RT Journal Article
SR Electronic
T1 Critical role of c-jun (NH2) terminal kinase in paracetamol- induced acute liver failure
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 982
OP 990
DO 10.1136/gut.2006.104372
VO 56
IS 7
A1 Neil C Henderson
A1 Katharine J Pollock
A1 John Frew
A1 Alison C Mackinnon
A1 Richard A Flavell
A1 Roger J Davis
A1 Tariq Sethi
A1 Kenneth J Simpson
YR 2007
UL http://gut.bmj.com/content/56/7/982.abstract
AB 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.