DNA Adducts and Carcinogenicity of Nitro-Polycyclic Aromatic Hydrocarbons

Abstract

We have been interested in the structure-activity relationships of nitro-polycyclic aromatic hydrocarbons (nitro-PAHs), and have focused on the corre- lation of structural and electronic features with biological activities, including mutagenicity and tumorigenicity.In our studies, we have emphasized 1-, 2-, 3-, and 6-nitrobenzo[a]pyrenes (nitro-B[a]Ps) and related compounds, all of which are derived from the potent carcinogen benzo[alpyrene.While 1-, 2-, and 3-nitro-B[a]P are potent mutagens in Salmonella, 6-nitro-B[a]P is a weak mutagen.In vitro metabolism of 1-and 3-nitro-B[a]P has been found to generate multiple pathways for mutagenic activation.The formation of the corresponding trans-7,8-dihydrodiols and 7,8,9,1 0-tetrahy- drotetrols suggests that 1-and 3-nitro-B[a]P trans-7,8-diol-9,1 0-epoxides are ultimate metabolites of the parent nitro-B[a]Ps.We have isolated a DNA adduct from the reaction between 3-nitro-B[a]P trans-7,8-diol-anti9,10-epoxide and calf thymus DNA, and identified it as 10-(deoxyguanosin-N2-yl)- 7,8,9-trihydroxy-7,8,9,10-tetrahydro-3-nitro-B[a]P.The same adduct was identified from in vitro metabolism of [3H]3-nitro-B[a]P by rat liver micro- somes in the presence of calf thymus DNA.A DNA adduct of 3-nitro-B[a]P formed from reaction of N-hydroxy-3-amino-B[a]P, prepared in situ with calf thymus DNA was also isolated.This adduct was identified as 6-(deoxyguanosin-N2-yl)-3-amino-B[a]P.The same adduct was obtained from incu- bating 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 nitrenium ion formation.Similar DNA adducts were obtained from ring-oxidation and nitroreduction of 1-nitro-B[aIP.Metabolism of 6-nitro-B[a]P resulted in a different pattern, and DNA adducts have not been detected from chemical or biologic activation.Based on these results, together with the other findings, we have proposed that orientation of the nitro functional group is a critical structural feature that can affect metabolism, DNA binding, mutagenicity, and tumorigenicity of nitro-PAHs.Additional data from the derivatives of the nitro-B[a]Ps support this hypothesis.-