Mutagenicity risk prediction of PAH and derivative mixtures by in silico simulations oriented from CYP compound I-mediated metabolic activation.

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 (R2 = 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 (MCFmin) 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.