title: Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6.
abstract: Naphthalene, phenanthrene, biphenyl, and their derivatives having different ethynyl, propynyl, butynyl, and propargyl ether substitutions were examined for their interaction with and oxidation by cytochromes P450 (P450) 2A13 and 2A6. Spectral interaction studies suggested that most of these chemicals interacted with P450 2A13 to induce Type I binding spectra more readily than with P450 2A6. Among the various substituted derivatives examined, 2-ethynylnaphthalene, 2-naphthalene propargyl ether, 3-ethynylphenanthrene, and 4-biphenyl propargyl ether had larger ΔAmax/Ks values in inducing Type I binding spectra with P450 2A13 than their parent compounds. P450 2A13 was found to oxidize naphthalene, phenanthrene, and biphenyl to 1-naphthol, 9-hydroxyphenanthrene, and 2- and/or 4-hydroxybiphenyl, respectively, at much higher rates than P450 2A6. Other human P450 enzymes including P450s 1A1, 1A2, 1B1, 2C9, and 3A4 had lower rates of oxidation of naphthalene, phenanthrene, and biphenyl than P450s 2A13 and 2A6. Those alkynylated derivatives that strongly induced Type I binding spectra with P450s 2A13 and 2A6 were extensively oxidized by these enzymes upon analysis with HPLC. Molecular docking studies supported the hypothesis that ligand-interaction energies (U values) obtained with reported crystal structures of P450 2A13 and 2A6 bound to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, indole, pilocarpine, nicotine, and coumarin are of use in understanding the basis of possible molecular interactions of these xenobiotic chemicals with the active sites of P450 2A13 and 2A6 enzymes. In fact, the ligand-interaction energies with P450 2A13 4EJG bound to these chemicals were found to relate to their induction of Type I binding spectra.
authors.affiliation: Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University , 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.affiliation: Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University , 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takenaka
authors.affiliation: Osaka Prefectural Institute of Public Health , 1-3-69 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan.
authors.forename: Kensaku
authors.initials: K
authors.lastname: Kakimoto
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: Department of Biological Sciences, Konkuk University , Seoul 143-701, Republic of Korea.
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Lim
authors.affiliation: Department of Biological Sciences, Konkuk University , Seoul 143-701, Republic of Korea.
authors.forename: Donghak
authors.initials: D
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , New Orleans, Louisiana 70125, United States.
authors.forename: Maryam K
authors.initials: MK
authors.lastname: Foroozesh
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University , Machida, Tokyo 194-8543, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.affiliation: Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences, Osaka Prefecture University , 1-58 Rinku-Orai-Kita, Izumisano, Osaka 598-8531, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komori
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry* / Q000378:metabolism; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001189:Aryl Hydrocarbon Hydroxylases; D001713:Biphenyl Compounds; D065637:Cytochrome P-450 CYP2A6; D009281:Naphthalenes; D010616:Phenanthrenes; C010574:biphenyl; C414206:CYP2A13 protein, human