Rat cytochromes P450 oxidize 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone

Mizerovská, Jana; Dračínská, Helena; Arlt, Volker; Hudeček, Jiří; Hodek, Petr; Schmeiser, Heinz; Frei, Eva; Stiborová, Marie

doi:10.2478/v10102-010-0031-1

Abstract

3-Aminobenzanthrone (3-ABA) is a human metabolite of carcinogenic 3-nitrobenzanthrone (3-NBA), which occurs in diesel exhaust and air pollution. Understanding which cytochrome P450 (CYP) enzymes are involved in metabolic activation and/or detoxication of this toxicant is important in the assessment of an individual's susceptibility to this substance. The aim of this study was to evaluate the efficiency of rat hepatic CYPs to oxidize 3-ABA and to examine the metabolites formed during such an oxidation. The metabolites formed by CYPs in rat hepatic microsomes were separated by high performance liquid chromatography (HPLC). 3-ABA is oxidized by these enzymes to three metabolites, which were separated by HPLC as distinguish product peaks. Using co-chromatography with synthetic standards, two of them were identified to be oxidative metabolites of 3-ABA, N-hydroxy-3-ABA and 3-NBA. The structure of another 3-ABA metabolite remains to be characterized. To define the role of rat hepatic CYP enzymes in metabolism of 3-ABA, we investigated the modulation of its oxidation using different inducers of CYPs for treatment of rats to enrich the liver microsomes with individual CYPs. Based on these studies, we attribute most of 3-ABA oxidation in rat hepatic microsomes to CYP2B, followed by CYP1A, although a role of other hepatic CYPs cannot be ruled out. Inhibition of 3-ABA oxidation by selective inhibitors of individual CYPs, supported this finding.

