3种新型蛋白酶体抑制剂对斑马鱼心脏毒性的评价  

Cardiotoxicity evaluation of three novel proteasome inhibitors in zebrafish

作　　者：胡丙雪 董雪 范宏伟 朱永强 张茵[1] 张朝[1] HU Bingxue;DONG Xue;FAN Hongwei;ZHU Yongqiang;ZHANG Yin;ZHANG Zhao(Jiangsu Key Laboratory for Molecular and Medical Biotechnology,College of Life Science,Nanjing Normal University,Nanjing 210023,China)

机构地区：[1]南京师范大学生命科学学院江苏省分子与医学技术重点实验室

出　　处：《中国药科大学学报》2019年第4期452-458,共7页Journal of China Pharmaceutical University

基　　金：国家自然科学基金资助项目(No.31171302);江苏省教育厅自然科学研究计划重大项目资助项目(No.16KJA18000);江苏省优势学科资助项目(No.1164320H106)~~

摘　　要：为了观察3种新型蛋白酶体抑制剂对斑马鱼的心脏毒性并初步探讨其机制,将斑马鱼胚胎分别暴露于一系列浓度的化合物NNU395、NNU458和NNU459。于显微镜下观察并拍摄斑马鱼的心脏形态,统计死亡率及心率,并检测斑马鱼心脏发育相关基因的表达情况。结果显示,NNU395、NNU458和NNU459呈浓度依赖地增加了斑马鱼的死亡率,对斑马鱼胚胎的半数致死浓度分别为(179.7±12.2),(27.5±1.3)和(24.4±2.6)μmol/L,且较之各自改构前体,3种化合物对斑马鱼的毒性更低。120~200μmol/L NNU395及30μmol/L的NNU458或NNU459处理后的斑马鱼出现明显的心包水肿和心脏畸形。120~200μmol/L的NNU395及0.1~30μmol/L的NNU458或10~30μmol/L的NNU459均显著降低斑马鱼的心率。3种化合物对斑马鱼心脏发育相关基因的表达都没有显著影响。本研究提示低浓度的NNU395、NNU458和NNU459对斑马鱼心脏无明显毒性,高浓度的3种化合物对斑马鱼可产生心血管毒性。To evaluate the cardiotoxicity of three novel proteasome inhibitors(NNU395,NNU458 and NNU459)in zebrafish,normal developmental zebrafish embryos at 6 hours post fertilization(hpf)were treated with different doses of NNU395 and NNU458 and NNU459 until 72 hpf,the zebrafish mortality was counted.Morphologic changes of the cardiovascular system were observed under a stereomicroscope,and the number of heart beats within 1 min was determined.The expression of cardiac development-related genes in zebrafish was detected by RT-qPCR(Quantitative Real-Time PCR).Results showed that NNU395,NNU458 and NNU459 increased the mortality of zebrafish in a concentration-dependent manner and the values of LC 50(50%lethal concentration)were(179.7±12.2),(27.5±1.3)and(24.4±2.6)μmol/L,respectively.Moreover,the toxicity of our three compounds in zebrafish are less when compared with their modified precursors.Upon administration of NNU395 at the concentrations of 12 0 200μmol/L,and NNU458 or NNU459 at the concentration of 30μmol/L,the zebrafish showed obvious pericardial edema cardiac malformation.12 0 200μmol/L NNU395 and 0.1 30μmol/L NNU458 or 1 0 30μmol/L NNU459 significantly reduced the heart rate of zebrafish.All of three compounds at the tested concentration had no significant effects on the expression of the heart development-related genes in zebrafish.Our results suggested that low concentrations of NNU395,NNU458 and NNU459 have no obvious toxicity on cardiac development of zebrafish.While,higher concentrations of them showed cardiovascular toxicity on zebrafish.

关 键 词：蛋白酶体抑制剂 NNU395 NNU458 NNU459 心脏毒性 斑马鱼 carfilzomib ixazomib 

分 类 号：R99[医药卫生—毒理学]