title: 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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: a University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics , Kansas City, KS, USA +1 913 588 7969 ; +1 913 588 7501 ; hjaeschke@kumc.edu.
authors.forename: Kuo
authors.initials: K
authors.lastname: Du
authors.affiliation: a University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics , Kansas City, KS, USA +1 913 588 7969 ; +1 913 588 7501 ; hjaeschke@kumc.edu.
authors.forename: Yuchao
authors.initials: Y
authors.lastname: Xie
authors.affiliation: a University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics , Kansas City, KS, USA +1 913 588 7969 ; +1 913 588 7501 ; hjaeschke@kumc.edu.
authors.forename: Mitchell R
authors.initials: MR
authors.lastname: McGill
authors.affiliation: a University of Kansas Medical Center, Department of Pharmacology, Toxicology and Therapeutics , Kansas City, KS, USA +1 913 588 7969 ; +1 913 588 7501 ; hjaeschke@kumc.edu.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Jaeschke
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000506:poisoning; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000503:physiopathology / Q000628:therapy; D004353:Drug Evaluation, Preclinical / Q000379:methods; D062787:Drug Overdose; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy
chemical_list: D000082:Acetaminophen; D048031:JNK Mitogen-Activated Protein Kinases
keywords: acetaminophen; c-jun N-terminal kinase; drug hepatotoxicity; mitochondrial dysfunction