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.
- 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.
- acetaminophen liver toxicity, chemical screen
- MeSH Terms
- Acetylcysteine*/therapeutic use
- Analgesics, Non-Narcotic/toxicity
- 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
- Genes, Reporter
- Liver/drug effects
- Liver Failure, Acute*/drug therapy
- Liver Failure, Acute*/metabolism
- Liver Failure, Acute*/pathology
- Signal Transduction/physiology*
- Zebrafish*/anatomy & histology
- 20855591 Full text @ Proc. Natl. Acad. Sci. USA
North, T.E., Babu, I.R., Vedder, L.M., Lord, A.M., Wishnok, J.S., Tannenbaum, S.R., Zon, L.I., and Goessling, W. (2010) PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury. Proceedings of the National Academy of Sciences of the United States of America. 107(40):17315-17320.
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.
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes