Department of Pathology, Beth Israel Deaconess Medical Center, MA 02115, USA.
Proc Natl Acad Sci U S A. 2010 Oct 5;107(40):17315-20. doi: 10.1073/pnas.1008209107. Epub 2010 Sep 20.
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.
对乙酰氨基酚（APAP）中毒是美国最常见的药物性急性肝衰竭的原因。唯一可用的治疗药物 N-乙酰半胱氨酸（NAC）的疗效时间窗口有限，表明需要额外的治疗选择。斑马鱼已成为药物发现的有力工具。在这里，我们开发了一种与临床相关的 APAP 毒性斑马鱼模型。APAP 耗尽了谷胱甘肽储备，升高了转氨酶水平，增加了细胞凋亡，并导致了剂量依赖性的肝细胞坏死。这些结果受到 NAC 的限制，并在斑马鱼胚胎中得到了保留。在靶向胚胎化学筛选中，前列腺素 E2（PGE2）被鉴定为一种潜在的治疗药物；在成年动物中，PGE2 同样降低了 APAP 相关的毒性。重要的是，当与 NAC 联合使用时，PGE2 延长了成功干预的时间窗口，协同减少细胞凋亡，改善肝酶，并防止死亡。使用 wnt 报告斑马鱼系和化学遗传上位性表明，PGE2 的作用是通过 wnt 信号通路介导的。斑马鱼可以作为一种与临床相关的毒理学模型，适用于鉴定额外的治疗方法和 APAP 损伤的生物标志物；我们的数据表明，PGE2 和 NAC 的联合治疗对 APAP 诱导的肝损伤患者将是有益的。
