Structure-Function Studies of Naphthalene, Phenanthrene, Biphenyl, and their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6 Tsutomu Shimada †,* , Shigeo Takenaka †,* , Kensaku Kakimoto ¶ , Norie Murayama ‡ , Young- Ran Lim ¶ , Donghak Kim ¶ , Maryam K. Foroozesh || , Hiroshi Yamazaki ‡,* , F. Peter Guengerich ∫,* , and Masayuki Komori †,* † 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 ‡ Laboratory of Drug Metabolism and Pharmacokinetics, Showa Pharmaceutical University, Machida, Tokyo 194-8543, Japan ∫ Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States ¶ Department of Biological Sciences, Konkuk University, Seoul 143-701, Republic of Korea || Department of Chemistry, Xavier University of Louisiana, New Orleans, Louisiana 70125, United States Abstract Naphthalene, phenanthrene, and 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 ΔA max /K s 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- * Corresponding authors: (T.S.) Telephone: 72-463-5326; Fax: 72-463-5326, t.shimada@vet.osakafu-u.ac.jp. (S.T.) Telephone: 72-463-5326; Fax: 72-463-5326, takenaka@vet.osakafu-u.ac.jp. (H.Y.) Telephone: 42-721-1406; Fax: 42-721-1406, hyamazak@ac.shoyaku.ac.jp. (F.P.G.) Telephone: 615-322-2261; Fax: 615-322-4349, f.guengerich@Vanderbilt.Edu. (M.K.) Telephone: 72-463-5326; Fax: 72-463-5326, komori@vet.osakafu-u.ac.jp. Correspondence to: Dr. Tsutomu Shimada, 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, Tel/Fax: +81-72-463-5326, t.shimada@vet.osakafu-u.ac.jp. Notes The authors declare no competing financial interests. SUPPORTING INFORMATION Correlation coefficients (r values) in ligand-interaction energies (U values) using reported structures of P450 2A13 and 2A6; oxidation of phenanthrene and 2EPh by P450 2A13 in the absence and presence of an NADPH-generating system (HPLC with UV detection) and docking simulation of interaction of nicotine, naphthalene, phenanthrene, and biphenyl with P450 2A13 (4EJG). This material is available free of charge via the Internet at http://pubs.acs.org. HHS Public Access Author manuscript Chem Res Toxicol. Author manuscript; available in PMC 2017 February 06. Published in final edited form as: Chem Res Toxicol. 2016 June 20; 29(6): 1029–1040. doi:10.1021/acs.chemrestox.6b00083. Author Manuscript Author Manuscript Author Manuscript Author Manuscript