摘要
目的使用毒理预测软件和细菌回复突变试验评价17种亚硝胺化合物的致突变风险,探讨亚硝胺化合物取代基结构与其致突变性风险的关联。方法使用Derek Nexus和Sarah Nexus对17种亚硝胺化合物的致突变风险进行预测,并使用鼠伤寒沙门氏菌TA97、TA98、TA100、TA102、TA1535和TA1537分别在无和有大鼠S9代谢活化条件下开展基于6孔板的细菌回复突变(Ames)试验,评价其致突变性风险。结果Derek Nexus基于亚硝基结构,预测16种亚硝胺化合物(不包括NDPh)均具有致突变风险。Sarah Nexus预测所有17种均有致突变性风险,但NMEA、NEIPA和NDIPA的致突变风险较低。非S9代谢活化条件下,除NMPEA外,其余所有亚硝胺化合物的细菌回复突变试验结果均为阴性。NMPEA仅能诱导TA1537菌株回复突变菌落数增加。经大鼠S9代谢活化后,NDEA、NMOR、NDPA、NPIP和NPYR在TA97、TA100和TA15353个菌株中均得到阳性结果,NDMA、NMEA、NEIPA、NDBA、NMPA、NNK、NDELA、NDPh和NMPEA则在TA97、TA100和TA1535中至少1种菌株中得到阳性结果。结论亚硝胺化合物致突变性与其结构中α-氢的数目和α-氢的取代、支链或较大/不可代谢的基团的存在,以及形成的重氮离子的稳定性等因素有关。本研究提供了最新的亚硝胺化合物体外致突变性和DNA损伤性试验数据,验证了取代基结构对亚硝胺化合物致突变性效力的影响,可为其监管提供数据支持。
Objective To evaluate the mutagenic risks of 17 nitrosamine compounds using toxicology software and bacterial reverse mutation test,and explore the relationship between the substituent structure of nitrosamine compounds and their mutagenicity risk.Methods Derek Nexus and Sarah Nexus were used to predict the mutagenic risks of 17nitrosamine compounds,and 6-well plate-based bacterial reverse mutation test of Salmonella typhimurium TA97,TA98,TA100,TA102,TA1535 and TA1537 in the absence and presence of rat S9 metabolic activation conditions was performed respectively,to evaluate their mutagenicity risks.Results Based on the nitroso structure,Derek Nexus predicted that 16 nitrosamines(excluding NDPh)had mutagenic risks.Sarah Nexus suggested all the 17 nitrosamines were mutagenic,whereas the mutagenic risks of NMEA,NEIPA and NDIPA were relatively lower.Under non-S9 metabolic activation conditions,except for NMPEA,the bacterial reverse mutation test results of all nitrosamine compounds were negative.NMPEA could only induce an increase in the number of revertants of TA1537 strain.Under rat S9 metabolic activation,NDEA,NMOR,NDPA,NPIP and NPYR showed positive results in all the TA97,TA100 and 1535 strains,and NDMA、NMEA、NEIPA、NDBA、NMPA、NNK、NDELA、NDPh and NMPEA were also positive in at least one of TA97,TA100 and TA1535 strains.Conclusion Mutagenicities of nitrosamine compounds are related to the factors of number ofα-hydrogens and substitution ofα-hydrogens,the presence of branched or larger/nonmetabolizable groups,and the stability of the formed diazonium ions in alkyl nitrosamine compounds,etc.This study provides the latest in vitro mutagenicity and DNA damage test data of nitrosamine compounds,validates the effect of substituent structure on the mutagenic potency of nitrosamine compounds,and can provide data support for their regulation.
作者
叶倩
汪祺
于敏
王雪
耿兴超
张乐帅
文海若
YE Qian;WANG Qi;YU Min;WANG Xue;GENG Xingchao;ZHANG Leshuai;WEN Hairuo(National Institutes for Food and Drug Control,Beijing 100050,China;China Pharmaceutical University,Nanjing Jiangsu 211198,China;Suzhou University,Suzhou Jiangsu 215123,China)
出处
《中国药物警戒》
2022年第8期881-888,共8页
Chinese Journal of Pharmacovigilance
基金
重大新药创制国家科技重大专项2018年度(2018ZX09201017)
国家自然科学基金资助项目(31971319,81503347)。
关键词
亚硝胺
致突变
构效分析
计算机毒理
细菌回复突变试验
nitrosamine
mutagenicity
structure-activity analysis
in silico toxicology
bacterial reverse mutation test
