Benzoquinolines represent an important class of environmental toxicants which, due to their mutagenic/carcinogenic properties, present a potential health hazard both to the general public and to workers involved in coking and fossil fuel conversion operations. One member of this class, benzo(f)quinoline, is carcinogenic in rats and mice. In spite of the potential carcinogenicity of this chemical, limited information is available on its metabolism or mechanism of action. The purpose of the proposed research is: (i) to characterize the B(f)Q metabolites and assess their biological activity in an attempt to elucidate the activation and detoxification pathways, and (ii) to investigate DNA-B(f)Q interactions as the potential basis for its mutagenic/carcinogenic action. We also plan to assess the role of nitrogen substitution in the biological activity and metabolism of polycyclic hydrocarbons, in an attempt to obtain a better understanding of the molecular properties which influence the formation of potentially reactive metabolites from a given PAH as well as their biological activity.
The specific aims of the research are as follows: (l) To identify the metabolites resulting from the incubation of B(f)Q with rat liver microsomes. (2) To prepare sufficient quantities of the various derivatives of B(f)Q metabolically or synthetically. (3) To assess the mutagenic activity of the derivatives of B(f)Q and establish a structure-mutagenicity relationship. (4) To compare the metabolism of B(f)Q with that of its homocyclic anlog phenanthrene in order to assess the influence of nitrogen substitution on the metabolism of PAHs. (5) To examine the influence of aza substitution on the biological activity of bay-region diol-epoxides of phenanthrene. (6) To study the covalent interaction of B(f)Q with DNA in vitro and in vivo and to characterize the B(f)Q-DNA adducts. The long-term aim of this research is to understand the mechanism(s) involved in the carcinogenesis of aza-PAHs and to assess the influence of the presence and position of nitrogen substitution on the biological activity and biotransformation of these chemicals.
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