Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China.
Sci Total Environ. 2021 Sep 15;787:147596. doi: 10.1016/j.scitotenv.2021.147596. Epub 2021 May 7.
PAHs and their derivatives are the main sources of mutagenicity and carcinogenicity in airborne particular matter and cause serious public health and environmental problems. Risk assessment is challenging due to the mixed nature and deficiency of toxicity data of most PAHs and their derivatives. Cytochrome P450 enzymes (CYPs) play important roles in PAH-induced carcinogenicity via metabolic activation, and CYP conformations with compound I structures strongly influence metabolic sites and metabolite species. In this study, complexes of BaP with CYP1A1, CYP1B1 or CYP2C19 compound I were successfully simulated by QM/MM methods and verified by metabolic clearance, and the mutagenicity of chemicals was then predicted by the BaP-7,8-epoxide-related metabolic conformation fitness (MCF) approach, which was validated by Ames tests, showing satisfying accuracy (R = 0.46-0.66). Furthermore, a prediction model of the mutagenicity risk of PAH and derivative mixtures was established based on the relative potential factor (RPF) approach and the RPF calculated from the mathematical relationship between the minimum MCF (MCF) and RPF, which was successfully validated by the mutagenesis of PAH and derivative mixture mimic-simulating PM2.5 samples collected in eastern China. This study provides fast reliable tools for assessing risk of the complex components of environmental PAHs and their derivatives.
多环芳烃及其衍生物是空气中颗粒物致突变性和致癌性的主要来源，造成严重的公共卫生和环境问题。由于大多数多环芳烃及其衍生物的混合性质和毒性数据的缺乏，风险评估具有挑战性。细胞色素 P450 酶（CYPs）在多环芳烃诱导的致癌性中通过代谢激活发挥重要作用，并且具有化合物 I 结构的 CYP 构象强烈影响代谢部位和代谢产物种类。在这项研究中，通过 QM/MM 方法成功模拟了 BaP 与 CYP1A1、CYP1B1 或 CYP2C19 化合物 I 的复合物，并通过代谢清除率进行了验证，然后通过 BaP-7,8-环氧化物相关代谢构象适合度（MCF）方法预测了化学品的致突变性，该方法通过 Ames 测试得到验证，具有令人满意的准确性（R = 0.46-0.66）。此外，基于相对潜在因子（RPF）方法和 MCF 与 RPF 之间的数学关系计算得到的 RPF，建立了多环芳烃及其衍生物混合物致突变风险的预测模型，并成功验证了中国东部采集的 PM2.5 模拟样中多环芳烃及其衍生物混合物模拟物的致突变性。这项研究为评估环境多环芳烃及其衍生物的复杂成分的风险提供了快速可靠的工具。
