Nitrogen-substituted heterocyclic aromatic compounds (NHA) are important, potentially carcinogenic environmental pollutants. While their structures are similar to those of the more widely studied polycyclic aromatic hydrocarbons, the principal investigator has demonstrated that the metabolic activation of NHA compounds to potent tumorigenic and mutagenic intermediates can proceed, in some cases, by different preferred pathways. This project is focussed entirely on two structurally related N-heterocyclic compounds, 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA). These two compounds differ from one another only in the aromaticity of the N-containing ring. DBC is a potent carcinogen in mouse lung and skin, while DBA is a carcinogen in mouse lung and skin only.
The specific aims are to characterize the mechanisms of metabolic activation and DNA binding in mouse skin, liver, and lung, and to study the biological effects associated with the covalent DNA adducts formed in these tissues. This will be accomplished by characterizing the NHA residues, as well as the DNA target bases in lung, liver, and skin.
Other specific aims i nclude the determination of the frequencies and dose dependences of point mutations in the ras oncogene in the same tissues, and to correlate these findings with the steady-state levels of DNA adducts and specific adduct sites in ras genes in acute and chronic exposure experiments to DBC or DBA. A variety of existing experimental techniques will be employed to achieve these goals. The overall aim is to achieve a better understanding of the mechanisms of carcinogenesis associated with N-heterocyclic aromatic compounds.
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