Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 40, Pages 17315-17320Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1008209107
Keywords
acetaminophen liver toxicity; chemical screen
Categories
Funding
- Dana-Farber fellowship
- Harvard Digestive Diseases Center
- Mount Desert Island Biological Laboratory
- American Cancer Society
- Harvard Stem Cell Institute
- National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases
- National Cancer Institute [CA26731]
- Massachusetts Institute of Technology Center for Environmental Health Sciences
- Howard Hughes Medical Institute
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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.
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