Nitrated polycyclic aromatic hydrocarbons (NO2PAH) are ubiquitous environmental contaminants and potential carcinogens. The purpose of this research is to improve our understanding of the genotoxicity and, of the factors involved in production, distribution and activation of mammalian metabolites from N02PAH. The model N02PAH isomers 1-nitropyrene (1-NP) and 2- and 3-nitrofluoranthene (2-NFA, 3-NFA) will be used to answer the following questions:, Do N02PAH in general form reduced, N-acetylated and hydroxylated (NAPAHOH) urinary metabolites, and if so, how much variability is there between N02PAH in metabolism in the rat? Are NAPAHOH metabolites generally mutagenic in the Ames assay? What enzymes (bacterial and mammalian) are involved in their activation? How important are transacetylase enzymes in the formation and activation of N02PAH and of NAPAHOH metabolites? Can formation of NAPAHOH represent a common pathway for metabolism and activation for N02PAH? Do the N02PAH or their metabolites form identifiable DNA adducts with calf thymus DNA and in Salmonella typhimurium ? Models for DNA adducts will be synthesized, and used to detect and if possible identify adducts formed in vitro. Do the N02PAH or their metabolites form identifiable DNA adducts in vivo ? Tissues and major organs from rats treated with N02PAH will be screened for the presence of DNA adducts characterized in Study III. Conclusions from the studies outlined above will be used to attempt to address the following questions: What factors determine the observed differences in metabolism and mutagenicity between different N02PAH isomers, and do these also influence differences in interaction with DNA and predict differences in carcinogenicity ? If N02PAH prove not to be substantive health hazards, can we explain the discrepancy between in vitro genotoxicity and in vivo potency ? Could our findings permit prediction of the activity of as-yet unidentified and uncharacterized N02PAH in the environment?
| Rosser, P F; Ramachandran, P; Sangaiah, R et al. (1996) Role of O-acetyltransferase in activation of oxidised metabolites of the genotoxic environmental pollutant 1-nitropyrene. Mutat Res 369:209-20 |
