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Carcinogenesis Advance Access originally published online on January 16, 2004
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Carcinogenesis, Vol. 25, No. 5, 833-840, May 2004
Carcinogenesis vol.25 no.5 © Oxford University Press 2004; all rights reserved.

ARTICLE

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

Marie Stiborová1,4, Markéta Miksanová1, Stanislav Smrcek2, Christian A. Bieler3, Andrea Breuer3, Karl A. Klokow3, Heinz H. Schmeiser3 and Eva Frei3

1 Department of Biochemistry and 2 Department of Organic Chemistry, Faculty of Science, Charles University, Albertov 2030, 128 40 Prague 2, Czech Republic and 3 Division of Molecular Toxicology, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany

4 To whom correspondence should be addressed Email: stiborov{at}natur.cuni.cz

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.


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