PGE2-regulated wnt signaling and N-acetylcysteine are synergistically hepatoprotective in zebrafish acetaminophen injury.
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.
North
Trista E
TE
Department of Pathology, Beth Israel Deaconess Medical Center, MA 02115, USA.
Babu
I Ramesh
IR
Vedder
Lea M
LM
Lord
Allegra M
AM
Wishnok
John S
JS
Tannenbaum
Steven R
SR
Zon
Leonard I
LI
Goessling
Wolfram
W
D000082:Acetaminophen / Q000633:toxicity*; D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D018712:Analgesics, Non-Narcotic / Q000633:toxicity; D000818:Animals; D030801:Animals, Genetically Modified; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015232:Dinoprostone / Q000378:metabolism*; D017930:Genes, Reporter; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D020543:Proteome / Q000032:analysis; D015398:Signal Transduction / Q000502:physiology*; D015027:Zebrafish / Q000033:anatomy & histology / Q000502:physiology
D018712:Analgesics, Non-Narcotic; D020543:Proteome; D000082:Acetaminophen; D005978:Glutathione; D015232:Dinoprostone; D000111:Acetylcysteine