Shimada Tsutomu, Takenaka Shigeo, Kakimoto Kensaku, Murayama Norie, Lim Young-Ran, Kim Donghak, Foroozesh Maryam K, Yamazaki Hiroshi, Guengerich F Peter, Komori Masayuki
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.
Osaka Prefectural Institute of Public Health , 1-3-69 Nakamichi, Higashinari-ku, Osaka 537-0025, Japan.
Chem Res Toxicol. 2016 Jun 20;29(6):1029-40. doi: 10.1021/acs.chemrestox.6b00083. Epub 2016 May 12.
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.
研究了萘、菲、联苯及其具有不同乙炔基、丙炔基、丁炔基和炔丙基醚取代基的衍生物与细胞色素P450（P450）2A13和2A6的相互作用及其被后者氧化的情况。光谱相互作用研究表明，这些化学物质中的大多数与P450 2A13相互作用时比与P450 2A6相互作用时更易诱导I型结合光谱。在所研究的各种取代衍生物中，2-乙炔基萘、2-萘炔丙基醚、3-乙炔基菲和4-联苯炔丙基醚在与P450 2A13诱导I型结合光谱时的ΔAmax/Ks值比其母体化合物更大。发现P450 2A13氧化萘、菲和联苯生成1-萘酚、9-羟基菲以及2-和/或4-羟基联苯的速率比P450 2A6高得多。包括P450 1A1、1A2、1B1、2C9和3A4在内的其他人类P450酶氧化萘、菲和联苯的速率比P450 2A13和2A6低。那些与P450 2A13和2A6强烈诱导I型结合光谱的炔基化衍生物在用HPLC分析时被这些酶大量氧化。分子对接研究支持这样的假设，即根据P450 2A13和2A6与4-（甲基亚硝基氨基）-1-（3-吡啶基）-1-丁酮、吲哚、毛果芸香碱、尼古丁和香豆素结合的报道晶体结构获得的配体相互作用能（U值）有助于理解这些外源性化学物质与P450 2A13和2A6酶活性位点可能的分子相互作用基础。事实上，发现与P450 2A13 4EJG结合这些化学物质的配体相互作用能与它们对I型结合光谱的诱导有关。
