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Computational Toxicological Investigation on the Mechanism and Pathways of Xenobiotics Metabolized by Cytochrome P450: A Case of BDE-47
journal contribution
posted on 2012-05-01, 00:00 authored by Xingbao Wang, Yong Wang, Jingwen Chen, Yuqin Ma, Jing Zhou, Zhiqiang FuUnderstanding 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.
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Keywords
transformation mechanismcytochrome P 450 enzymeshydroxylated polybrominated diphenyl etherstheory computationrisk assessmentCompoundBDEXenobiotics MetabolizedComputational Toxicological InvestigationepoxideC 2C 4 atomspolarizable continuum modelpolycyclic compoundCYPphenoxidexenobioticB 3LYPnonsubstituted C atomsnovel mechanism
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