QUINOLINES & BENZOQUINOLINES: MUTAGENS & CARCINOGENESIS

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Quinoline, methylquinolines, and benzoquinolines are the major aza-arenes which have been detected as pollutants in the human respiratory environment. Our objective is to determine the mechanism(s) by which quinoline, methylquinolines, and benzoquinolines are metabolically activated to genotoxic agents. We will determine the mechanism by which quinoline is ultimately activated to a hepatocarcinogen in mice and rats. It is known that rat liver microsomes can metabolically activate quinoline to a mutagen. Our studies on the metabolism of quinoline will be extended to include the identification of all water-soluble metabolites formed using this activation system. Based upon our most recent studies, the oxaziridine of 1,2-dihydroquinoline and 3,4-epoxy-3,4-dihydroquinoline are the suspect ultimate genotoxic metabolites of quinoline. These electrophiles will be synthesized and their biological activities evaluated relative to quinoline. While mice and rats are known to be sensitive to the hepatocarcinogenic effects of quinoline, hamsters and guinea pigs are reported to be resistant. We will compare the DNA-adducts of quinoline formed in vivo in both mice and rats with those formed in hamsters and guinea pigs. We will structurally identify the major DNA adduct(s) of quinoline formed in vivo. Ultimately, we will compare the metabolites of quinoline and the DNA-adduct(s) of quinoline formed with human hepatocytes with those formed in rat hepatocytes. Benzo(f)quinoline has been shown to be a weak hepatocarcinogen in newborn mice. Bioassays are in progress to further evaluate the relative carcinogenic potential of quinoline, methylquinolines, and benzoquinolines. We will also examine the contribution of each of the major metabolites of benzo(f)quinoline, benzo(h)quinoline, and phenanthridine to their mutagenic activity. The major mutagenic metabolites of these aza-arenes will also be evaluated for their carcinogenic activity. These bicyclic and tricyclic compounds represent the major aza-arenes which are present in the human environment. This research is intended to increase our understanding of their genotoxic potential as well as the molecular basis for their biological activities.