A novel approach to predict the comprehensive EROD potency: Mechanism-based curve fitting of CYP1A1 activity by PAHs

• Published in: The Science of the total environment 2022-10, Vol.843, p.157052-157052, Article 157052
• Main Authors: Chen, Chao, Zhang, Di, Yuan, Anjie, Shen, Jiemiao, Wang, Li, Wang, Shou-Lin
• Format: Article
• Language: English
• Subjects: 7-ethoxyresorufin-O-deethylase activity (EROD); Cytochrome P450s 1A1 (CYP1A1); EROD potency; In silico models; Polycyclic aromatic hydrocarbons (PAHs)
• ISSN: 0048-9697; 1879-1026
• DOI: 10.1016/j.scitotenv.2022.157052

Cytochrome P450 1A1 (CYP1A1) plays critical roles in polycyclic aromatic hydrocarbon (PAH) toxicity, including DNA adduction and ROS generation. Therefore, CYP1A1 activity quantified by the 7-ethoxyresorufin-O-deethylase (EROD) assay (named EROD potency) has been considered a typical biomarker of PAH exposure and toxicity. The EROD dose–response curve always presents a biphasic style, increasing at low concentrations and decreasing at high concentrations of PAHs, but relative effect potency (REP) commonly used in PAH risk assessment is only involved in the increasing phase. In this study, a full bell-shaped EROD curve fitting formula Eq. (1) was obtained by considering both CYP1A1 mRNA induction and enzyme inhibition to completely assess the EROD potency of PAHs. Correspondingly, in silico models of QSAR and docking methods successfully predicted the full EROD curves of PAHs, and the structure-activity relationship indicated that PAHs with heavy molecular weight and large diameter showed stronger EROD potency. Further EROD potency with predicted curve parameters (EC50,ind and area index) was confirmed by the reported REP (R2 = 0.697–0.977) and experimental data from human and mouse cells (R2 = 0.700–0.804). This study provides a novel curve fitting for the EROD dose–response relationship and a prediction model for PAH EROD potency. [Display omitted] •A fitting method for full bell-shaped EROD curves of PAHs with better universality•A combined model considering both CYP1A1 mRNA induction and enzyme inhibition•Risk assessment of PAHs based on the full EROD dose-response relationship•Establish a in silico prediction method for EROD curves and the risk of PAHs