An aromatic amine, o-anisidine (2-methoxyaniline) and its oxidative counterpart, 2-nitroanisole (2-methoxynitrobenzene), are the industrial and environmental pollutants causing tumors of the urinary bladder in rats and mice. Both carcinogens are activated to the same proximate carcinogenic metabolite, N-(2-methoxyphenyl)hydroxylamine, which spontaneously decomposes to nitrenium and/or carbenium ions responsible for formation of deoxyguanosine adducts in DNA in vitro and in vivo. In other words, generation of N-(2-methoxyphenyl)hydroxylamine is responsible for the genotoxic mechanisms of the o-anisidine and 2-nitroanisole carcinogenicity. Analogous enzymes of human and rat livers are capable of activating these carcinogens. Namely, human and rat cytochorme P4502E1 is the major enzyme oxidizing o-anisidine to N-(2-methoxyphenyl)hydroxylamine, while xanthine oxidase of both species reduces 2-nitroanisole to this metabolite. Likewise, O-demethylation of 2-nitroanisole, which is the detoxication pathway of its metabolism, is also catalyzed by the same human and rat enzyme, cytochorme P450 2E1. The results demonstrate that the rat is a suitable animal model mimicking the fate of both carcinogens in humans and suggest that both compounds are potential carcinogens also for humans.

Department of Biochemistry Faculty of Science Charles University Prague Albertov 2030 128 40 Prague 2 Czech Republic

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Branner B, Kutzer C, Zwickenpflug W, Scherer G, Heller W-D, Richter E. Haemoglobin adducts from aromatic amines and tobacco-specific nitrosamines in pregnant smoking and non-smoking women. Biomarkers. 1998;3:35–47. PubMed

Dračínská H, Mikšanová M, Svobodová M, Smrček S, Frei E, Schmeiser HH, Stiborová M. Oxidative detoxication of carcinogenic 2-nitroanisole by human, rat and rabbit cytochrome P450. Neuro Endocrinol. Lett. 2006;27:9–13. PubMed

Falter B, Kutzer C, Richter E. Biomonitoring of hemoglobin adducts: aromatic amines and tobacco-specific nitrosamines. Clin Investig. 1994;72:364–371. PubMed

Garner RC, Martin CN, Clayson DB. Carcinogenic aromatic amines and related compounds. In: Searle C, editor. Chemical Carcinogens, ACS Monograph 182. 2nd ed. Vol. 1. Washington, DC: American Chemical Society; 1984. pp. 175–302.

Hauthal HG. Rosenmontag und die Folgen die Störfälle der Hoechst AG. Nach Chem Tech Lab. 1993;41:440.

IARC. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans. Lyon: IARC; 1982. Ortho- and para-anisidine and their hydrochlorides. No. 27. PubMed

IARC. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Vol. 88. Lyon: IARC; 2006. Formaldehyde, 2-butoxyethanol and 1-terc-butoxypropan-2-ol; pp. 39–325. PubMed PMC

Mikšanová M, Novák P, Frei E, Stiborová M. Metabolism of carcinogenic 2-nitroanisole by rat, rabbit, porcine and human hepatic cytosol. Collect Czech Chem Commun. 2004a;69:589–602.

Mikšanová M, Sulc M, Rýdlová H, Schmeiser HH, Frei E, Stiborová M. Enzymes involved in the metabolism of the carcinogen 2-nitroanisole: evidence for its oxidative detoxication by human cytochromes P450. Chem. Res. Toxicol. 2004b;17:663–671. PubMed

Naiman K, Dračínská H, Dračínský M, Martínková M, Martínek V, Hodek P, Štícha M, Frei E, Stiborová M. Cytochrome P450-mediated metabolism of N-(2-methoxyphenyl)-hydroxylamine, a human metabolite of the environmental pollutants and carcinogens o-anisidine and o-nitroanisole Interdisc. Toxicol. 2008a;1:218–224. PubMed PMC

Naiman K, Dračínská H, Martínková M, Šulc M, Dračínský M, Kejíková L, Hodek P, Hudeček J, Liberda J, Schmeiser HH, Frei E, Stiborová M. Redox cycling in the metabolism of the environmental pollutant and suspected human carcinogen o-anisidine by rat and rabbit hepatic microsomes. Chem Res Toxicol. 2008b;21:1610–1621. PubMed

NTP. NTP Technical Report 89. Bethesda, MD: National Institute of Health, US Department of Health and Human Services; 1978. Bioassay of o-anisidine hydrochloride for possible carcinogenicity.

