斑马鱼
氧化应激
毒性
药理学
抗氧化剂
生物
阿霉素
化学
生物化学
基因
遗传学
有机化学
化疗
作者
Akihito Yamashita,Jiro Deguchi,Yayoi Honda,Tōru Yamada,Izuru Miyawaki,Yuhei Nishimura,Toshio Tanaka
标识
DOI:10.1016/j.vascn.2018.12.006
摘要
Oxidative stress plays an important role in drug-induced toxicity. Oxidative stress-mediated toxicities can be detected using conventional animal models but their sensitivity is insufficient, and novel models to improve susceptibility to oxidative stress have been researched. In recent years, gene targeting methods in zebrafish have been developed, making it possible to generate homozygous null mutants. In this study, we established zebrafish deficient in the nuclear factor erythroid 2-related factor 2a (nrf2a), a key antioxidant-responsive gene, and its potential to detect oxidative stress-mediated toxicity was examined. Nrf2a-deficient zebrafish were generated using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR–associated 9 technique. The loss of nrf2a function was confirmed by the tolerability to hydrogen peroxide and hydrogen peroxide-induced gene expression profiles being related to antioxidant response element (ARE)-dependent signaling. Subsequently, vulnerability of nrf2a-deficient zebrafish to acetaminophen (APAP)- or doxorubicin (DOX)-induced toxicity was investigated. Nrf2a-deficient zebrafish showed higher mortality than wild type accompanied by less induction of ARE-dependent genes with hydrogen peroxide treatment. Subsequently, this model showed increased severity and incidence of APAP-induced hepatotoxicity or DOX-induced cardiotoxicity than wild type. Our results demonstrated that anti-oxidative response might not fully function in this model, and resulted in higher sensitivity to drug-induced oxidative stress. Our data support the usefulness of nrf2a-deficient model as a tool for evaluation of oxidative stress-related toxicity in drug discovery research.
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