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Carcinogenesis Advance Access published online on January 16, 2004
Carcinogenesis, doi:10.1093/carcin/bgh061
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CARCINOGENESIS

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

Marie Stiborová 1*, Markéta Miksanová 1, Stanislav Smrcek 2, Christian A. Bieler 3, Andrea Breuer 3, Karl A. Klokow 3, Heinz H. Schmeiser 3, and Eva Frei 3

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

* Corresponding author. E-mail: stiborov{at}natur.cuni.cz.

Received 2 September 2003 ; revised 9 December 2003 ; accepted 12 December 2003

Abstract

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 used two independent methods, 32P-postlabeling and tritium-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 weight daily for five days), and DNA from several organs was analyzed by 32P-postlabeling. 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 per 107 nucleotides), 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 to be 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 cytosols, 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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