Computational Toxicological
Investigation on the Mechanism and Pathways of Xenobiotics
Metabolized by Cytochrome P450: A Case of BDE-47
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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<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