title: CHOP is a critical regulator of acetaminophen-induced hepatotoxicity.
abstract: OBJECTIVE
  The liver is a major site of drug metabolism and elimination and as such is susceptible to drug toxicity. Drug induced liver injury is a leading cause of acute liver injury, of which acetaminophen (APAP) is the most frequent causative agent. APAP toxicity is initiated by its toxic metabolite NAPQI. However, downstream mechanisms underlying APAP induced cell death are still unclear. Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have recently emerged as major regulators of metabolic homeostasis. UPR regulation of the transcription repressor CHOP promotes cell death. We analyzed the role of UPR and CHOP in mediating APAP hepatotoxicity.
  
  
  METHODS
  A toxic dose of APAP was orally administered to wild type (wt) and CHOP knockout (KO) mice and damage mechanisms were assessed.
  
  
  RESULTS
  CHOP KO mice were protected from APAP induced damage and exhibited decreased liver necrosis and increased survival. APAP metabolism in CHOP KO mice was undisturbed and glutathione was depleted at similar kinetics to wt. ER stress and UPR activation were overtly seen 12h following APAP administration, a time that coincided with strong upregulation of CHOP. Remarkably, CHOP KO but not wt mice exhibited hepatocyte proliferation at sites of necrosis. In vitro, large T immortalized CHOP KO hepatocytes were protected from APAP toxicity in comparison to wt control cells.
  
  
  CONCLUSIONS
  CHOP upregulation during APAP induced liver injury compromises hepatocyte survival in various mechanisms, in part by curtailing the regeneration phase following liver damage. Thus, CHOP plays a pro-damage role in response to APAP intoxication.
authors.affiliation: Institute for Drug Research, School of Pharmacy, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
authors.forename: Dotan
authors.initials: D
authors.lastname: Uzi
authors.forename: Liran
authors.initials: L
authors.lastname: Barda
authors.forename: Viviana
authors.initials: V
authors.lastname: Scaiewicz
authors.forename: Maya
authors.initials: M
authors.lastname: Mills
authors.forename: Tobias
authors.initials: T
authors.lastname: Mueller
authors.forename: Agueda
authors.initials: A
authors.lastname: Gonzalez-Rodriguez
authors.forename: Angela M
authors.initials: AM
authors.lastname: Valverde
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.forename: Yaacov
authors.initials: Y
authors.lastname: Nahmias
authors.forename: Ramnik
authors.initials: R
authors.lastname: Xavier
authors.forename: Ray T
authors.initials: RT
authors.lastname: Chung
authors.forename: Boaz
authors.initials: B
authors.lastname: Tirosh
authors.forename: Oren
authors.initials: O
authors.lastname: Shibolet
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008115:Liver Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D056811:Unfolded Protein Response / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018712:Analgesics, Non-Narcotic; C497249:DDIT3 protein, human; C497250:Ddit3 protein, mouse; D051742:Transcription Factor CHOP; D000082:Acetaminophen
keywords: ALI; ALT; APAP; AST; Acetaminophen hepatotoxicity; DILI; Drug induced liver injury; ER; Endoplasmic reticulum stress; GSH; N-acetylbenzoquinoneimine; NAPQI; ROS; UPR; Unfolded protein response; acetaminophen (N-acetyl-p-aminophenol); acute liver injury; alanine aminotransferase; aspartate aminotransferase; drug induced liver injury; endoplasmic reticulum; glutathione; reactive oxygen species; unfolded protein response