Application of zebrafish to safety evaluation in drugdiscovery

摘要

Traditionally, safety evaluation at the early stage of drug discovery research has beendone using in silico, in vitro, and invivo systems in this order because of limitations on the amount of compoundsavailable and the throughput ability of the assay systems. While these invitro assays are very effective tools for detecting particular tissue-specifictoxicity phenotypes, it is difficult to detect toxicity based on complex mechanismsinvolving multiple organs and tissues. Therefore, the development of novel high throughputin vivo evaluation systems has been expected for a long time. Thezebrafish (Danio rerio) is a vertebrate with many attractivecharacteristics for use in drug discovery, such as a small size, transparency, gene andprotein similarity with mammals (80% or more), and ease of genetic modification toestablish human disease models. Actually, in recent years, the zebrafish has attractedinterest as a novel experimental animal. In this article, the author summarized thefeatures of zebrafish that make it a suitable laboratory animal, and introduced anddiscussed the applications of zebrafish to preclinical toxicity testing, includingevaluations of teratogenicity, hepatotoxicity, and nephrotoxicity based on morphologicalfindings, evaluation of cardiotoxicity using functional endpoints, and assessment ofseizure and drug abuse liability.