Differential Distribution of CYP2A6 and CYP2A13 in the Human Respiratory Tract

Chiang, Huai-chih; Wang, Chia-Woei; Tsou, Tsui‐Chun

doi:10.1159/000339591

Cited by 24 publications

(23 citation statements)

References 67 publications

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“…15 However, Zhu et al 16 used an anti-P450 2A13 antibody and reported immunostaining in trachea and bronchiole but not alveolar cells. The difference in the bronchiole data of Chiang et al 15 are not understood at this time. The P450 2A13 proximal promoter has been reported to interact with members pf the CCAAT/enhancer binding protein (C/EBP) family in the respiratory tract, and silencing by epigentic mechasnisms has also been reported.…”

Section: Discussionmentioning

confidence: 99%

Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition

Shimada

Kim

Murayama

et al. 2013

Chem. Res. Toxicol.

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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.

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Section: Discussionmentioning

confidence: 99%

Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition

Shimada

Kim

Murayama

et al. 2013

Chem. Res. Toxicol.

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“…coumarin and phenacetin, and also metabolic activation of tobacco-related nitrosamines (including NNK and NNN) to carcinogenic metabolites (140,141). However, CYP2A13 is shown to be more active than CYP2A6 in activating NNK and NNN (140,141) and these findings are of interest because the latter enzyme is mainly expressed in respiratory organs, the sites of exposure to numerous environmental chemicals including NNK, NNN, and PAHs (4,138,139). As described above, several chemicals that inhibit CYP2A13 and 2A6 enzymes suppress tumor formation caused by NNK, 7,12-DMBA, B[ a ]P, and azoxymethane (Table 3) (47–51), it is interesting to examine whether various xenobiotic chemicals interact with and inhibit CYP2A13 and 2A6-dependent catalytic activities and are metabolized by these P450 enzymes (26,27).…”

Section: Introductionmentioning

confidence: 99%

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

Shimada

2017

ToxicolRes

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A variety of xenobiotic chemicals, such as polycyclic aromatic hydrocarbons (PAHs), aryl- and heterocyclic amines and tobacco related nitrosamines, are ubiquitous environmental carcinogens and are required to be activated to chemically reactive metabolites by xenobiotic-metabolizing enzymes, including cytochrome P450 (P450 or CYP), in order to initiate cell transformation. Of various human P450 enzymes determined to date, CYP1A1, 1A2, 1B1, 2A13, 2A6, 2E1, and 3A4 are reported to play critical roles in the bioactivation of these carcinogenic chemicals. In vivo studies have shown that disruption of Cyp1b1 and Cyp2a5 genes in mice resulted in suppression of tumor formation caused by 7,12-dimethylbenz[a]anthracene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, respectively. In addition, specific inhibitors for CYP1 and 2A enzymes are able to suppress tumor formation caused by several carcinogens in experimental animals in vivo, when these inhibitors are applied before or just after the administration of carcinogens. In this review, we describe recent progress, including our own studies done during past decade, on the nature of inhibitors of human CYP1 and CYP2A enzymes that have been shown to activate carcinogenic PAHs and tobacco-related nitrosamines, respectively, in humans. The inhibitors considered here include a variety of carcinogenic and/or non-carcinogenic PAHs and acethylenic PAHs, many flavonoid derivatives, derivatives of naphthalene, phenanthrene, biphenyl, and pyrene and chemopreventive organoselenium compounds, such as benzyl selenocyanate and benzyl selenocyanate; o-XSC, 1,2-, 1,3-, and 1,4-phenylenebis( methylene)selenocyanate.

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“…4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), N -nitrosonornicotine) and to metabolize different kinds of chemicals including coumarin, nicotine, phenacetin, naphthalene, 4-aminobiphenyl, and styrene (Su et al, 2000; Chiang et al, 2011; Fukami et al, 2008; Wong et al, 2005a; Wong et al, 2005b). P450 2A13 is mainly expressed in the respiratory tract and P450 2A6 is primarily found in the liver (Su et al, 2000; Chiang et al, 2012; Zhu et al, 2006). Recent studies have shown that P450 2A13 is more active than P450 2A6 in activating NNK, N -nitrosonornicotine, and other environmental carcinogens that cause cancer in the respiratory organs (Wong et al, 2005a; Wong et al, 2005b; Chiang et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13

et al. 2015

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The polycyclic hydrocarbons (PAHs), pyrene, 1-hydroxypyrene, 1-nitropyrene, and 1-acetylpyrene, were found to induce Type I binding spectra with human cytochrome P450 (P450) 2A13 and were converted to various mono- and di-oxygenated products by this enzyme.Pyrene was first oxidized by P450 2A13 to 1-hydroxypyrene which was further oxidized to di-oxygenated products, i.e. 1,8- and 1,6-dihydroxypyrene. Of five other human P450s examined, P450 1B1 catalyzed pyrene oxidation to 1-hydroxypyrene at a similar rate to P450 2A13 but was less efficient in forming dihydroxypyrenes. P450 2A6, a related human P450 enzyme, which did not show any spectral changes with these four PAHs, showed lower activities in oxidation of these compounds than P450 2A13.1-Nitropyrene and 1-acetylpyrene were also found to be efficiently oxidized by P450 2A13 to several oxygenated products, based on mass spectrometry analysis.Molecular docking analysis supported preferred orientations of pyrene and its derivatives in the active site of P450 2A13, with lower interaction energies (U values) than observed for P450 2A6 and that several amino acid residues (including Ala-301, Asn-297, and Ala-117) play important roles in directing the orientation of these PAHs in the P450 2A13 active site. In addition, Phe-231 and Gly-329 were found to interact with pyrene to orient this compound in the active site of P450 1B1.These results suggest that P450 2A13 is one of the important enzymes that oxidizes these PAH compounds and may determine how these chemicals are detoxicated and bioactivated in humans.

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Differential Distribution of CYP2A6 and CYP2A13 in the Human Respiratory Tract

Cited by 24 publications

References 67 publications

Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition

Binding of Diverse Environmental Chemicals with Human Cytochromes P450 2A13, 2A6, and 1B1 and Enzyme Inhibition

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

Oxidation of pyrene, 1-hydroxypyrene, 1-nitropyrene and 1-acetylpyrene by human cytochrome P450 2A13

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