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

Abstract

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 are of usemore » 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:

Shimada, Tsutomu ^[1]; Takenaka, Shigeo ^[1]; Kakimoto, Kensaku ^[2]; Murayama, Norie ^[3]; Lim, Young-Ran ^[4]; Kim, Donghak ^[4]; Foroozesh, Maryam K. ^[5]; Yamazaki, Hiroshi ^[3]; Guengerich, F. Peter ^[6]; Komori, Masayuki ^[1]

---

+ Show Author Affiliations

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:

Tue May 03 00:00:00 EDT 2016

Research Org.:

Tulane Univ., New Orleans, LA (United States)

Sponsoring Org.:

USDOE

OSTI Identifier:

1466774

Grant/Contract Number:  

FC26-00NT40843

Resource 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)

Country of Publication:

United States

Language:

English

Subject:

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 59 BASIC BIOLOGICAL SCIENCES