稠环与非稠环芳烃对大鼠致癌性的定量构效关系研究  

QSAR Modeling on Carcinogenicity of Fused and Non-fused Aromatic Hydrocarbons(FNFAHs)Toward Rats

作　　者：李非凡[1] 范腾蛟 孙国辉[1] 赵丽娇[1] 钟儒刚[1] LI Fei-fan;FAN Teng-jiao;SUN Guo-hui;ZHAO Li-jiao;ZHONG Ru-gang(Beijing Key Laboratory of Environmental and Viral Oncology,Faculty of Environment and Life,Beijing University of Technology,Beijing 100124,China;Department of Medical Technology,Beijing Pharmaceutical University of Staff and Workers,Beijing 100079,China)

机构地区：[1]北京工业大学环境与生命学部环境与病毒肿瘤学北京市重点实验室,北京100124 [2]北京医药职工大学医学技术系,北京100079

出　　处：《化学试剂》2022年第7期990-1000,共11页Chemical Reagents

基　　金：国家自然科学基金资助项目(82003599,21778011);北京市教委科技计划一般项目(KM202110005005);北京市教委重点实验室项目(PXM2015014204500175)。

摘　　要：稠环与非稠环芳烃(FNFAHs)的致癌性与人类的健康密切相关。用传统实验测试方法进行毒理学研究成本昂贵、耗时,且涉及伦理问题。因此,用于致癌性预测的定量构效关系(QSAR)等计算机替代方法受到了监管机构的广泛关注。根据严格的OECD指南,基于2D分子描述符采用遗传算法(GA)结合多元线性回归(MLR)方法建立了FNFAHs对雌性大鼠、雄性大鼠和大鼠的致癌性QSAR模型,所有模型均通过国际广泛接受的内部和外部验证指标,并进行应用域(AD)分析。同时,机理解释确定了结构信息(描述符)和致癌性之间的详细关系。此外,还首次应用所建立的模型预测了没有实验值的真实外部集化合物的致癌效力。就监管目的而言,所构建的模型在其AD内可用于预测新的或未经测试的FNFAHs的致癌性。The carcinogenicity of fused and non-fused aromatic hydrocarbons(FNFAHs)is closely related to human health.Traditional,experimental testing methods for toxicology research are expensive,and time-consuming and involve ethical issues.Therefore,in silico alternative methods such as the quantitative structure-activity relationship(QSAR)for the carcinogenicity prediction have attracted extensive attention from regulatory agencies.In this study,we established QSAR models of carcinogenicity of FNFAHs to female rats,male rats and rats by using genetic algorithm(GA)and multiple linear regression(MLR)based on 2D molecular descriptors in accordance with strict OECD guidelines.All models were validated using internationally accepted internal and external validation indicators,and applicability domain(AD)analysis was performed to define a reliable extrapolated chemical space.Meanwhile,the mechanism interpretation determines the detailed relationship between structural information(descriptor)and carcinogenicity.In addition,we applied the established models for the first time to predict the carcinogenic potency of real external set compounds without experimental values.In conclusion,for regulatory purposes,the models constructed in this study can be used to predict the carcinogenicity of new or untested FNFAHs with their AD.

关 键 词：稠环与非稠环芳烃 致癌性 替代方法 定量构效关系 风险评估 

分 类 号：R99[医药卫生—毒理学]