Understanding the transformation pathways and products of xenobiotics, especially persistent organic pollutants like polychlorinated biphenyls (PCBs) in mammals, is vital for risk assessment. Multitudinous <i>in vivo</i> and <i>in vitro</i> studies have attested that the metabolism of PCBs involved the role of cytochrome P450 enzymes (CYPs), whereas the underlying transformation mechanism remains unclarified. In this study, we adopted density functional theory (DFT) and molecular docking calculations to simulate the metabolism of two PCB congeners, 2,2’,5,5’-PCB (PCB-52) and 3,3’,4,4’-PCB (PCB-77) catalyzed by the active center (Compound I) of human CYP 2B6. The enzymatic environment was simulated by the polarizable continuum model. DFT results unveiled that electrophilic attack of Compound I to the aromatic carbons of the two PCBs is the rate-limiting step, with the reaction energy barrier in the orders of C3 ≈ C4 &lt; C6 &lt; C1 ≈ C2 ≈ C5 for PCB-52, and C5 ≈ C6 &lt; C2 &lt; C4 &lt; C3 ≈ C1 for PCB-77. The results are substantiated by experimental observations that C3 and C4-hydroxylated products were dominant in PCB-52 metabolism. The combination of Compound I to the nonchloro-substituted C atoms forms tetrahedral δ-adducts which further rearrange to arene epoxides. By contrast, addition to Cl-substituted sites overall requires higher barriers than addition to the nonchloro-substituted C atoms, giving cyclohexadienone intermediates with the Cl atoms shifted to neighboring C atoms. Molecular docking results reveal that PCB-77 has a higher binding affinity with CYP 2B6 than PCB-52. However, the binding conformation with C3 and C4 orienting to Compound I makes it unlikely to be oxidized, which accounts for the congener-selective metabolism of PCBs by CYPs. This study implies that the DFT computation can be an effective tool for predicting biotransformation of xenobiotics catalyzed by CYPs.

Metabolic pathways of polychlorinated biphenyls (PCBs) mediated by the active center of cytochrome P450s: A computational study with PCB-52 and PCB-77

249th National Meeting (2015)

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