title: 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.
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 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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Prague, Albertov 2030, 128 40 Prague 2, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.forename: Karel
authors.initials: K
authors.lastname: Naiman
authors.forename: Markéta
authors.initials: M
authors.lastname: Martínková
authors.forename: Václav
authors.initials: V
authors.lastname: Martínek
authors.forename: Martina
authors.initials: M
authors.lastname: Svobodová
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.forename: Eva
authors.initials: E
authors.lastname: Frei