Metabolic Activation of N-Heterocyclic Aromatics

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DESCRIPTION (provided by applicant): N-heterocyclic aromatics (NHA) are a subgroup pf polycyclic aromatic hydrocarbons (PAH) which are environmentally important pollutants which are found in complex mixtures. The overall goal of this research program has been to evaluate the role of NHA in the carcinogenicity of PAH mixtures in the environment. We have focused on the relative carcinogenicity of two model NHA, dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA). We have discovered that there are distinct differences in the metabolism of these compounds, which affects profoundly the carcinogenicity. We are now beginning to understand how small structural and chemical differences, between DBC and DBA, contribute to large differences in metabolism, organotropism and carcinogenicity. Building on these results and our experience, we hypothesize that the structural and metabolic differences between these two compounds will have an impact at multiple stages in the carcinogenic process including DNA adduction and repair, mutational spectra, and global gene expression. We also hypothesize that these structural and metabolic differences will cause DBA and DBC to interact differently with a model PAH, benzo[a]pyrene (BAP), when there is co-exposure in binary mixtures. These will be addressed by the following specific aims involving the characterization of the metabolic activation, DNA damage and biological effects of the lesions produced by DBC and DBA in mouse skin, and liver and in human liver cells: 1) Elucidate the mechanism of activation of DBC and DBA in vitro and in vivo. 2) Characterize the types of DNA lesions induced by DBC and DBA in human liver cells and in mouse liver and skin including bulky adducts, apurinic sites and oxidative damage. 3) Determine the effects of binary mixtures of DBC and BaP, or DBA and BaP on biological endpoints including metabolism, DNA adducts and ras mutational spectra. This approach will provide valuable information on the metabolic activation and biological consequences of mixtures of NHA and lead to a better understanding of the mechanism(s) of carcinogenesis. An important effort, in the next research period, will be to relate the differences we are discovering in the structure of DBC and DBA with their biological effects, up to and including, how each behave as components of PAH mixtures. Using this approach, we will begin to understand the interaction between components of mixtures.