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Metabolism and DNA-binding of 3-nitrobenzanthrone in primary rat alveolar type II cells, in human fetal bronchial, rat epithelial and mesenchymal cell lines

 
: Borlak, J.; Hansen, T.; Yuan, Z.-X.; Kumar, S.; Sikka, H.C.; Frank, H.; Seidel, A.

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Polycyclic aromatic compounds 21 (2000), No.1/4, pp.73-86
ISSN: 1040-6638
English
Journal Article
Fraunhofer ITA ( ITEM) ()
metabolism; DNA adduct

Abstract
3-Nitrobezanthrone (NBA) is a suspected human carcinogen and has been identified is diesel exhaust and in airborne particulates. Human exposure to NBA is thought to occur primarily via the respiratory tract and bronchial as well as alveolar epithelial cells are believed to be primary targets for lung carcinogenesis. Nitroarenes require metabolic activation to DNA binding metabolites to become genotoxic carcinogens. In this study the metabolism of NBA as well as its metabolic intermediate 3-nitrosobenzanthrone was investigated in cultures of rat lung alveolar type II cells, in human fetal bronchial (HFBE) and rat bronchial epithelial (R3/1) as well mesenchymal Rwd009 cells. 3-Aminobenzanthrone (ABA) was identified as the major metabolite from both substrates, but also small amounts of 3-acetyl-ABA were observed during short term incubations (6 to 24 h) with NBA. Inhibition studies with allopurinol in alveolar type II cells indicate that the cytosolic enzyme xanthine oxidase contributes substantially to the biotransformation of NBA. 32P-Postlabeling analysis of DNA adducts in these cells demonstrates the formation of 5 and 6 different adducts after exposure of the cells with NBA and 3-nitrosobenzanthrone, respectively. Different oligonucleotides were modified with N-acetoxy-N-acetyl-3-ABA and used as reference materials for postlabeling analysis. Based on co-chromatography experiments, the presence of N-acetoxy-ABA-dA adducts in alveolar type II epithelial cells could be excluded. In conclusion, it was shown that metabolic conversion of NBA is associated with DNA adduct formation in rat alveolar type II epithelial cells. The formation and covalent DNA binding of reactive NBA metabolites may provide the rational for a mechanism of lung carcinogenesis based on direct genotoxicity.

: http://publica.fraunhofer.de/documents/N-6438.html