TITLE

Critical role of c-jun (NH2) terminal kinase in paracetamol-induced acute liver failure

AUTHOR(S)
Henderson, Neil C.; Pollock, Katharine J.; Frew, John; MacKinnon, Alison C.; Flavell, Richard A.; Davis, Roger J.; Sethi, Tariq; Simpson, Kenneth J.
PUB. DATE
July 2007
SOURCE
Gut;Jul2007, Vol. 56 Issue 7, p982
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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. 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 routine 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 factor α (TNF α) production after paracetamol poisoning. Conclusions: These data demonstrated a central role far JNK in the pathogenesis of paracetamol-induced liver failure, thereby identifying JNK as an important therapeutic target in the treatment of paracetamol hepatotoxicity.
ACCESSION #
25602407

 

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