title: The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation.
abstract: Acetaminophen (APAP) overdose is the predominant cause of acute liver failure in the United States. Toxicity begins with a reactive metabolite that binds to proteins. In rodents, this leads to mitochondrial dysfunction and nuclear DNA fragmentation, resulting in necrotic cell death. While APAP metabolism is similar in humans, the later events resulting in toxicity have not been investigated in patients. In this study, levels of biomarkers of mitochondrial damage (glutamate dehydrogenase [GDH] and mitochondrial DNA [mtDNA]) and nuclear DNA fragments were measured in plasma from APAP-overdose patients. Overdose patients with no or minimal hepatic injury who had normal liver function tests (LTs) (referred to herein as the normal LT group) and healthy volunteers served as controls. Peak GDH activity and mtDNA concentration were increased in plasma from patients with abnormal LT. Peak nuclear DNA fragmentation in the abnormal LT cohort was also increased over that of controls. Parallel studies in mice revealed that these plasma biomarkers correlated well with tissue injury. Caspase-3 activity and cleaved caspase-3 were not detectable in plasma from overdose patients or mice, but were elevated after TNF-induced apoptosis, indicating that APAP overdose does not cause apoptosis. Thus, our results suggest that mitochondrial damage and nuclear DNA fragmentation are likely to be critical events in APAP hepatotoxicity in humans, resulting in necrotic cell death.
authors.affiliation: Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Sharpe
authors.forename: C David
authors.initials: CD
authors.lastname: Williams
authors.forename: Mohammad
authors.initials: M
authors.lastname: Taha
authors.forename: Steven C
authors.initials: SC
authors.lastname: Curry
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000633:toxicity; D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D015415:Biomarkers; D053148:Caspase 3 / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004247:DNA / Q000097:blood; D053938:DNA Fragmentation / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000032:analysis / Q000187:drug effects*; D062787:Drug Overdose; D005260:Female; D005969:Glutamate Dehydrogenase / Q000032:analysis; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D009336:Necrosis; D013045:Species Specificity; D055815:Young Adult
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial; D000082:Acetaminophen; D004247:DNA; D005969:Glutamate Dehydrogenase; D000410:Alanine Transaminase; D053148:Caspase 3