Mechanisms of the different DNA adduct forming potentials of the urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone
| Autor: | Vilim Simanek, Jana Sistkova, Marie Stiborová, Zdenek Dvorák, David H. Phillips, Eva Frei, Martina Svobodová, Volker M. Arlt, Heinz H. Schmeiser, Václav Martínek, Jitka Ulrichova |
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| Rok vydání: | 2010 |
| Předmět: |
Stereochemistry
3-Nitrobenzanthrone Mutagen Toxicology medicine.disease_cause Adduct chemistry.chemical_compound DNA Adducts Isomerism Catalytic Domain DNA adduct medicine Benz(a)Anthracenes NAD(P)H Dehydrogenase (Quinone) Humans Computer Simulation Xanthine oxidase Carcinogen Cells Cultured Air Pollutants Binding Sites Chemistry Cytochrome P450 reductase General Medicine Biochemistry Liver Carcinogens Hepatocytes |
| Zdroj: | Chemical research in toxicology. 23(7) |
| ISSN: | 1520-5010 |
| Popis: | 2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. We compared the efficiencies of human enzymatic systems [hepatic microsomes and cytosols, NAD(P)H:quinone oxidoreductase 1 (NQO1), xanthine oxidase, NADPH:cytochrome P450 reductase, N,O-acetyltransferases, and sulfotransferases] and human primary hepatocytes to activate 2-NBA and its isomer 3-NBA to species forming DNA adducts. In contrast to 3-NBA, 2-NBA was not metabolized at detectable levels by the tested human enzymatic systems and enzymes expressed in human hepatocytes, and no DNA adducts detectable by (32)P-postlabeling were generated by 2-NBA. Even NQO1, the most efficient human enzyme to bioactive 3-NBA, did not activate 2-NBA. Molecular docking of 2-NBA and 3-NBA to the active site of NQO1 showed similar binding affinities; however, the binding orientation of 2-NBA does not favor the reduction of the nitro group. This was in line with the inhibition of 3-NBA-DNA adduct formation by 2-NBA, indicating that 2-NBA can compete with 3-NBA for binding to NQO1, thereby decreasing the metabolic activation of 3-NBA. In addition, the predicted equilibrium conditions favor a 3 orders of magnitude higher dissociation of N-OH-3-ABA in comparison to N-OH-2-ABA. These findings explain the very different genotoxicity, mutagenicity, and DNA adduct forming potential of the two compounds. Collectively, our results suggest that 2-NBA possesses a relatively lower risk to humans than 3-NBA. |
| Databáze: | OpenAIRE |
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