title: Mechanisms of the different DNA adduct forming potentials of the urban air pollutants 2-nitrobenzanthrone and carcinogenic 3-nitrobenzanthrone.
abstract: 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.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Albertov 2030, Prague 2, Czech Republic. stiborov@natur.cuni.cz
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
authors.forename: Václav
authors.initials: V
authors.lastname: Martínek
authors.forename: Martina
authors.initials: M
authors.lastname: Svobodová
authors.forename: Jana
authors.initials: J
authors.lastname: Sístková
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Dvorák
authors.forename: Jitka
authors.initials: J
authors.lastname: Ulrichová
authors.forename: Vilím
authors.initials: V
authors.lastname: Simánek
authors.forename: Eva
authors.initials: E
authors.lastname: Frei
authors.forename: Heinz H
authors.initials: HH
authors.lastname: Schmeiser
authors.forename: David H
authors.initials: DH
authors.lastname: Phillips
authors.forename: Volker M
authors.initials: VM
authors.lastname: Arlt
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D001665:Binding Sites; D002273:Carcinogens / Q000633:toxicity*; D020134:Catalytic Domain; D002478:Cells, Cultured; D003198:Computer Simulation; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007536:Isomerism; D008099:Liver / Q000201:enzymology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000737:chemistry
chemical_list: D000393:Air Pollutants; D001551:Benz(a)Anthracenes; D002273:Carcinogens; D018736:DNA Adducts; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; C117220:3-nitrobenzanthrone