title: Transformation pathways of MeO-PBDEs catalyzed by active center of P450 enzymes: a DFT investigation employing 6-MeO-BDE-47 as a case.
abstract: Recent in vivo and in vitro experiments indicated that methoxylated polybrominated diphenyl ethers (MeO-PBDEs) can be biotransformed into hydroxylated PBDEs (HO-PBDEs) that are more toxic than PBDEs and MeO-PBDEs. Nevertheless, the enzymatic transformation mechanism is not clear. We hypothesized that cytochrome P450 enzymes (CYPs) play a key role in the transformation and employed the density functional theory calculations to unveil the mechanism. The transformation of a model compound, 6-MeO-BDE-47, catalyzed by the active center of CYPs (Compound I), was computed. For the first time, our results show that the energy barriers for the addition of Compound I to the C atoms on the phenyl of 6-MeO-BDE-47 are much higher than that for hydroxylation of the methoxyl, indicating that O-demethylation is a dominating metabolic pathway. This is in line with experimental observations performed by others. The pathways for the transformation of 6-MeO-BDE-47 catalyzed by Compound I were clarified. A C-H bond of the methoxyl is activated by Compound I, followed by radical rebound to form carbinol intermediates, then the carbinols decompose to form 6-HO-BDE-47 with the assistance of water molecules. The computational method can be potentially employed to develop models that predict 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; State Key Laboratory of Fine Chemicals, School of Pharmaceutical Science and Technology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Xingbao
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Industrial Ecology and Environmental Engineering (MOE), School of Environmental Science and Technology, Dalian University of Technology, Dalian 116024, China. Electronic address: jwchen@dlut.edu.cn.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
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: Hongbin
authors.initials: H
authors.lastname: Xie
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: Zhiqiang
authors.initials: Z
authors.lastname: Fu
mesh_terms: D000840:Anisoles / Q000378:metabolism*; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D055768:Halogenated Diphenyl Ethers / Q000378:metabolism* / Q000633:toxicity; D006900:Hydroxylation; D008954:Models, Biological; D015394:Molecular Structure; D011166:Porphyrins / Q000378:metabolism*
chemical_list: C496823:2-(2',4'-dibromophenoxy)-3,5-dibromoanisole; D000840:Anisoles; D055768:Halogenated Diphenyl Ethers; D011166:Porphyrins; D003577:Cytochrome P-450 Enzyme System
keywords: Biotransformed; Density functional theory calculations; Methoxylated polybrominated diphenyl ethers; P450 enzymes