环境中N-亚硝基化合物分子结构与致癌活性关系及其生物标志物研究

N-nitroso compounds (NNCs) are important carcinogens existing in the environment. The risk assessment of the carcinogenesis of NNCs and their integrated control measures are key points in the fields of environmental chemistry and cancer prevention. In our previous works, we performed intensive investigations on the mechanism of DNA damages induced by NNCs, as well as the relationship between the molecular structure and carcinogenicity. The quantitative structural-activity relationship (QSAR) of NNCs and the analysis methodology for DNA damages were established. The critical distinction between the carcinogenic and anticancer mechanisms of NNCs was clarified. In this project, based on our previous achievements, we will explore the mechanisms for the activation and detoxification of NNCs, the mechanisms for DNA and protein damages induced by various NNCs metabolites, and the reparation of these DNA and protein damages, by using theoretical chemistry methods. The metabolites of NNCs and the damages of DNA and protein will be quantitatively analyzed in the samples from in vitro, cell lines and animal experiments by using chromatograph coupled with mass spectrometry. By combining the theoretical and experimental investigations, we expect to establish a QSAR model for NNCs with higher applicability and higher correct discrimination, and to screen out biomarkers being able to accurately reflect the environmental exposure level of NNCs. This work will lay a foundation for further revealing the environmental hazard level of NNCs and for putting forward effective integrated control measures of NNCs related cancer. Moreover, this project will be very significant for establishing environmental pollution standards and countermeasures in high cancer incidence areas.

N-亚硝基化合物(NNCs)是环境中重要的致癌物质，其致癌风险评价和综合防治措施是环境化学和癌症防治研究领域中的关键问题。我们在前期工作中，对NNCs导致DNA损伤的作用机制及其分子结构与致癌活性关系进行了深入研究，已建立了NNCs构效关系和DNA损伤产物分析方法，阐明了NNCs致癌与抗癌机制的关键差异。在此基础上，本课题将采用理论化学方法研究NNCs的代谢活化和脱毒机制、不同代谢产物对DNA和蛋白的损伤机制、损伤的修复机制等，获取更广泛的结构参数；结合体外、细胞和动物实验水平上的NNCs代谢物及DNA和蛋白损伤产物的色谱-质谱定量分析，建立适用性更强、判对率更高的定量构效关系模型，并筛选出能够准确反应NNCs环境暴露水平的生物标志物。本课题将为深入揭示NNCs的环境危害水平、提出有效的NNCs致癌综合防治措施奠定基础；并将对环境污染标准和癌症高发区环境应对措施的制定具有重要意义。

N-亚硝基化合物(NNCs)是环境中广泛存在的一类重要致癌物质，其致癌风险评价和综合防治措施是环境化学和癌症防治研究领域中的关键问题。本课题采用量子化学方法对NNCs的代谢活化、NNCs导致DNA碱基和磷酸基团的烷化、DNA单链断裂、DNA股间交联以及O6-烷基鸟嘌呤-DNA烷基转移酶介导的DNA烷化损伤修复的作用机理进行了研究。比较了抗癌氯乙基亚硝基脲和致癌亚硝胺双官能团代谢产物导致DNA股间交联的反应机理，提出了两个亲电中心烷基化活性的差异是导致这两类化合物具有不同生理活性的关键因素，分别建立了亚硝胺的定量分子结构与致癌活性关系和亚硝基脲的定量分子结构与抗癌活性关系。使用HPLC-MS/MS方法对不同种类NNCs导致的多种DNA损伤产物进行了定量分析，建立了具有高灵敏度、高准确性和高专属性的定量分析方法。在生物标志物研究方面，筛选出了7-吡啶丁酮基鸟嘌呤作为烟草特异亚硝胺——N-亚硝基去甲烟碱导致食管癌的生物标志物；筛选出了dG-dC股间交联可作为评价氯乙基亚硝基脲抗癌活性的生物标志物。该课题一方面将为深入揭示NNCs的环境危害水平、提出有效的NNCs致癌综合防治措施奠定基础，对于建立有效的NNCs环境健康风险评价体系、提出合理的环境污染标准和制定可行的癌症高发区环境应对措施具有重要意义；另一方面该研究为设计开发出具有自主知识产权的新型高效低毒亚硝基脲类抗癌药物提供了重要的科学依据。