title: Activation of autophagy protects against acetaminophen-induced hepatotoxicity.
abstract: Autophagy can selectively remove damaged organelles, including mitochondria, and, in turn, protect against mitochondria-damage-induced cell death. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing mitochondria damage and subsequent necrosis in hepatocytes. Although many detrimental mechanisms have been reported to be responsible for APAP-induced hepatotoxicity, it is not known whether APAP can modulate autophagy to regulate hepatotoxicity in hepatocytes. To test the hypothesis that autophagy may play a critical protective role against APAP-induced hepatotoxicity, primary cultured mouse hepatocytes and green fluorescent protein/light chain 3 transgenic mice were treated with APAP. By using a series of morphological and biochemical autophagic flux assays, we found that APAP induced autophagy both in the in vivo mouse liver and in primary cultured hepatocytes. We also found that APAP treatment might suppress mammalian target of rapamycin in hepatocytes and that APAP-induced autophagy was suppressed by N-acetylcysteine, suggesting APAP mitochondrial protein binding and the subsequent production of reactive oxygen species may play an important role in APAP-induced autophagy. Pharmacological inhibition of autophagy by 3-methyladenine or chloroquine further exacerbated APAP-induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP-induced hepatotoxicity.
  
  
  CONCLUSIONS
  APAP overdose induces autophagy, which attenuates APAP-induced liver cell death by removing damaged mitochondria.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Ni
authors.forename: Abigail
authors.initials: A
authors.lastname: Bockus
authors.forename: Nikki
authors.initials: N
authors.lastname: Boggess
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
authors.forename: Wen-Xing
authors.initials: WX
authors.lastname: Ding
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000633:toxicity*; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D049452:Green Fluorescent Proteins / Q000235:genetics; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D016166:Free Radical Scavengers; D049452:Green Fluorescent Proteins; D000082:Acetaminophen; C025946:3-methyladenine; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D000225:Adenine; D000111:Acetylcysteine