title: Binding of diverse environmental chemicals with human cytochromes P450 2A13, 2A6, and 1B1 and enzyme inhibition.
abstract: A total of 68 chemicals including derivatives of naphthalene, phenanthrene, fluoranthene, pyrene, biphenyl, and flavone were examined for their abilities to interact with human P450s 2A13 and 2A6. Fifty-one of these 68 chemicals induced stronger Type I binding spectra (iron low- to high-spin state shift) with P450 2A13 than those seen with P450 2A6, i.e., the spectral binding intensities (ΔAmax/Ks ratio) determined with these chemicals were always higher for P450 2A13. In addition, benzo[c]phenanthrene, fluoranthene, 2,3-dihydroxy-2,3-dihydrofluoranthene, pyrene, 1-hydroxypyrene, 1-nitropyrene, 1-acetylpyrene, 2-acetylpyrene, 2,5,2',5'-tetrachlorobiphenyl, 7-hydroxyflavone, chrysin, and galangin were found to induce a Type I spectral change only with P450 2A13. Coumarin 7-hydroxylation, catalyzed by P450 2A13, was strongly inhibited by 2'-methoxy-5,7-dihydroxyflavone, 2-ethynylnaphthalene, 2'-methoxyflavone, 2-naphththalene propargyl ether, acenaphthene, acenaphthylene, naphthalene, 1-acetylpyrene, flavanone, chrysin, 3-ethynylphenanthrene, flavone, and 7-hydroxyflavone; these chemicals induced Type I spectral changes with low Ks values. On the basis of the intensities of the spectral changes and inhibition of P450 2A13, we classified the 68 chemicals into eight groups based on the order of affinities for these chemicals and inhibition of P450 2A13. The metabolism of chemicals by P450 2A13 during the assays explained why some of the chemicals that bound well were poor inhibitors of P450 2A13. Finally, we compared the 68 chemicals for their abilities to induce Type I spectral changes of P450 2A13 with the Reverse Type I binding spectra observed with P450 1B1: 45 chemicals interacted with both P450s 2A13 and 1B1, indicating that the two enzymes have some similarty of structural features regarding these chemicals. Molecular docking analyses suggest similarities at the active sites of these P450 enzymes. These results indicate that P450 2A13, as well as Family 1 P450 enzymes, is able to catalyze many detoxication and activation reactions with chemicals of environmental interest.
authors: Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine , Nashville, Tennessee 37232-0146, United States.
authors: Tsutomu
authors: T
authors: Shimada
authors: Donghak
authors: D
authors: Kim
authors: Norie
authors: N
authors: Murayama
authors: Katsuhiro
authors: K
authors: Tanaka
authors: Shigeo
authors: S
authors: Takenaka
authors: Leslie D
authors: LD
authors: Nagy
authors: Lindsay M
authors: LM
authors: Folkman
authors: Maryam K
authors: MK
authors: Foroozesh
authors: Masayuki
authors: M
authors: Komori
authors: Hiroshi
authors: H
authors: Yamazaki
authors: F Peter
authors: FP
authors: Guengerich
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D002273:Carcinogens / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D065637:Cytochrome P-450 CYP2A6; D004785:Environmental Pollutants / Q000378:metabolism*; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism; D006801:Humans; D062105:Molecular Docking Simulation; D011084:Polycyclic Aromatic Hydrocarbons / Q000378:metabolism
chemical_list: D002273:Carcinogens; D004785:Environmental Pollutants; D005419:Flavonoids; D011084:Polycyclic Aromatic Hydrocarbons; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; C414206:CYP2A13 protein, human; D065633:Cytochrome P-450 CYP1B1; D065637:Cytochrome P-450 CYP2A6