Journal Article

Identification of a genotoxic mechanism for 2-nitroanisole carcinogenicity and of its carcinogenic potential for humans

Marie Stiborová, Markéta Mikšanová, Stanislav Smrček, Christian A. Bieler, Andrea Breuer, Karl A. Klokow, Heinz H. Schmeiser and Eva Frei

in Carcinogenesis

Volume 25, issue 5, pages 833-840
Published in print May 2004 | ISSN: 0143-3334
Published online May 2004 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgh061
Identification of a genotoxic mechanism for 2-nitroanisole carcinogenicity and of its carcinogenic potential for humans

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2-Nitroanisole (2-NA) is an important industrial pollutant and a potent bladder carcinogen for rodents. The mechanism of its carcinogenicity was investigated in this study. Here we have used two independent methods, 32P-post-labeling and 3H-labeled 2-NA, to show that 2-NA binds covalently to DNA in vitro after reductive activation by human hepatic cytosol and xanthine oxidase (XO). We also investigated the capacity of 2-NA to form DNA adducts in vivo. Male Wistar rats were treated i.p. with 2-NA (0.15 mg/kg body wt daily for 5 days) and DNA from several organs was analyzed by 32P-post-labeling. Two 2-NA-specific DNA adducts, identical to those found in DNA incubated with 2-NA and human hepatic cytosol or XO in vitro, were detected in the urinary bladder (3.4 adducts/107 nt), the target organ, and, to a lesser extent, in liver, kidney and spleen. The two DNA adducts found in rat tissues in vivo were identified as deoxyguanosine adducts derived from a 2-NA reductive metabolite, N-(2-methoxyphenyl)hydroxylamine. This reactive metabolite of 2-NA was identified in incubations with human hepatic cytosol, besides 2-methoxyaniline (o-anisidine). The results of our study, the first report on the potential of human cytosolic enzymes to contribute to the activation of 2-NA by nitroreduction, strongly suggest a carcinogenic potency of this rodent carcinogen for humans.

Keywords: acetylCoA, acetylcoenzyme A; dAp, deoxyadenosine 3′-monophosphate; CT-DNA, calf thymus DNA; dGp, deoxyguanosine 3′-monophosphate; HPLC, high performance liquid chromatography; NAT, N,O-acetyltransferase; 2-NA, 2-nitroanisole; NQO1, NAD(P)H:quinone oxidoreductase; PEI, polyethylenimine; PAPS, 3′-phosphoadenosyl 5′-phosphosulfate; RAL, relative adduct labeling; r.t., retention time; SULT, sulfotransferase; TLC, thin layer chromatography; XO, xanthine oxidase

Journal Article.  6742 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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