Insights into the metabolic mechanism of PBDEs catalyzed by cytochrome P450 enzyme 3A4: A QM/MM study.

Elucidating the metabolic mechanism and the derivatives of polybrominated diphenyl ethers (PBDEs) is significant to risk assessment. This study delineated the metabolic mechanism of 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) catalyzed by P450 enzymes using a combination of molecular dynamic (MD), quantum mechanics/molecular mechanics (QM/MM) and density functional theory (DFT). The calculation results reveal that the electrophilic addition is the main pathway for the biotransformation of BDE-47 catalyzed by P450 enzymes. 6-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (6-OH-BDE-47) is a more kinetically preferable product than 5-hydroxy-2,2',4,4'-tetrabromodiphenyl ether (5-OH-BDE-47). Electrophilic addition reaction can lead to the formation of polybrominated dibenzo-p-dioxins and dibenzofurans (PBDD/Fs). The ecotoxicity assessment indicates that the final products of BDE-47 are still toxic to aquatic organisms, but the solubility increase of the hydroxylated products can accelerate their excretion from the body. We expect that the established metabolic mechanism and the derivatives will be used to predict the biotransformation of other PBDE congeners catalyzed by P450 enzymes in human livers.