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.