title: Computational toxicological investigation on the mechanism and pathways of xenobiotics metabolized by cytochrome P450: a case of BDE-47.
abstract: 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(-) 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.
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Xingbao
authors.initials: X
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Jingwen
authors.initials: J
authors.lastname: Chen
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000465:Algorithms; D053138:Cyclohexenes / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls / Q000378:metabolism* / Q000633:toxicity; D015262:Xenobiotics / Q000378:metabolism* / Q000633:toxicity
chemical_list: D053138:Cyclohexenes; D004852:Epoxy Compounds; D055768:Halogenated Diphenyl Ethers; D011075:Polybrominated Biphenyls; D015262:Xenobiotics; C507608:cyclohexadienone; C511295:2,2',4,4'-tetrabromodiphenyl ether; D003577:Cytochrome P-450 Enzyme System