10.1021/es203718u.s001 Xingbao Wang Xingbao Wang Yong Wang Yong Wang Jingwen Chen Jingwen Chen Yuqin Ma Yuqin Ma Jing Zhou Jing Zhou Zhiqiang Fu Zhiqiang Fu Computational Toxicological Investigation on the Mechanism and Pathways of Xenobiotics Metabolized by Cytochrome P450: A Case of BDE-47 American Chemical Society 2012 transformation mechanism cytochrome P 450 enzymes hydroxylated polybrominated diphenyl ethers theory computation risk assessment Compound BDE Xenobiotics Metabolized Computational Toxicological Investigation epoxide C 2 C 4 atoms polarizable continuum model polycyclic compound CYP phenoxide xenobiotic B 3LYP nonsubstituted C atoms novel mechanism 2012-05-01 00:00:00 Journal contribution https://acs.figshare.com/articles/journal_contribution/Computational_Toxicological_Investigation_on_the_Mechanism_and_Pathways_of_Xenobiotics_Metabolized_by_Cytochrome_P450_A_Case_of_BDE_47/2527123 Understanding the transformation mechanism and products of xenobiotics catalyzed by cytochrome P450 enzymes (CYPs) is vital to risk assessment. By density functional theory computation with the B3LYP functional, we simulated the reaction of 2,2′,4,4′-tetrabromodiphenyl ether (BDE-47) catalyzed by the active species of CYPs (Compound I). The enzymatic and aqueous environments were simulated by the polarizable continuum model. The results reveal that the addition of Compound I to BDE-47 is the rate-determining step. The addition of Compound I to the ipso and nonsubstituted C atoms forms tetrahedral σ-adducts that further transform into epoxides. Hydroxylation of the epoxides leads to hydroxylated polybrominated diphenyl ethers and 2,4-dibromophenol. The addition to the Br-substituted C2 and C4 atoms has a higher barrier than addition to the nonsubstituted C atoms, forming phenoxide and cyclohexadienone which subsequently undergo debromination/hydroxylation. A novel mechanism was identified in which the approach of Compound I to C2 led to formation of a phenoxide and an expelled Br<sup>–</sup> ion. The predicted products were consistent with the metabolites identified by others. As a first attempt to simulate the enzymatic transformation of a polycyclic compound, this study may enlighten a computational method to predict the biotransformation of xenobiotics catalyzed by CYPs.