Effects of esterase inhibitors and buthionine sulfoximine on the prevention of acetaminophen hepatotoxicity by N-acetylcysteine.

Abstract

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.

• Authors: B K Wong, G B Corcoran
• Journal: Research communications in chemical pathology and pharmacology (Res Commun Chem Pathol Pharmacol) Vol. 55 Issue 3 Pg. 397-408 (Mar 1987) ISSN: 0034-5164 [Print] United States
• PMID: 3107095 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Nitrophenols
• Organophosphorus Compounds
• Isoflurophate
• N(alpha)-acetyllysine
• Methionine Sulfoximine
• nitrophenylphosphate
• Acetaminophen
• Buthionine Sulfoximine
• Phenylmethylsulfonyl Fluoride
• Esterases
• Lysine
• Acetylcysteine

Topics

• Acetaminophen (antagonists & inhibitors, toxicity)
• Acetylcysteine (antagonists & inhibitors, therapeutic use)
• Animals
• Buthionine Sulfoximine
• Chemical and Drug Induced Liver Injury (prevention & control)
• Esterases (antagonists & inhibitors)
• Isoflurophate (pharmacology)
• Lysine (analogs & derivatives, pharmacology)
• Male
• Methionine Sulfoximine (analogs & derivatives, pharmacology)
• Mice
• Mice, Inbred ICR
• Nitrophenols (pharmacology)
• Organophosphorus Compounds (pharmacology)
• Phenylmethylsulfonyl Fluoride (pharmacology)