title: Identification and in silico prediction of metabolites of the model compound, tebufenozide by human CYP3A4 and CYP2C19.
abstract: The metabolites of tebufenozide, a model compound, formed by the yeast-expressed human CYP3A4 and CYP2C19 were identified to clarify the substrate recognition mechanism of the human cytochrome P450 (CYP) isozymes. We then determined whether tebufenozide metabolites may be predicted in silico. Hydrogen abstraction energies were calculated with the density functional theory method B3LYP/6-31G(∗). A docking simulation was performed using FRED software. Several alkyl sites of tebufenozide were hydroxylated by CYP3A4 whereas only one site was modified by CYP2C19. The accessibility of each site of tebufenozide to the reaction center of CYP enzymes and the susceptibility of each hydrogen atom for metabolism by CYP enzymes were evaluated by a docking simulation and hydrogen abstraction energy estimation, respectively.
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Shirotani
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Moe
authors.initials: M
authors.lastname: Togawa
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu-shi, Toyama 939-0398, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ikushiro
authors.affiliation: Faculty of Engineering, Toyama Prefectural University, 5180, Kurokawa, Imizu-shi, Toyama 939-0398, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Sakaki
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Harada
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Miyagawa
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Matsui
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Nagahori
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Mikata
authors.affiliation: Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugade-naka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nishioka
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Hirai
authors.affiliation: Graduate School of Agriculture, Kyoto University, Kitashirakawa-oiwake-cho, Sakyo-ku, Kyoto 606-8502, Japan. Electronic address: akamatsu@kais.kyoto-u.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Akamatsu
mesh_terms: D003198:Computer Simulation; D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D006801:Humans; D006834:Hydrazines / Q000032:analysis* / Q000378:metabolism*; D062105:Molecular Docking Simulation; D012984:Software
chemical_list: D006834:Hydrazines; C045793:CYP2C19 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C082026:tebufenozide
keywords: CYP2C19; CYP3A4; Docking simulation; Hydrogen abstraction energy; In silico prediction; Tebufenozide metabolites