title: From the Cover: Structural Determinants of the Position of 2,3',4,4',5-Pentachlorobiphenyl (CB118) Hydroxylation by Mammalian Cytochrome P450 Monooxygenases.
abstract: Polychlorinated biphenyls (PCBs) accumulate in mammals via the food chain because of their characteristics such as slow degradation and high hydrophobicity. One of the 209 PCB congeners, 2,3',4,4',5-pentachlorobiphenyl (CB118), is abundantly found in the environment and in mammals. Understanding the metabolic fate of CB118 can provide important information toward evaluating its toxicity. In vitro studies on the metabolism of CB118 by cytochrome P450 enzymes (P450 or CYP) revealed that human CYP2B6 and rat CYP2B1 primarily metabolized it to 3-hydroxy (OH)-CB118, whereas rat CYP1A1 metabolized CB118 to 4-hydroxy-2,3,3',4',5-pentachlorobiphenyl (4-OH-CB107). Docking models of CYP2Bs with CB118 revealed a short distance between the 3-position of CB118 and the heme iron caused by polarization of the substrate-binding cavity, and maintenance of this pose through interaction with the peripheral amino acids determines the activity and position of hydroxylation. 4-Hydroxylation by rat CYP1A1 occurs owing to the longitudinal shape of the substrate-binding cavity toward the heme of CYP1A1. The metabolites 3-OH-CB118 and 4-OH-CB107 decreased potential for activating the aryl hydrocarbon receptor compared with that of CB118, thereby leading to a decrease in dioxin-like toxicity; however, the neurodevelopmental toxicity of 4-OH-CB107 has been previously reported. The results suggest that these 3 P450 isoforms play an important role in determining the extent of CB118 toxicity. This study will contribute to understanding of the metabolic fates and toxicity of CB118 in vivo.
authors.affiliation: *Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo, 657-8501, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Mise
authors.affiliation: Hyogo Prefectural Institute of Environmental Sciences, Kobe, Hyogo, 654-0037, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Haga
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Kato
authors.affiliation: *Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo, 657-8501, Japan Research Center for Food Safety and Security, Kobe University, Kobe, Hyogo, 657-8501, Japan Faculty of Agriculture, Kobe University, Kobe, Hyogo, 657-8501, Japan.
authors.forename: Itsuko
authors.initials: I
authors.lastname: Fukuda
authors.affiliation: Faculty of Agriculture, Kobe University, Kobe, Hyogo, 657-8501, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Goto
authors.affiliation: Laboratory of Drug Design and Medicinal Chemistry, Showa Pharmaceutical University, Machida, Tokyo, 194-8543, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: *Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo, 657-8501, Japan.
authors.forename: Miku
authors.initials: M
authors.lastname: Yabu
authors.affiliation: Hyogo Prefectural Institute of Environmental Sciences, Kobe, Hyogo, 654-0037, Japan.
authors.forename: Chisato
authors.initials: C
authors.lastname: Matsumura
authors.affiliation: Research Center for Environmental Preservation, Osaka University, Suita, Osaka, 565-0871, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, Imizu, Toyama, 939-0398, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.affiliation: *Graduate School of Agricultural Science, Kobe University, Kobe, Hyogo, 657-8501, Japan Faculty of Agriculture, Kobe University, Kobe, Hyogo, 657-8501, Japan Research Center for Environmental Genomics, Kobe University, Kobe, Hyogo, 657-8501, Japan hinui@kobe-u.ac.jp.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Inui
mesh_terms: D000818:Animals; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D011078:Polychlorinated Biphenyls / Q000378:metabolism* / Q000633:toxicity; D011487:Protein Conformation; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D007527:Isoenzymes; D018336:Receptors, Aryl Hydrocarbon; C070055:2,3',4,4',5-pentachlorobiphenyl; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls
keywords: 3D structure; cytochrome P450 monooxygenase; docking model; hydroxylation; polychlorinated biphenyl