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c-Jun N-terminal kinase plays a major role in murine acetaminophen hepatotoxicity

Basuki K Gunawan1, Zhang-Xu Liu, Derick Han

  • 1Research Center for Liver Disease, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA. gbasuki@usc.edu

Gastroenterology
|July 13, 2006
PubMed
Abstract

Insights

Acetaminophen (APAP) causes liver damage by activating stress kinases, specifically c-jun N-terminal kinase (JNK). Inhibiting JNK, particularly JNK2, protects liver cells from APAP toxicity.

Area of Science:

  • Hepatology
  • Toxicology
  • Molecular Biology

Background:

  • Acetaminophen (APAP) overdose is a leading cause of acute liver failure.
  • The precise molecular mechanisms by which APAP induces hepatotoxicity remain incompletely understood.
  • Stress kinases, such as c-jun N-terminal kinase (JNK), are implicated in cellular stress responses and apoptosis.

Purpose of the Study:

  • To investigate the role of stress kinases, specifically JNK, in acetaminophen-induced hepatotoxicity.
  • To determine if JNK activation is a downstream event of APAP metabolism contributing to liver injury.
  • To evaluate the therapeutic potential of JNK inhibition in preventing APAP toxicity.

Main Methods:

  • Hepatocytes and mice were treated with toxic doses of APAP, with or without a JNK inhibitor (SP600125).
  • JNK activity was assessed by measuring phospho-c-jun levels.
  • Experiments were conducted in JNK1/JNK2 knockout mice and using antisense oligonucleotides (ASOs) to knockdown JNK.
  • Liver injury was evaluated by serum ALT levels and histological examination.
  • Bax translocation was assessed as a downstream target of JNK.

Main Results:

  • Sustained JNK activation was observed in hepatocytes and livers following APAP treatment.
  • JNK inhibition with SP600125 significantly protected against APAP-induced hepatotoxicity both in vitro and in vivo.
  • Knockdown of JNK1 and JNK2 using ASOs confirmed the protective effect.
  • JNK2 knockout mice and those treated with JNK2 ASO showed partial protection.
  • APAP-induced Bax translocation was blocked by JNK inhibition.
  • Protection was specific to APAP toxicity, as JNK inhibition did not protect against CCl(4) or concanavalin A toxicity.

Conclusions:

  • JNK activation plays a critical role downstream of APAP metabolism in promoting hepatotoxicity.
  • JNK2 appears to be the predominant isoform involved, but reducing both JNK1 and JNK2 provides maximal protection.
  • Targeting JNK represents a potential therapeutic strategy for acetaminophen-induced liver injury.

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