ZFIN ID: ZDB-PUB-101004-27
PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury
North, T.E., Babu, I.R., Vedder, L.M., Lord, A.M., Wishnok, J.S., Tannenbaum, S.R., Zon, L.I., and Goessling, W.
Date: 2010
Source: Proceedings of the National Academy of Sciences of the United States of America   107(40): 17315-17320 (Journal)
Registered Authors: Goessling, Wolfram, Lord, Allegra, North, Trista, Vedder, Lea, Zon, Leonard I.
Keywords: acetaminophen liver toxicity, chemical screen
MeSH Terms:
  • Acetaminophen/toxicity*
  • Acetylcysteine*/pharmacology
  • Acetylcysteine*/therapeutic use
  • Analgesics, Non-Narcotic/toxicity
  • Animals
  • Animals, Genetically Modified
  • Chemical and Drug Induced Liver Injury*/drug therapy
  • Chemical and Drug Induced Liver Injury*/metabolism
  • Chemical and Drug Induced Liver Injury*/pathology
  • Dinoprostone/metabolism*
  • Genes, Reporter
  • Glutathione/metabolism
  • Liver/drug effects
  • Liver/metabolism
  • Liver/pathology
  • Liver Failure, Acute*/drug therapy
  • Liver Failure, Acute*/metabolism
  • Liver Failure, Acute*/pathology
  • Proteome/analysis
  • Signal Transduction/physiology*
  • Zebrafish*/anatomy & histology
  • Zebrafish*/physiology
PubMed: 20855591 Full text @ Proc. Natl. Acad. Sci. USA
Acetaminophen (APAP) toxicity is the most common drug-induced cause of acute liver failure in the United States. The only available treatment, N-acetylcysteine (NAC), has a limited time window of efficacy, indicating a need for additional therapeutic options. Zebrafish have emerged as a powerful tool for drug discovery. Here, we developed a clinically relevant zebrafish model of APAP toxicity. APAP depleted glutathione stores, elevated aminotransferase levels, increased apoptosis, and caused dose-dependent hepatocyte necrosis. These outcomes were limited by NAC and conserved in zebrafish embryos. In a targeted embryonic chemical screen, prostaglandin E2 (PGE2) was identified as a potential therapeutic agent; in the adult, PGE2 similarly decreased APAP-associated toxicity. Significantly, when combined with NAC, PGE2 extended the time window for a successful intervention, synergistically reducing apoptosis, improving liver enzymes, and preventing death. Use of a wnt reporter zebrafish line and chemical genetic epistasis showed that the effects of PGE2 are mediated through the wnt signaling pathway. Zebrafish can be used as a clinically relevant toxicological model amenable to the identification of additional therapeutics and biomarkers of APAP injury; our data suggest combinatorial PGE2 and NAC treatment would be beneficial for patients with APAP-induced liver damage.