抗坏血酸联合全反式维甲酸建立斑马鱼新药早期评价模型的研究  

Zebrafish Model of New Drug Early Evaluation Established by Ascorbic Acid and All-trans Retinoic Acid

作　　者：高绪聪[1,2] 孙程颖 张云 何秋霞[3] 申秀萍[1,2] GAO Xucong;SUN Chengying;ZHANG Yun;HE Qiuxia;SHEN Xiuping(Tianjin Institute of Pharmaceutical Research New Drug Evaluation Co.,Ltd.,Tianjin 300301,China;Tianjin Engineering Research Center of Drug Preclinical Assessment Technology,Tianjin 300301,China;Shandong Province Biology Institute of Shandong Academy of Sciences,Jinan 250014,China)

机构地区：[1]天津药物研究院新药评价有限公司,天津300301 [2]天津市新药非临床评价技术工程中心,天津300301 [3]山东省科学院生物研究所,济南250014

出　　处：《中国现代应用药学》2018年第12期1761-1764,共4页Chinese Journal of Modern Applied Pharmacy

基　　金：国家科技重大专项(2015ZX09501004);天津市科技计划项目(16PTGCCX00090)

摘　　要：目的以抗坏血酸和全反式维甲酸为工具药,建立斑马鱼药物早期评价模型,为药物毒性的早期筛查提供实验方法。方法以斑马鱼胚胎培养用水为空白对照,二甲基亚砜为助溶剂,抗坏血酸为阴性药物,全反式维甲酸为阳性药物,对脱膜斑马鱼受精卵连续染毒5d后,检测受精卵和幼鱼的死亡率,及幼鱼自由活动度、全身组织器官形态发育和骨骼发育情况。结果 0.5%二甲基亚砜和10 mg·L^(-1)抗坏血酸对斑马鱼致死作用较弱,且无明显发育毒性作用,可分别用作常规助溶剂和质量控制标志药;全反式维甲酸随给药浓度升高,致畸效应加强,很好地呈现了自主活动缓慢到丧失、形态发育轻微异常到全身各组织器官严重畸形、骨骼矿化正常到抑制的全效应谱,为药物毒性的评价提供了很好的参照,其中7.5μg·L^(-1)可作为药物评价中阳性对照选用浓度。结论用抗坏血酸和全反式维甲酸建立的斑马鱼模型设计合理,可用于药物毒性的早期评价。OBJECTIVE To establish a zebrafish model of drug early evaluation,using ascorbic acid and all-trans retinoic acid as tools,so as to provide a test method for early screening of drug toxicity.METHODS The zebrafish embryos were incubated for 5 days with water as the blank control,dimethyl sulfoxide as solvent,ascorbic acid(AA) as negative drug,all-trans retinoic acid(ATRA) as positive drug.Detected the mortality,movement,organs and skeleton morphogenesis of fertilized eggs and juveniles.RESULTS 0.5% DMSO and 10mg·L^-1 AA had weak lethal effect on zebrafish,and no obvious developmental toxicity,which could be used as cosolvent and quality control drug,respectively.ATRA had a strengthened teratogenic effect with the concentration increased,and showed a full-effect spectrum as follows: normal,slow and losed spontaneous activities,slight to severe tissues and organs malformations,vertebra mineralization inhibition.It provided a good reference for the evaluation of drug toxicity,and ATRA 7.5 μg·L^-1 could be selected as the positive control drug evaluated concentration.CONCLUSION The zebrafish model designed with AA and ATRA reasonably can be used for early evaluation of drug toxicity.

关 键 词：抗坏血酸 全反式维甲酸 斑马鱼 药物毒性检测 

分 类 号：R965.1[医药卫生—药理学]