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

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 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 interaction of these xenobiotic chemicals with active sites of P4502A13 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.

Inhibition of Carcinogen-Activating Cytochrome P450 Enzymes by Xenobiotic Chemicals in Relation to Antimutagenicity and Anticarcinogenicity

“…6C) and 2A6 (Fig. 6D) (26,(28)(29)(30). All of these chemicals induce type I binding spectra with CYP2A13 having high affinities with 2-ethynylnaphthalene, 2-naphthalene propargyl ether, naphthalene, 1-naphthalene ethylpropargyl ether, 2-naphthalene ethylpropargyl ether, 3-ethynylnaphthalene, 9-ethynylnaphthalene, 3-(1-propynyl)phenanthrene, 2-ethynylnaphthalene, 2-(1-propynyl)phenanthrene, phenanthrene, 4-biphenyl propargyl ether, biphenyl, and 4-ethynylbiphenyl (Fig.…”

“…Our previous studies using umu genotoxicity assay with human P450 enzymes in conjunction with the results obtained from Ames mutagenicity assay and other detection systems reported so far (6,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) have suggested that human CYP1A1, 1A2, 1B1, 2A6, 2A13, 2E1, and 3A4 are major enzymes involved in the activation of various environmental carcinogens including PAHs and tobacco-related nitrosamines (Table 1). In this review, we first describe in vivo studies on the roles of CYP1 and 2A enzymes in the formation of tumors caused by various chemical carcinogens; these are reported using (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31).…”

“…Since CYP1A1, 1A2, 1B1, 2A6, and 2A13 have been recognized to be key enzymes in understanding the basis of chemical carcinogenesis caused by a variety of carcinogenic PAHs and tobacco-related nitrosamines, we summarize, mainly our recent studies during the past decade, on the nature of numerous xenobiotic chemicals that inhibit these human P450 enzymes (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Followings are described here that a) inhibition of CYP1 enzymes by a variety of PAHs and acetylenic PAH inhibitors, b) different mechanisms of inhibition of CYP1 enzymes by PAHs and acetylenic PAH inhibitors, c) inhibition of P450 enzymes by flavonoid derivatives, d) interaction of xenobiotic chemicals with CYP2A13 and 2A6, and e) inhibition of CYP1 and 2A enzymes by chemopreventive organoselenium compounds.…”

“…Since molecular docking analysis has been shown to be a useful tool for the studies of the interactions of various ligands with active sites of enzymes, such as P450s, we examined and compared the ligand-interaction energies (U values) with these 24 chemicals using reported crystal structures of CYP2A13 (4EJH), 2A13 (2P85), 2A13 (3T3S), and 2A13 (4EJG) (142)(143)(144) bound to NNK, indole, pilocarpine, and nicotine, respectively, and CYP2A6 (1Z10), 2A6 (3T3R), and 2A6 4EJJ) (145,146) bound to coumarin, pilocarpine, and nicotine, respectively (30). We first determined the U values of interaction of 2-ethynylnaphthalene, 2-ethynylphenanthrene, and 4-biphenylpropagyl ether with CYP2A13 (4EJH), CYP2A13 (2P85), CYP2A13 (3T3S), and CYP2A13 (4EJG) (Fig.…”

“…We first determined the U values of interaction of 2-ethynylnaphthalene, 2-ethynylphenanthrene, and 4-biphenylpropagyl ether with CYP2A13 (4EJH), CYP2A13 (2P85), CYP2A13 (3T3S), and CYP2A13 (4EJG) (Fig. 7) and obtained optimal U values on analysis with MMFF94x force field (30). The U values are somewhat different when different crystal structures of CYP2A13 were used (Fig.…”