Formation of the adduct 6-(deoxyguanosin-N²-yl)-3-amino-benzo[a]pyrene from the mutagenic environmental contaminant 3-nitrobenzo[a]pyrene

Abstract

3-Nitrobenzo[a]pyrene (3-nitro-B[a]P) is a potent bacterial mutagen as a result of nitroreduction. Reaction of N-hydroxy-3-amino-B[a]P, prepared in situ from reduction of 3-nitro-B[a]P with calf thymus DNA, was studied. After enzymatic digestion of the DNA, the resulting modified nucleosides were analyzed by thermospray HPLC-MS and high-resolution proton NMR spectroscopy. The major adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P. The same adduct was obtained from incubation of DNA with 3-nitro-B[a]P in the presence of the mammalian nitroreductase xanthine oxidase, and hypoxanthine. These data indicate that a mammalian nitroreductase can metabolize 3-nitro-B[a]P to an activated derivative that reacts with DNA to give a novel adduct distant from the site of N-hydroxylation.

NMR‐invisible nucleosides in adducts formed from carcinogenic nitrobenzo[a]pyrenes

“…All chemical shift differences between subspectra of the 2'-deoxyribose protons are in the range of 0.7-1. 3 a Data for the nucleoside moiety were obtained at -31 C from the NOESY spectrum. All data are based on a twostate model unless indicated otherwise.…”

An Unusual DNA Adduct Derived from the Powerfully Mutagenic Environmental Contaminant 3-Nitrobenzanthrone

“…The adduct formation of nitro-PAH metabolites generally occurs at C-8 of dG through the amino or amide group, or at N-2 of dG through the most cationic ring carbon resulting from the resonance stabilization of the initial nitrenium ion intermediate (8,9,29,37). For nitropyrenes, nitrofluoranthenes, and nitrobiphenyls, the C-8-substituted dG adducts are known to make a significant contribution to the total DNA adducts (7,(25)(26)(27)(28).…”

“…The conformation of the glycoside linkage appears to play an important role in adduct persistence in vivo, and consequently, it may influence the toxicological properties of DNA adducts (29,(44)(45)(46)(47)(48). The syn type adduct appears to induce a greater distortion of the DNA helix than the anti type one, resulting in rapid disappearance of the former adduct and greater persistence of the latter.…”

DNA adducts of chemical carcinogens

“…Agents are known that react fairly exclusively with each of these sites, i.e. the simple alkylating agents, such as methyl methane sulfonate, yield principally N-7 substituted products (6), 1-naphthylhydroxylamine is reported to react exclusively at the O 6 position (22) and the dihydrodiol epoxides of the polycyclic aromatic hydrocarbons (17) and 3-benzo[a]pyrenylhydroxylamine (23) react exclusively at the N 2 position. In the reactivity diagram, these chemicals are positioned, therefore, close to the appropriate corners of the diagram.…”