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In Vitro and in Silico Analyses for Predicting Hepatic Cytochrome P450-Dependent Metabolic Potencies of Polychlorinated Biphenyls in the Baikal Seal
journal contribution
posted on 2015-12-15, 00:00 authored by Jean Yoo, Masashi Hirano, Hazuki Mizukawa, Kei Nomiyama, Tetsuro Agusa, Eun-Young Kim, Shinsuke Tanabe, Hisato IwataThe aim of this study was to understand
the cytochrome P450 (CYP)-dependent
metabolic pathway and potency of polychlorinated biphenyls (PCBs)
in the Baikal seal (Pusa sibirica).
In vitro metabolism of 62 PCB congener mixtures was investigated by
using liver microsomes of this species. A decreased ratio of over
20% was observed for CB3, CB4, CB8, CB15, CB19, CB22, CB37, CB54,
CB77, and CB105, suggesting the preferential metabolism of low-chlorinated
PCBs by CYPs. The highly activated metabolic pathways in Baikal seals
that were predicted from the decreased PCBs and detected hydroxylated
PCBs (OH-PCBs) were CB22 to 4′OH-CB20 and CB77 to 4′OH-CB79.
The total amount of OH-PCBs detected as identified and unidentified
congeners accounted for only a 3.8 ± 1.7 mol % of loaded PCBs,
indicating many unknown PCB metabolic pathways. To explore factors
involved in CYP-dependent PCB metabolism, we examined the relationships
among the structural and physicochemical properties of PCBs, the in
silico PCB-CYP docking parameters, and the in vitro PCB decreased
ratios by principal component analysis. Statistical analysis showed
that the decreased PCB ratio was at least partly accounted for by
the substituted chlorine number of PCBs and the distance from the
Cl-unsubstituted carbon of docked PCBs to the heme Fe in CYP2A and
2B.
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Baikal sealsBaikal SealThe aimCB 222 Bchlorine numberPolychlorinated BiphenylsBaikal sealheme FeSilico Analysescomponent analysisPusa sibiricaCB 77PCB ratiohydroxylated PCBsliver microsomesCYP 2Aphysicochemical propertiesStatistical analysiscytochrome P 45062 PCB congener mixturespolychlorinated biphenyls
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