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

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aryl Hydrocarbon Hydroxylases / chemistry*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Biphenyl Compounds / chemistry*
  • Biphenyl Compounds / metabolism
  • Cytochrome P-450 CYP2A6 / chemistry*
  • Cytochrome P-450 CYP2A6 / metabolism
  • Humans
  • Molecular Structure
  • Naphthalenes / chemistry*
  • Naphthalenes / metabolism
  • Oxidation-Reduction
  • Phenanthrenes / chemistry*
  • Phenanthrenes / metabolism


  • Biphenyl Compounds
  • Naphthalenes
  • Phenanthrenes
  • diphenyl
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A13 protein, human
  • Cytochrome P-450 CYP2A6