<abstract xml:lang="en" xmlns="http://www.w3.org/1999/xhtml"><p>An aromatic amine, <italic>o</italic>-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, <italic>N</italic>-(2-methoxyphenyl)hydroxylamine, which spontaneously decomposes to nitrenium and/or carbenium ions responsible for formation of deoxyguanosine adducts in DNA <italic>in vitro</italic> and <italic>in vivo</italic>. In other words, generation of <italic>N</italic>-(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 P450 2E1 is the major enzyme oxidizing <italic>o</italic>-anisidine to <italic>N</italic>-(2-methoxyphenyl)hydroxylamine, while xanthine oxidase of both species reduces 2-nitroanisole to this metabolite. Likewise, <italic>O</italic>-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.</p></abstract>

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 P450 2E1 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.

Genotoxic mechanisms for the carcinogenicity of the environmental pollutants and carcinogens <italic>o</italic>-anisidine and 2-nitroanisole follow from adducts generated by their metabolite <italic>N</italic>-(2-methoxyphenyl)hydroxylamine with deoxyguanosine in DNA

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

German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

Interdisciplinary Toxicology

Genotoxic mechanisms for the carcinogenicity of the environmental pollutants and carcinogens -anisidine and 2-nitroanisole follow from adducts generated by their metabolite -(2-methoxyphenyl)hydroxylamine with deoxyguanosine in DNA

An aromatic amine, o-anisidine (2-methoxyaniline) and its oxidative counterpart, 2-nitroanisole (2-methoxynitrobenzene), are the industrial and environmental...

Genotoxic mechanisms for the carcinogenicity of the environmental pollutants and carcinogens o-anisidine and 2-nitroanisole follow from adducts generated by their metabolite N-(2-methoxyphenyl)hydroxylamine with deoxyguanosine in DNA

Online veröffentlicht: 19. Juni 2009

Seitenbereich: 24 - 27

DOI: https://doi.org/10.2478/v10102-009-0004-4

Schlüsselwörter
carcinogens, -anisidine, 2-nitroanisole, -(2-methoxyphenyl)hydroxylamine, metabolism, DNA adducts, cancer

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