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Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure
  1. Neil C Henderson1,
  2. Katharine J Pollock1,
  3. John Frew1,
  4. Alison C Mackinnon1,
  5. Richard A Flavell2,
  6. Roger J Davis3,
  7. Tariq Sethi1,
  8. Kenneth J Simpson1
  1. 1Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK
  2. 2Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, USA
  3. 3Howard Hughes Medical Institute and Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
  1. Correspondence to:
    K J Simpson
    Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, 51 Little France Crescent, Edinburgh EH16 4TJ, UK; k.simpson{at}


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.

Aim: 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 α (TNF α) 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.

  • ALF, acute liver failure
  • ALT, alanine aminotransferase
  • AP-1, activating protein 1
  • CCl4, carbon tetrachloride
  • d-JNKI1, c-jun N-terminal kinase peptide inhibitor 1, d-stereoisomer
  • IP, intraperitoneal
  • JNK, c-jun (NH2) terminal kinase
  • NAC, N-acetylcysteine
  • NAPQI, N-acetyl-p-quinoneimine
  • PBS, phosphate-buffered saline
  • ROS, reactive oxygen species
  • TNFα, tumour necrosis factor α
  • TNFR1, TNF receptor 1
  • WT, wild type

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  • Published Online First 21 December 2006

  • Competing interests: None.