References

Arlt VM (2005) 3-Nitrobenzanthrone, a potential human cancer hazard in diesel exhaust and urban air pollution: A review of the evidence. Mutagenesis 20: 399-410.10.1093/mutage/gei057
Search in Google Scholar
Arlt VM, Bieler CA, Mier W, Wiessler M and Schmeiser HH (2001) DNA adduct formation by the ubiquitous environmental contaminant 3-nitrobenzanthrone in rats determined by 32P-postlabeling. Int J Cancer 93: 450-454.10.1002/ijc.1346
Search in Google Scholar
Arlt VM, Cole KJ and Phillips DH (2004a) Activation of 3-nitrobenzanthrone and its metabolites to DNA-damaging species in human B-lymphoblastoid MCL-5 cells. Mutagenesis 19: 149-156.10.1093/mutage/geh008
Search in Google Scholar
Arlt VM, Glatt HR, Muckel E, Pabel U, Sorg BL, Schmeiser HH and Phillips DH (2002) Metabolic activation of the environmental contaminant 3-nitrobenzanthrone by human acetyltransferases and sulfotransferase. Carcinogenesis 23: 1937-1945.10.1093/carcin/23.11.1937
Search in Google Scholar
Arlt VM, Glatt H, Muckel E, Pabel U, Sorg BL, Seidel A, Frank H, Schmeiser HH and Phillips DH (2003a) Activation of 3-nitrobenzanthrone and its metabolites by human acetyltransferases, sulfotransferases and cytochrome P450 expressed in Chinese hamster V79 cells. Int J Cancer 105: 583-592.10.1002/ijc.11143
Search in Google Scholar
Arlt VM, Henderson CJ, Wolf CR, Schmeiser HH, Phillips DH and Stiborová M (2006a) Bioactivation of 3-aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone: evidence for DNA adduct formation mediated by cytochrome P450 enzymes and peroxidases. Cancer Lett 234: 220-231.10.1016/j.canlet.2005.03.035
Search in Google Scholar
Arlt VM, Hewer A, Sorg BL, Schmeiser HH, Phillips DH and Stiborová M (2004b) 3-Aminobenzanthrone, a human metabolite of the environmental pollutant 3-nitrobenzanthrone, forms DNA adducts after metabolic activation by human and rat liver microsomes: evidence for activation by cytochrome P450 1A1 and P450 1A2. Chem Res Toxicol 17: 1092-1101.10.1021/tx049912v
Search in Google Scholar
Arlt VM, Schmeiser HH, Osborne MR, Kawanishi M, Kanno T, Yagi T, Phillips DH and Takamura-Enya T (2006b) Identification of three major DNA adducts formed by the carcinogenic air pollutant 3-nitrobenzanthrone in rat lung at the C8 and N2 position of guanine and at the N6 position of adenine. Int J Cancer 118: 2139-2146.10.1002/ijc.21622
Search in Google Scholar
Arlt VM, Sorg BL, Osborne M, Hewer A, Seidel A, Schmeiser HH and Phillips DH (2003b) DNA adduct formation by the ubiquitous environmental pollutant 3-nitrobenzanthrone and its metabolites in rats. Biochem Biophys Res Commun 300: 107-114.10.1016/S0006-291X(02)02789-4
Search in Google Scholar
Arlt VM, Stiborová M, Henderson CJ, Osborne MR, Bieler CA, Frei E, Martínek V, Sopko B, Wolf CR, Schmeiser HH and Phillips DH (2005) The environmental pollutant and potent mutagen 3-nitrobenzanthrone forms DNA adducts after reduction by NAD(P)H:quinone oxidoreductase and conjugation by acetyltransferases and sulfotransferases in human hepatic cytosols. Cancer Res 65: 2644-2652.10.1158/0008-5472.CAN-04-354415805261
Search in Google Scholar
Arlt VM, Stiborová M, Hewer A, Schmeiser HH and Phillips DH, (2003c) Human enzymes involved in the metabolic activation of the environmental contaminant 3-nitrobenzanthrone: evidence for reductive activation by human NADPH:cytochrome P450 reductase. Cancer Res 63: 2752-2761.
Search in Google Scholar
Arlt, VM, Zhan L, Schmeiser HH, Honma M, Hayashi M, Phillips DH and Suzuki T environmental pollutant 3-nitrobenzanthrone in Muta Mouse. Environ Mol Mutagen 43: 186-195.10.1002/em.20014
Search in Google Scholar
Bieler CA, Cornelius M, Klein R, Arlt VM, Wiessler M, Phillips DH and Schmeiser HH (2005) DNA adduct formation by the environmental contaminant 3-nitrobenzanthrone after intratracheal instillation in rats. Int J Cancer 118: 833-838.10.1002/ijc.21095
Search in Google Scholar
Bieler CA, Cornelius MG, Stiborova M, Arlt VM, Wiessler M, Phillips DH and Schmeiser HH (2007) Formation and persistence of DNA adducts formed by the carcinogenic air pollutant 3-nitrobenzanthrone in target and non-target organs after intratracheal instillation in rats. Carcinogenesis 28: 1117-1121.10.1093/carcin/bgl219
