title: Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13.
abstract: 1. The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme. 2. Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6-dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13. 3. 1-Nitropyrene and 1-acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis. 4. Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297 and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1. 5. These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans.
authors.affiliation: a Laboratory of Cellular and Molecular Biology , Graduate School of Life and Environmental Sciences, Osaka Prefecture University , Izumisano , Osaka , Japan .
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Shimada
authors.affiliation: a Laboratory of Cellular and Molecular Biology , Graduate School of Life and Environmental Sciences, Osaka Prefecture University , Izumisano , Osaka , Japan .
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takenaka
authors.affiliation: b Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan .
authors.forename: Norie
authors.initials: N
authors.lastname: Murayama
authors.affiliation: c Department of Biochemistry and Center in Molecular Toxicology , Vanderbilt University School of Medicine , Nashville , TN , USA .
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Kramlinger
authors.affiliation: d Department of Biological Sciences , Konkuk University , Seoul , Republic of Korea , and.
authors.forename: Joo-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: d Department of Biological Sciences , Konkuk University , Seoul , Republic of Korea , and.
authors.forename: Donghak
authors.initials: D
authors.lastname: Kim
authors.affiliation: e Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.affiliation: e Department of Chemistry , Xavier University of Louisiana , New Orleans , LA , USA.
authors.forename: Maryam K
authors.initials: MK
authors.lastname: Foroozesh
authors.affiliation: b Laboratory of Drug Metabolism and Pharmacokinetics , Showa Pharmaceutical University , Machida , Tokyo , Japan .
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamazaki
authors.affiliation: c Department of Biochemistry and Center in Molecular Toxicology , Vanderbilt University School of Medicine , Nashville , TN , USA .
authors.forename: F Peter
authors.initials: FP
authors.lastname: Guengerich
authors.affiliation: a Laboratory of Cellular and Molecular Biology , Graduate School of Life and Environmental Sciences, Osaka Prefecture University , Izumisano , Osaka , Japan .
authors.forename: Masayuki
authors.initials: M
authors.lastname: Komori
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism*; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6 / Q000378:metabolism; D006801:Humans; D007915:Lepidoptera / Q000166:cytology / Q000378:metabolism; D008954:Models, Biological; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D011083:Polycyclic Compounds / Q000378:metabolism; D011721:Pyrenes / Q000378:metabolism*
chemical_list: D011083:Polycyclic Compounds; D011721:Pyrenes; C030984:pyrene; D001189:Aryl Hydrocarbon Hydroxylases; C414206:CYP2A13 protein, human; C585710:CYP2A6 protein, human; D019363:Cytochrome P-450 CYP1A1; D065637:Cytochrome P-450 CYP2A6; C033146:1-hydroxypyrene; C032668:1-nitropyrene
keywords: 1-Acetylpyrene; 1-hydroxypyrene; 1-nitropyrene; P450 2A13; oxidation; pyrene