Theoretical investigations on the formation of nitrobenzanthrone-DNA Adducts

Abstract

3-Nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. The thermochemical formation cascades were calculated for six 3-NBA-derived DNA adducts employing its arylnitrenium ion as precursor using density functional theory (DFT). Clear exothermic pathways were found for four adducts, i.e., 2-(2'-deoxyadenosin-N(6)-yl)-3-aminobenzanthrone, 2-(2'-deoxyguanosin-N(2)-yl)-3-aminobenzanthrone, N-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone and 2-(2'-deoxyguanosin-8-yl)-3-aminobenzanthrone. All four have been observed to be formed in cell-free experimental systems. The formation of N-(2'-deoxyadenosin-8-yl)-3-aminobenzanthrone is predicted to be not thermochemically viable explaining its absence in either in vitro or in vivo model systems. However, 2-(2'-deoxyadenosin-8-yl)-3-aminobenzanthrone, can be formed, albeit not as a major product, and is a viable candidate for an unknown adenine adduct observed experimentally. 2-nitrobenzanthrone (2-NBA), an isomer of 3-NBA, was also included in the calculations; it has a higher abundance in ambient air than 3-NBA, but a much lower genotoxic potency. Similar thermochemical profiles were obtained for the calculated 2-NBA-derived DNA adducts. This leads to the conclusion that enzymatic activation as well as the stability of its arylnitrenium ion are important determinants of 2-NBA genotoxicity.

Mechanisms of Enzyme-Catalyzed Reduction of Two Carcinogenic Nitro-Aromatics, 3-Nitrobenzanthrone and Aristolochic Acid I: Experimental and Theoretical Approaches

“…N -OH-3-ABA can be further reduced to 3-aminobenzanthrone (3-ABA; step 4 in Figure 1) [14,51,52,54]. Of the 3-NBA-derived DNA adducts generated by NQO1, three major adducts were identified as 2-(2'-deoxyadenosin- N 6 -yl)-3-aminobenzanthrone (dA- N 6 -3-ABA), dG- N 2 -3-ABA and dG-C8- N -3-ABA [16,20,55,56,57,58] (Figure 1). Interestingly, 3-NBA and its amino metabolite, 3-ABA, are potent inducers of NQO1 in liver, lung and kidney of rats.…”

“…In contrast, other nitroarenes lacking the carboxylic group including 3-NBA can form DNA adducts both at nitrogen and ortho carbon. Indeed, besides dA- N 6 -3-ABA and dG- N 2 -3-ABA, the dG-C8- N -ABA adduct is also generated from the cation formed from the N -hydroxylated intermediate of 3-NBA, N -OH-3-ABA (Figure 1) [20,21,55,56]. …”

Pre-steady-state kinetic investigation of bypass of a bulky guanine lesion by human Y-family DNA polymerases

“…It has one of the most mutagenic profiles of known pollutants tested in the Ames Salmonella typhimurium (TA98) assay and is responsible for inducing mostly G→T transversions 1; 3 . Upon inhalation, 3-NBA is metabolized into various mutagenic and potentially carcinogenic metabolites that can react with purines in DNA 4 . These reactions lead to the formation of bulky, aromatic DNA lesions which act as roadblocks to genomic replication.…”

“…One such product, N -(2′-deoxyguanosin-8-yl)-3-aminobenzanthrone (dG C8- N -ABA ), is of particular interest because it is a major lesion formed in mice after intraperitoneal treatment with 3-NBA 5 . The bulky lesion dG C8- N -ABA , produced by the electrophilic attack of deoxyguanosine (dG) by a 3-NBA metabolite 4 (Figure S1), has been found to severely block replication fork progression 6 .…”

Mechanism of Error‐Free Bypass of the Environmental Carcinogen N‐(2′‐Deoxyguanosin‐8‐yl)‐3‐aminobenzanthrone Adduct by Human DNA Polymerase η

“…Enzymatic reduction in vivo engenders a conversion of 3‐NBA to aminobenzanthrone (ABA, Scheme ) . Intermediates in the reduction pathway can form reactive nitrenium ions that alkylate DNA, thereby resulting in ABA adducts . Three different adducts have been identified; they occur on the C8 (Scheme ) or N 2 positions of guanine (major adducts), or the N 6 position of adenine (minor adduct) .…”