An integrated approach to the study of chemically reactive metabolites of acetaminophen.
I have examined in mice the kinetics of covalent binding of a metabolite of acetaminophen, as well as the binding to target tissue (and hence toxic reactions). At low doses, the chemically reactive metabolite seems to be converted to a glutathione conjugate that is ultimately excreted as a mercapturic acid. High acetaminophen doses that deplete available glutathione in the liver lead to toxic reactions. Manipulation of the system with agents that affect either glutathione availability or activity of the operative enzyme system has suggested that a chemically reactive acetaminophen metabolite is the active agent in hepatotoxic reactions from the drug. The chemically reactive intermediate seems to be short lived; it reacts with glutathione and is easily reduced by ascorbic acid. Acetylcysteine prevents liver necrosis caused by acetaminophen, and some possible mechanisms are discussed.
D000082:Acetaminophen / Q000378:metabolism* / Q000506:poisoning; D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D001711:Biotransformation; D006224:Cricetinae; D003543:Cysteamine / Q000494:pharmacology; D003545:Cysteine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009336:Necrosis; D051381:Rats
D000931:Antidotes; D000082:Acetaminophen; D003543:Cysteamine; D005978:Glutathione; D003545:Cysteine