Quinoline, methylquinolines, and benzoquinolines are the major aza-arenes which have been detected as pollutants in the human respiratory environemt. The objective of this proposal is to determine the mechanism(s) by which quinoline, methylquinoline, and benzoquinolines are metabolically activated to mutagens and carcinogens. We propose to examine species differences in the metabolism and DNA binding of quinoline in liver tissue. In contrast to mice and rats, guinea pigs and hamsters are not susceptible to the hepatocarcinogenic activity of quinoline. Metabolites of quinoline will be identified by methods previously developed in our laboratory. Studies on the metabolites of quinoline formed in vitro will be extended to include human liver tissue. It is our hypothesis that quinoline is metabolically activated in rat liver to a carcinogen by the formation of 5,6-epoxy-5,6-dihydroxyquinoline. The susceptibility of a particular species to the hepatocarcinogenic activity of quinoline may be related to its ability to form this metabolite. To further evaluate this hypothesis, the major DNA adducts of quinoline formed in vivo in the liver of rats will be indentified and compared to those obtained from the liver of species who are resistant to the hepathocarcinogenic activity of quinoline. The metabolites of 4-, 6-, and 8-methylquinoline will be identified to determine a molecular basis for the differences in the mutagenic and tumorigenic activity of these isomeric methylquinolines. These findings will be compared with those obtained with quinoline. We will determine whether a single mechanism or several routes of activation are associated with the tumorigenicity of methylquinolines. Benzo(f)quinoline, benxo(h)quinoline, phenanthridine, benz(f)isoquinoline, and benz(h)isoquinoline are among the major aza-areness present as environmental pollutants. We propose to also delineate the molecular basis for the differences in the biological activity of these azaphenanthrenes. In view of the limited bioassay data available on these aza-arenes, we propose to further evaluate the carcinogenic potential of select isomers in newborn mice and rats. Suspect proximate and ultimate carcinogenic metabolites of these aza-arenes will also be assayed for tumorigenicity. This proposal is intended to increase our understanding of the metabolic activation of these aza-arenes. This proposal is intended to increase our understanding of the metabolic activation of these aza-arenes. This is of particular importance because of the extent to which they are present in the human environment.
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