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Review
, 33 (2), 79-96

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

Affiliations
Review

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

Tsutomu Shimada. Toxicol Res.

Abstract

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.

Keywords: Chemical carcinogenesis; Cytochrome P450; Enzyme inhibition; Metabolic activation; Polycyclic aromatic hydrocarbons; Tobacco-related nitrosamines.

Figures

Fig. 1
Fig. 1
Inhibition (IC50 values) of 7-ethoxyresorufin O-deethylation (EROD) activities of CYP1B1 (A), 1A2, (B), and 1A1 (C) by PAHs, PAH metabolites, Trp-P-1 and Trp-P-2, and flavonoids and acetylenic PAHs. IC50 values exceeded over 1.0 μM are indicated in the figure. Data are taken from Shimada and Guengerich (20) with modification.
Fig. 2
Fig. 2
Effects of preincubation time on inhibition of CYP1A1 (A–D), CYP1A2 (E–H), and CYP1B1 (I–L) dependent EROD activities by 1PP (A, E, and I), 1EP (B, F, and J), 2-EP (C, G, and K), and 4Pbi (D, H, and L). P450 (50 pmol) was pre-incubated with different concentrations of 1PP, 1EP, 2EP, and 4Pbi in the presence of 1mM NADPH during indicated periods of time, and then the reactions were started by the addition of 5 μM 7-ethoxyresorufin to determine EROD activities. The reactions were monitored at 25°C. Data are taken from Shimada et al. (21) with modification.
Fig. 3
Fig. 3
Three different mechanisms of inhibition of CYP1 enzymes by PAHs and acetylenic PAHs. Data are from Shimada et al. (21).
Fig. 4
Fig. 4
Intensities of reverse type I binding spectra of CYP1B1 with 27 flavonoids (A) and inhibition by these flavonoids of EROD activities catalyzed by CYP1B1 (B), 1A1 (C), and 1A2 (D), flurbiprofen 4-hydroxylation activities catalyzed by CYP2C9 (E), midazolam 4-hydroxylation activities catalyzed by CYP3A4 (F). The spectral changes are shown as spectral binding efficiency (ΔAmax/Km values). IC50 values are shown to be 0~1.0 μM for CYP1B1, 1A2, and 1A1, and 0~30 μM for CYP2C9 and 3A4. Abbreviations used; 3HF, 3-hydroxyflavone; 5HF, 5-hydroxyflavone; 7HF, 7-hydroxyflavone; 57DHF, 5,7-dihydroxyflavone; 357THF, 3,5,7-trihydroxyflavone; 457THF, 45,7-trihydroxytrihydroxyflavone; 457THIF, 4,5,7-trihydroxyisoflavone; 457THFva, 4,5,7-trihydroxyflavanone; 457THFvaG, 4,5,7-trihydroxyflavanone glycoside; 567THF, 5,6,7-trihydroxyflavone; 3457TetraHF, 3,4,5,7-tetrahydroxyflavone; 33457PHF, 3,3,4,5,7-pentahydroxyflavone; 4M57DHF, 4-methoxy-5,7-dihydroxyflavone; 4M57DHisoF, 4-methoxy-5,7-dihydroxyisoflavone; 2MF, 2-methoxyflavone; 3MF, 3-methoxyflavone; 4MF, 4-methoxyflavone; 34DMF, 3,4-dimethoxyflavone; 2M57DHF, 2-methoxy-5,7-dihydroxyflavone; 3M57DHF, 3-methoxy-5,7-dihydroxyflavone; 34M57DHF, 34-dimethoxy-5,7-dihydroxyflavone; 2M78DHF, 2-methoxy-7,8-dihydroxyflavone; 3M78DHF, 3-methoxy-7,8-dihydroxyflavone; 4M78DHF, 4-methoxy-7,8-dihydroxyflavone; and 34M78DHF, 3,4-dimethoxy-7,8-dihydroxyflavone. Data are taken from Shimada et al. (30) with modification.
Fig. 5
Fig. 5
Compounds that show strong inhibition of CYP2A13-dependent coumarin 7-hydroxylation activities. Data are taken from Shimada et al. (26) with modification.
Fig. 6
Fig. 6
Type I binding spectra of interaction of naphthalene, phenanthrene, biphenyl, and their derivatives with CYP2A13 (A) and 2A6 (B) and inhibition of coumarin 7-hydroxylation activities of CYP2A13 (C) and 2A6 (D) by these chemicals. Data are taken from Shimada et al. (,–30) with modification.
Fig. 7
Fig. 7
Molecular docking analysis of ligand-interaction energies (U values) of 2-ethynylnaphthalene, 2-ethynylphenanthrene, and 4-biphenyl propargyl ether obtained using reported crystal structures of CYP2A13 (4EJH), 2A13 (2P85), 2A13 (3T3S), and 2A13 (4EJG) bound to NNK, indole, pilocarpine, and nicotine, respectively. Data are from Murayama, N., Shimada, T. and Yamazaki, H. (unpublished results).
Fig. 8
Fig. 8
Correlations of ligand-interaction energies (U values) of interaction of 24 chemicals (and also NNK, indole, pilocarpine, nicotine, and coumarin) with crystal structures of CYP2A13 4EJG (nicotine-type) and 4EJH (NNK-type) (A) and of CYP2A6 4EJJ (nicotine-type) and 3T3R (pilocarpine-type) (B). Points obtained with naphthalene, phenanthrene, and biphenyl are shown in red, other 21 chemicals in open square, and coumarin, indole, NNK, nicotine, and pilocarpine in blue. Abbreviations used in this figure: 4-biphenyl propargyl ether (4BPE), 9-(1-propynyl)phenanthrene (9PPh), 4-butynylbiphenyl (4BuB), 2,2-biphenyl dipropargyl ether (22BDPE), and 4,4-biphenyl dipropargyl ether (44BDPE). Data are taken from Shimada et al. (30) with modification.
Fig. 9
Fig. 9
Molecular docking analysis of interaction of m-XSC with CYP1A1 (A), 1A2 (B), 1B1 (C), 2A6 (D), and 2A13 (E). The ligand-P450 interaction energies (U values) and distances between the N-atom in one of the -CH2SeCN moieties of m-XSC and the Fe-atom (calculated using in silico analysis) in these P450s are shown in the figure.

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