QUINOLINES AND CARBAZOLES: MUTAGENS AND CARCINOGENS

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Quinoline, carbazole, and their methylated derivatives are widely distributed environmental pollutants and are carcinogenic in laboratory animals. The objective of this research program is to determine the mechanism(s) by which these aza-arenes ultimately exert their genotoxic activity. It is our hypothesis that quinoline is metabolically transformed to an oxaziridine capable of interacting with DNA and other cellular macromolecules to form adducts. The electrophilic metabolites of quinoline formed in vivo will be investigated using radiolabeled quinoline. Electrophilic metabolites will be identified through the analysis of the adducts formed with glutathione and cellular macromolecules including protein, RNA, and DNA. These biochemical studies will direct synthetic efforts in the preparation of reference standards for comparison with the products resulting from interaction of suspect electrophilic metabolites with cellular macromolecules. There are major species differences in the hepatocarcinogenic activity of quinoline. Macromolecular adducts and metabolites formed in the liver of rats, mice, hamsters, and guinea pigs will be analyzed to determine a possible correlation with susceptibility. Metabolites and adducts formed in hepatocytes from rats and humans will also be compared. Elucidation of the mechanisms by which quinoline exerts its genotoxic activity is of particular importance in view of these and species differences observed in its carcinogenic activity, as well as the extent to which it is present in the environment. Carbazole is the second principal carcinogenic agent targeted for study in this program. It is our hypothesis that carbazole is being transformed in vivo to 9-hyrdoxymethylcarbazole which ultimately forms an electrophilic 9- methiminium derivative. This hypothesis will be investigated by characterizing the metabolites and the liver DNA adducts formed from carbazole and 9-methylcarbazole in mice. 9-Hydroxycarbazole and 9- acetoxycarbazole are direct-acting mutagens in S. typhimurium and extensive adduct formation has been observed after incubation of 9-acetoxycarbazole with DNA using the 32P-postlabeling technique. We will determine the extent to which similar adducts are formed in vivo in mouse liver.