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.