Naphthalene, phenanthrene, biphenyl, and their derivatives having di
fferent 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 o
f 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 o
f oxidation o
f 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 o
f P450 2A13 and 2A6 bound to 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, indole, pilocarpine, nicotine, and coumarin are o
f use in understanding the basis o
f possible molecular interactions o
f these xenobiotic chemicals with the active sites o
f P450 2A13 and 2A6 enzymes. In
fact, the ligand-interaction energies with P450 2A13
f="http://www.rcsb.org/pdb/search/structidSearch.do?structureId=4EJG">4EJG bound to these chemicals were found to relate to their induction of Type I binding spectra.