Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity

Abstract

Background: Acetaminophen (APAP) overdose is the leading cause of acute liver failure in the US. Although substantial progress regarding the mechanisms of APAP hepatotoxicity has been made in the past several decades, therapeutic options are still limited and novel treatments are clearly needed. c-jun N-terminal Kinase (JNK) has emerged as a promising therapeutic target in recent years.

Areas covered: Early studies established the critical role of JNK activation and mitochondrial translocation in APAP hepatotoxicity. However, this concept has also been challenged. Initial studies failed to reproduce the protection of JNK deficiency in APAP toxicity and concerns over off-target effects of JNK inhibitors and even in knock-out mice are increasing. Interestingly, recent studies have even shown that liver injury can be altered with or without effects on JNK activation. The current review addresses these discrepancies and tries to explain or reconcile some of the conflicting results.

Expert opinion: JNK is a potential therapeutic target for APAP poisoning. However, controversies still exist regarding its actual role in APAP hepatotoxicity. Future studies are warranted for more in-depth testing of specific inhibitors in well-defined preclinical models and human hepatocytes before JNK can be considered a relevant therapeutic target for APAP poisoning.

Keywords:

• acetaminophen
• c-jun N-terminal kinase
• drug hepatotoxicity
• mitochondrial dysfunction

Declaration of interest

H Jaeschke is supported by the NIH (R01 DK102142, R01 AA12916, and 8 P20 GM103549 – 07) and MR McGill is supported in part by an NIH fellowship from the ‘Training Program in Environmental Toxicology’ (T32 ES007079 – 26A2). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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