title: Deletion of apoptosis signal-regulating kinase 1 attenuates acetaminophen-induced liver injury by inhibiting c-Jun N-terminal kinase activation.
abstract: OBJECTIVE
  Acetaminophen (APAP) overdose is the most frequent cause of drug-induced liver failure. C-jun N-terminal kinase (JNK) is thought to play a central role in APAP-induced liver injury, although its upstream activator has not yet been identified. Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein kinase kinase kinase family and is important for stress-induced JNK activation. We tested the hypothesis that ASK1 was involved in APAP-induced JNK activation and liver injury.
  
  
  METHODS
  ASK1-deficient (ASK1(-/-)) mice and wild-type (WT) mice were given 300 mg/kg of APAP. Serum alanine aminotransferase levels and liver histology were assessed. To investigate the involvement of ASK1 in direct hepatocellular damage and the subsequent inflammatory response, we used primary hepatocytes and splenocytes from WT and ASK1(-/-) mice.
  
  
  RESULTS
  In ASK1(-/-) mouse liver, APAP toxicity was attenuated significantly and the prolonged activation of JNK was inhibited. In addition, thioredoxin, a direct ASK1 inhibitor, dissociated from ASK1 after APAP overdose with concomitant ASK1 activation. Although the prolonged activation of p38 also was attenuated in ASK1(-/-) mice, the p38 signaling pathway was not likely to be involved in APAP-induced liver injury. Primary hepatocyte culture also revealed that ASK1 and JNK, but not p38, contributed to direct APAP-induced cellular damage.
  
  
  CONCLUSIONS
  Our data suggest that ASK1 is activated by APAP overdose, most likely via a mechanism involving thioredoxin-ASK1 dissociation, and that it plays a role in APAP-induced liver injury through JNK activation.
authors.affiliation: Department of Gastroenterology, University of Tokyo, Hongo, Bunkyo-ku, Tokyo.
authors.forename: Hayato
authors.initials: H
authors.lastname: Nakagawa
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Yohko
authors.initials: Y
authors.lastname: Hikiba
authors.forename: Tomoya
authors.initials: T
authors.lastname: Ohmae
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.forename: Ayako
authors.initials: A
authors.lastname: Yanai
authors.forename: Kei
authors.initials: K
authors.lastname: Sakamoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Ogura
authors.forename: Takuya
authors.initials: T
authors.lastname: Noguchi
authors.forename: Michael
authors.initials: M
authors.lastname: Karin
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D062787:Drug Overdose / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse