p-nitrophenyl)-phosphate, and diisopropylfluorophosphate, had no effect on the antidote effectiveness of N-acetylcysteine, although each provided partial protection against acetaminophen poisoning. Buthionine sulfoximine, a specific inhibitor of gamma-glutamyl cysteine synthetase, antagonized the antidote effect of N-acetylcysteine. Acetaminophen-induced hepatotoxicity, as measured by plasma alanine aminotransferase activity, and mortality failed to decline, consistent with stimulation of glutathione synthesis as the primary mechanism of antidote protection. N-Acetyl-L-lysine was given at doses up to ten-fold higher than N-acetylcysteine yet had no effect on acetaminophen hepatotoxicity or its prevention by N-acetylcysteine. These results advance the view that N-acetylcysteine acts primarily as a glutathione precursor. They further suggest the esterase inhibitors limit poisoning by acetaminophen and may be useful agents in antagonizing the toxicity of other metabolically activated drugs.
D000082:Acetaminophen / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000111:Acetylcysteine / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D000818:Animals; D019328:Buthionine Sulfoximine; D056486:Chemical and Drug Induced Liver Injury / Q000517:prevention & control*; D004950:Esterases / Q000037:antagonists & inhibitors*; D007531:Isoflurophate / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009596:Nitrophenols / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000494:pharmacology; D010664:Phenylmethylsulfonyl Fluoride / Q000494:pharmacology
D009596:Nitrophenols; D009943:Organophosphorus Compounds; D007531:Isoflurophate; C002315:N(alpha)-acetyllysine; D008717:Methionine Sulfoximine; C008644:nitrophenylphosphate; D000082:Acetaminophen; D019328:Buthionine Sulfoximine; D010664:Phenylmethylsulfonyl Fluoride; D004950:Esterases; D008239:Lysine; D000111:Acetylcysteine