Search in Google Scholar
Bieler CA, Wiessler M, Erdinger L, Suzuki H, Enya T and Schmeiser HH (1999) DNA adduct formation from the mutagenic air pollutant 3-nitrobenzanthrone. Mutat Res 439: 307-311.10.1016/S1383-5718(98)00197-1
Search in Google Scholar
Borlak J, Hansen T, Yuan Z, Sikka HC, Kumar S, Schmidbauer S, Frank H, Jacob J and Seidel A (2000) Metabolism and DNA-binding of 3-nitrobenzanthrone in primary rat alveolar type II cells, in human fetal bronchial, rat epithelial and mesenchymal cell lines. Polycyclic Aromat Compounds 21: 73-86.10.1080/10406630008028525
Search in Google Scholar
Enya T, Suzuki H, Watanabe T, Hirayama T and Hisamatsu Y (1997) 3-Nitrobenzanthrone, a powerful bacterial mutagen and suspected human carcinogen found in diesel exhausts and airborne particulates. Environ Sci Technol 31: 2772-2776.10.1021/es961067i
Search in Google Scholar
Grabchev I, Moneva I, Betcheva R and Elyashevich G (2002) Colored microporous polyethylene films: effect of porous structure on dye adsorption. Mat Res Innovat 6: 34-37.10.1007/s10019-001-0154-2
Search in Google Scholar
Hansen T, Seidel A and Borlak J (2007) The environmental carcinogen 3-nitrobenzanthrone and its main metabolite 3-aminobenzanthrone Genhance formation of reactive oxygen intermediates in human A549 lung epithelial cells. Toxicol Appl Pharmacol 221: 222-234.10.1016/j.taap.2007.03.00317477947
Search in Google Scholar
Nagy E, Zeisig M, Kawamura K, Hisumatsu Y, Sugeta A, Adachi S and Moller L (2005) DNA-adduct and tumor formations in rats after intratracheal administration of the urban air pollutant 3-nitrobenzanthrone. Carcinogenesis 26: 1821-1828.10.1093/carcin/bgi14115917305
Search in Google Scholar
Rendic S and DiCarlo FJ (1997) Human cytochrome P450 enzymes: A status report summarizing their reactions, substrates, inducers, and inhibitors. Drug Metab Rev 29: 413-480.10.3109/036025397090375919187528
Search in Google Scholar
Seidel A, Dahmann D, Krekeler H and Jacob J (2002) Biomonitoring of polycyclic aromatic compounds in the urine of mining workers occupationally exposed to diesel exhaust. Int J Hyg Environ Health 204: 333-338.10.1078/1438-4639-0011611885357
Search in Google Scholar
Stiborová M, Dračínská H, Hájková J, Kadeřábková P, Frei E, Schmeiser HH, Souček P, Phillips DH and Arlt VM (2006) The environmental pollutant and carcinogen 3-nitrobenzanthrone and its human metabolite 3-aminobenzanthrone are potent inducers of rat hepatic cytochromes P450 1A1 and -1A2 and NAD(P)H:quinone oxidoreductase. Drug Metab Dispos 34: 1398-1405.10.1124/dmd.106.00937316714372
Search in Google Scholar
Stiborová M, Dračínská H, Mizerovská J, Frei E, Schmeiser HH, Hudeček J, Hodek P, Phillips DH and Arlt VM 2008 The environmental pollutant and carcinogen 3-nitrobenzanthrone induces cytochrome P450 1A1 and NAD(P)H:quinone oxidoreductase in rat lung and kidney, thereby enhancing its own genotoxicity. Toxicology 247: 11-22.10.1016/j.tox.2008.01.01818329153
Search in Google Scholar
Stiborová M, Martínek V, Rýdlová H, Hodek P and Frei E (2002) Sudan I is a potential carcinogen for humans: evidence for its metabolic activation and detoxication by human recombinant cytochrome P450 1A1 and liver microsomes. Cancer Res 62: 5678-5684.
Search in Google Scholar
Svobodová M, Šístková J, Dračínská H, Hudeček J, Hodek P, Schmeiser HH, Arlt VM, Frei E and Stiborová M (2007) Reductive activation of environmental pollutants 3-nitrobenzanthrone and 2-nitrobenzanthrone. Chem Listy 100: s277-s279.
Search in Google Scholar
Sykora J, Mudago V, Hutterer R, Nepras M, Vanerka J, Kapusta P, Fidler V and Hof M (2002) ABA-C-15: A new dye for probing solvent relaxation in phospholipid bilayers. Langmuir 18: 9276-9282.10.1021/la026435c
Search in Google Scholar

Rat cytochromes P450 oxidize 3-aminobenzanthrone, a human metabolite of the carcinogenic environmental pollutant 3-nitrobenzanthrone

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