The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation

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…

• MU
  McGill University
• NI
  National Institutes of Health

  Awards: 8 P20 GM103549, RR016475, R01 DK070195, RR021940, T32 ES007079, P20 GM103549, P20 RR016475, P20 GM103549-07, DK070195, R01 DK070195 and R01 AA12916, ES007079, P20 RR021940, AA12916, 8 P20 GM103549-07, GM103549, R01 AA12916, ES007079-26A2
• NI
  National Institute of General Medical Sciences

  Awards: RR021940, T32 ES007079, GM103549, P20 GM103549, 8 P20 GM103549, P20 RR016475, 8 P20 GM103549-07
• NI
  National Institute of Environmental Health Sciences

  Awards: T32 ES007079-26A2, ES007079, T32 ES007079
• NC
  National Center for Research Resources

  Awards: RR021940, RR016475, 8 P20 GM103549-07, P20 GM103549, P20 RR016475, T32 ES007079-26A2, P20 RR021940