title: Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition.
abstract: Large doses of the analgesic acetaminophen cause centrilobular hepatic necrosis in man and in experimental animals. It has been previously shown that acetaminophen is metabolically activated by CYP enzymes to N-acetyl-p-benzoquinone imine. This species is normally detoxified by GSH, but following a toxic dose GSH is depleted and the metabolite covalently binds to a number of different proteins. Covalent binding occurs only to the cells developing necrosis. Recently we showed that these cells also contain nitrated tyrosine residues. Nitrotyrosine is mediated by peroxynitrite, a reactive nitrogen species formed by rapid reaction between nitric oxide and superoxide and is normally detoxified by GSH. Thus, acetaminophen toxicity occurs with increased oxygen/nitrogen stress. This manuscript will review current data on acetaminophen covalent binding, increased oxygen/nitrogen stress, and mitochondrial permeability transition, a toxic mechanism that is both mediated by and leads to increased oxygen/nitrogen stress.
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. HinsonJackA@uams.edu
authors.forename: Jack A
authors.initials: JA
authors.lastname: Hinson
authors.forename: Angela B
authors.initials: AB
authors.lastname: Reid
authors.forename: Sandra S
authors.initials: SS
authors.lastname: McCullough
authors.forename: Laura P
authors.initials: LP
authors.lastname: James
mesh_terms: D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D026361:Reactive Nitrogen Species / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D007473:Ion Channels; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D026361:Reactive Nitrogen Species; D017382:Reactive Oxygen Species; D000082:Acetaminophen