SYNTHESIS, CHARACTERIZATION, AND MUTAGENICITY OF NITRATED 7H-DIBENZO[C,G]CARBAZOLE AND ITS PHENOLIC DERIVATIVES

The nitrated N-heterocyclic aromatic hydrocarbons (NAHs) are found in a variety of environmental sources; many of them have been determined to be mutagenic in short-term assays and/or carcinogenic in animal tes ts. In this laboratory, we synthesized and characterized nitrated 7H-d ibenzo[c,g]carbazole (DEC) and the nitrophenolic metabolites of DEC as potential mutagenic and carcinogenic xenobiotics. The nitro group was formed exclusively at the 5 and/or the symmetric 9 position of DEC, 2 -hydroxy-DBC, 3-hydroxy-DBC, and 4-hydroxy-DBC. Ames plate incorporati on mutagenicity assays were conducted using Salmonella typhimurium str ains TA98 and TA100, with or without rat liver homogenates (S9). Mutag enicities of the nitrated DBCs were higher than the parent DEC in stra in TA98. 5,9-Dinitro-DBC had stronger mutagenic responses than 5-nitro -DBC in all assays, particularly in strain TA98 with S9. 5,9-Dinitro-D BC had a higher reduction potential relative to 5-nitro-DBC (-1.09 V a nd -1.37 V, respectively). Hydroxyl derivatives of 5-nitro-DBC at the 2, 3, 4, 10, or 12 position, synthesized through nitration of the corr esponding hydroxy-DBC, possessed greater mutagenicity than the parent 5-nitro-DBC, especially in strain TA100 with or without S9. Our data s uggest that nitrated DEC undergoes both nitroreduction and ring oxidat ion as the primary pathways for the metabolic activation leading to mu tagenesis. The relative mutagenicities of the nitrohydroxy-DBC isomers are generally consistent with the resonance stabilization of the posi tive charge at the arylnitrenium ion, formed from the nitro functional group, as the proposed active electrophile responsible for genotoxic effects.