NTP. NTP Technical Report 416. Bethesda, MD: National Institute of Health, US Department of Health and Human Services; 1993. Toxicology and Carcinogenesis. Studies of 2-nitroanisole.

Purohit V, Basu A. Mutagenicity of nitroaromatic compounds. Chem Res Toxicol. 2000;13:673–692. PubMed

Richter E, Rosler S, Scherer G, Gostomzyk JG, Grubl A, Kamer U, Behrendt H. Haemoglobin adducts from aromatic amines in children in relation to area of residence and exposure to environmental tobacco smoke. Int Arch Occup Environ Health. 2001;74:421–428. PubMed

Rýdlová H, Mikšanová M, Ryšlavá H, Stiborová M. Carcinogenic pollutants o-nitroanisole and o-anisidine are substrates and inducers of cytochromes P450. Biomed Papers. 2005;49:441–447. PubMed

Stabbert R, Schäfer K-H, Biefel C, Rustemeier K. Analysis of aromatic amines in cigarette smoke. Rapid Commun Mass Spectrom. 2003;17:2125–2132. PubMed

Stiborová M, Mikšanová M, Havlíček V, Schmeiser HH, Frei E. Mechanism of peroxidase-mediated oxidation of carcinogenic o-anisidine and its binding to DNA. Mutat Res. 2002;500:49–66. PubMed

Stiborová M, Mikšanová M, Smrček S, Bieler CA, Breuer A, Klokow KA, Schmeiser HH, Frei E. Identification of a genotoxic mechanism for 2-nitroanisole carcinogenicity and of its carcinogenic potential for humans. Carcinogenesis. 2004;25:833–840. PubMed

Stiborová M, Mikšanová M, Šulc M, Rýdlová H, Schmeiser HH, Frei E. Identification of a genotoxic mechanism for the carcinogenicity of the environmental pollutant and suspected human carcinogen o-anisidine. Int J Cancer. 2005;116:667–678. PubMed

Stiborová M, Schmeiser HH, Breuer A, Frei E. Evidence for activation of carcinogenic o-anisidine by prostaglandin H synthase: 32P-postlabelling analysis of DNA adducts formation. Gen Physiol Biophys. 2001;20:267–279. PubMed

Stiborová M, Schmeiser HH, Frei E. To the mechanism of 2-nitroanisole carcinogenicity: in vitro metabolism of 2-nitroanisole mediated by peroxidases and xanthine oxidase. Collect Czech Chem Commun. 1998;63:857–869.

Svobodová M, Dračínská H, Martínková M, Hudeček J, Hodek P, Frei E, Stiborová M. Oxidation of carcinogenic 2-nitroanisole by rat cytochrome P450 – similarity between human and rat systems. Interdisc Toxicol. 2008;1:180–185. PubMed PMC

Traupe H, Menge G, Kandt J, Karmaus W. Higher frequency of atopic dermatitis and decrease in viral warts among children exposed to chemicals liberated in a chemical accident in Frankfurt, Germany. Dermatology. 1997;195:112–118. PubMed

U.S. Department of Health and Human Services. 11th Report on Carcinogens. Washington, DC: U.S. Government Printing Office; 2004.

Weiss T, Angerer J. Simultaneous determination of various aromatic amines and metabolites of aromatic nitro compounds in urine for low level exposure using gas chromatography-mass spectrometry. J Chromatogr B. 2003;778:179–192. PubMed