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Title: Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6

In this study, 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 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-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. Additionally, 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 aremore » 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.« less
Authors:
 [1] ;  [1] ;  [2] ;  [3] ;  [4] ;  [4] ;  [5] ;  [3] ;  [6] ;  [1]
  1. Osaka Prefecture University, Osaka (Japan). Laboratory of Cellular and Molecular Biology, Graduate School of Life and Environmental Sciences
  2. Osaka Prefectural Institute of Public Health, Osaka (Japan)
  3. Showa Pharmaceutical University, Machida, Tokyo (Japan). Laboratory of Drug Metabolism and Pharmacokinetics
  4. Konkuk University, Seoul (Republic of Korea). Department of Biological Sciences
  5. Xavier University of Louisiana, New Orleans, LA (United States). Department of Chemistry
  6. Vanderbilt University School of Medicine, Nashville, TN (United States). Department of Biochemistry
Publication Date:
Grant/Contract Number:
FC26-00NT40843
Type:
Accepted Manuscript
Journal Name:
Chemical Research in Toxicology
Additional Journal Information:
Journal Volume: 29; Journal Issue: 6; Journal ID: ISSN 0893-228X
Publisher:
American Chemical Society (ACS)
Research Org:
Tulane Univ., New Orleans, LA (United States)
Sponsoring Org:
USDOE
Country of Publication:
United States
Language:
English
Subject:
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES
OSTI Identifier:
1466774

Shimada, Tsutomu, Takenaka, Shigeo, Kakimoto, Kensaku, Murayama, Norie, Lim, Young-Ran, Kim, Donghak, Foroozesh, Maryam K., Yamazaki, Hiroshi, Guengerich, F. Peter, and Komori, Masayuki. Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6. United States: N. p., Web. doi:10.1021/acs.chemrestox.6b00083.
Shimada, Tsutomu, Takenaka, Shigeo, Kakimoto, Kensaku, Murayama, Norie, Lim, Young-Ran, Kim, Donghak, Foroozesh, Maryam K., Yamazaki, Hiroshi, Guengerich, F. Peter, & Komori, Masayuki. Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6. United States. doi:10.1021/acs.chemrestox.6b00083.
Shimada, Tsutomu, Takenaka, Shigeo, Kakimoto, Kensaku, Murayama, Norie, Lim, Young-Ran, Kim, Donghak, Foroozesh, Maryam K., Yamazaki, Hiroshi, Guengerich, F. Peter, and Komori, Masayuki. 2016. "Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6". United States. doi:10.1021/acs.chemrestox.6b00083. https://www.osti.gov/servlets/purl/1466774.
@article{osti_1466774,
title = {Structure–Function Studies of Naphthalene, Phenanthrene, Biphenyl, and Their Derivatives in Interaction with and Oxidation by Cytochromes P450 2A13 and 2A6},
author = {Shimada, Tsutomu and Takenaka, Shigeo and Kakimoto, Kensaku and Murayama, Norie and Lim, Young-Ran and Kim, Donghak and Foroozesh, Maryam K. and Yamazaki, Hiroshi and Guengerich, F. Peter and Komori, Masayuki},
abstractNote = {In this study, 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. Additionally, 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.},
doi = {10.1021/acs.chemrestox.6b00083},
journal = {Chemical Research in Toxicology},
number = 6,
volume = 29,
place = {United States},
year = {2016},
month = {5}
}