title: Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure.
abstract: BACKGROUND
  Acute hepatic failure secondary to paracetamol poisoning is associated with high mortality. C-jun (NH2) terminal kinase (JNK) is a member of the mitogen-activated protein kinase family and is a key intracellular signalling molecule involved in controlling the fate of cells.
  
  
  OBJECTIVE
  To examine the role of JNK in paracetamol-induced acute liver failure (ALF).
  
  
  METHODS
  A previously developed mouse model of paracetamol poisoning was used to examine the role of JNK in paracetamol-induced ALF.
  
  
  RESULTS
  Paracetamol-induced hepatic JNK activation both in human and murine paracetamol hepatotoxicity and in our murine model preceded the onset of hepatocyte death. JNK inhibition in vivo (using two JNK inhibitors with different mechanisms of action) markedly reduced mortality in murine paracetamol hepatotoxicity, with a significant reduction in hepatic necrosis and apoptosis. In addition, delayed administration of the JNK inhibitor was more effective than N-acetylcysteine after paracetamol poisoning in mice. JNK inhibition was not protective in acute carbon tetrachloride-mediated or anti-Fas antibody-mediated hepatic injury, suggesting specificity for the role of JNK in paracetamol hepatotoxicity. Furthermore, disruption of the JNK1 or JNK2 genes did not protect against paracetamol-induced hepatic damage. Pharmacological JNK inhibition had no effect on paracetamol metabolism, but markedly inhibited hepatic tumour necrosis foctor alpha (TNF alpha) production after paracetamol poisoning.
  
  
  CONCLUSIONS
  These data demonstrated a central role for JNK in the pathogenesis of paracetamol-induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity.
authors.affiliation: Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4TJ, UK.
authors.forename: Neil C
authors.initials: NC
authors.lastname: Henderson
authors.forename: Katharine J
authors.initials: KJ
authors.lastname: Pollock
authors.forename: John
authors.initials: J
authors.lastname: Frew
authors.forename: Alison C
authors.initials: AC
authors.lastname: Mackinnon
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Tariq
authors.initials: T
authors.lastname: Sethi
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Simpson
mesh_terms: D000082:Acetaminophen / Q000506:poisoning*; D018712:Analgesics, Non-Narcotic / Q000506:poisoning*; D000818:Animals; D000873:Anthracenes / Q000008:administration & dosage / Q000627:therapeutic use; D001706:Biopsy; D002251:Carbon Tetrachloride; D016923:Cell Death; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D008099:Liver / Q000201:enzymology; D017114:Liver Failure, Acute / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D018712:Analgesics, Non-Narcotic; D000873:Anthracenes; D004791:Enzyme Inhibitors; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D000082:Acetaminophen; D002251:Carbon Tetrachloride; D048031:JNK Mitogen-Activated Protein Kinases