title: In Vitro and in Silico Analyses for Predicting Hepatic Cytochrome P450-Dependent Metabolic Potencies of Polychlorinated Biphenyls in the Baikal Seal.
abstract: The 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.
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Jean
authors.initials: J
authors.lastname: Yoo
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Hirano
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Hazuki
authors.initials: H
authors.lastname: Mizukawa
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Nomiyama
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Agusa
authors.affiliation: Department of Life and Nanopharmaceutical Science and Department of Biology, Kyung Hee University , Hoegi-Dong, Dongdaemun-Gu, Seoul 130-701, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Kim
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Tanabe
authors.affiliation: Center for Marine Environmental Studies (CMES), Ehime University , Bunkyo-cho 2-5, Matsuyama 790-8577, Japan.
authors.forename: Hisato
authors.initials: H
authors.lastname: Iwata
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D006900:Hydroxylation; D008658:Inactivation, Metabolic; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D011078:Polychlorinated Biphenyls / Q000378:metabolism / Q000493:pharmacokinetics*; D025341:Principal Component Analysis; D046048:Seals, Earless / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014874:Water Pollutants, Chemical / Q000378:metabolism / Q000493:pharmacokinetics
chemical_list: D014874:Water Pollutants, Chemical; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase