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

Publication ,  Journal Article
Du, K; Xie, Y; McGill, MR; Jaeschke, H
Published in: Expert Opin Drug Metab Toxicol
2015

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.

Duke Scholars

Published In

Expert Opin Drug Metab Toxicol

DOI

EISSN

1744-7607

Publication Date

2015

Volume

11

Issue

11

Start / End Page

1769 / 1779

Location

England

Related Subject Headings

  • Pharmacology & Pharmacy
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Mice
  • JNK Mitogen-Activated Protein Kinases
  • Humans
  • Hepatocytes
  • Drug Overdose
  • Drug Evaluation, Preclinical
  • Chemical and Drug Induced Liver Injury
 

Citation

APA
Chicago
ICMJE
MLA
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Du, K., Xie, Y., McGill, M. R., & Jaeschke, H. (2015). Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity. Expert Opin Drug Metab Toxicol, 11(11), 1769–1779. https://doi.org/10.1517/17425255.2015.1071353
Du, Kuo, Yuchao Xie, Mitchell R. McGill, and Hartmut Jaeschke. “Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity.Expert Opin Drug Metab Toxicol 11, no. 11 (2015): 1769–79. https://doi.org/10.1517/17425255.2015.1071353.
Du K, Xie Y, McGill MR, Jaeschke H. Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity. Expert Opin Drug Metab Toxicol. 2015;11(11):1769–79.
Du, Kuo, et al. “Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity.Expert Opin Drug Metab Toxicol, vol. 11, no. 11, 2015, pp. 1769–79. Pubmed, doi:10.1517/17425255.2015.1071353.
Du K, Xie Y, McGill MR, Jaeschke H. Pathophysiological significance of c-jun N-terminal kinase in acetaminophen hepatotoxicity. Expert Opin Drug Metab Toxicol. 2015;11(11):1769–1779.

Published In

Expert Opin Drug Metab Toxicol

DOI

EISSN

1744-7607

Publication Date

2015

Volume

11

Issue

11

Start / End Page

1769 / 1779

Location

England

Related Subject Headings

  • Pharmacology & Pharmacy
  • Molecular Targeted Therapy
  • Mice, Knockout
  • Mice
  • JNK Mitogen-Activated Protein Kinases
  • Humans
  • Hepatocytes
  • Drug Overdose
  • Drug Evaluation, Preclinical
  • Chemical and Drug Induced Liver Injury