斑马鱼在药物毒理学评估中应用及机制的研究进展

Research progress on application and mechanism of zebrafish in drug toxicology assessment

与其他哺乳动物相比,斑马鱼具有繁殖能力强、繁殖量大、生命周期短、养殖费用低、身体透明等特点。主要从心血管毒性、肝脏毒性、肾脏毒性、神经毒性、脾脏毒性和急性毒性6个方面进行归纳总结,结果发现斑马鱼的多个器官在形态、基因表达及生理特性方面均与哺乳动物高度相似,已被广泛应用于药物的毒性物质筛选研究。药物对斑马鱼毒性研究主要集中在死亡率和畸形率增加,心、肝、肾、脾等脏器形态、表型改变并伴有水肿及神经毒性等方面;其毒性机制主要涉及影响器官中细胞凋亡(p53通路)、炎症(NF-κB通路、白介素)或影响该器官功能蛋白、酶或mRNA,如丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、乙酰胆碱酯酶(AChE)、微球蛋白前体(mbp)和α微管蛋白(αtubulin)等。斑马鱼模型可作为一种评估药物安全性与毒性最为高效、快速、便捷的方法,阐明药物的毒性作用及其多组分多靶点的毒性作用机制,可为药物毒理学中的毒性评估提供新的思路。

Compared with other mammals,zebrafish have the characteristics of strong reproduction ability,large reproduction capacity,short life cycle,low breeding cost,and transparent body.The cardiovascular,liver,kidney,nerve,spleen and acute toxicity of zebrafish were reviewed in this paper.The results showed that multiple organs of zebrafish were highly similar to mammals in terms of morphology,gene expression and physiological characteristics,and they have been widely used in drug screening studies.Studies on drug toxicity to zebrafish mainly focus on:increased mortality and malformation rate,changes in the morphology and phenotype of the heart,liver,kidney,spleen and other organs,as well as whether it is accompanied by edema,neurotoxicity,etc.;The toxicity mechanism mainly involves affecting cell apoptosis in organs(p53 pathway),inflammation(NF-κB and interleukin),or proteins,enzymes or mRNA that affect the function of the organ,such as ALT,AST,AChE,mbp,andαtubulin.It shows that the zebrafish model can be used as the most efficient,fast and convenient method for evaluating the safety and toxicity of drugs,elucidating the toxic effects of drugs and their multi-component and multi-target toxic mechanisms,which can provide new ideas for drug toxicology.