Mechanisms of the different DNA adduct forming potentials of the urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20545351
DOI
10.1021/tx100052d
Knihovny.cz E-resources
- MeSH
- DNA Adducts chemistry metabolism MeSH
- Benz(a)Anthracenes toxicity MeSH
- Hepatocytes metabolism MeSH
- Isomerism MeSH
- Liver enzymology MeSH
- Carcinogens toxicity MeSH
- Catalytic Domain MeSH
- Cells, Cultured MeSH
- Air Pollutants toxicity MeSH
- Humans MeSH
- NAD(P)H Dehydrogenase (Quinone) chemistry MeSH
- Computer Simulation MeSH
- Binding Sites MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- 3-nitrobenzanthrone MeSH Browser
- DNA Adducts MeSH
- Benz(a)Anthracenes MeSH
- Carcinogens MeSH
- Air Pollutants MeSH
- NAD(P)H Dehydrogenase (Quinone) MeSH
- NQO1 protein, human MeSH Browser
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.
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