The simultaneous or sequential exposure of biological systems to a chemical or the existence of a secondary pathological state can enhance or promote the toxicological response induced by another agent. For example, it has been recognized that malignancies often develop at sites of ongoing inflammation. It is an overall goal of this project to define the relationships between these two pathological states and, in particular, the possibility that polymorphonuclear leukocytes (PMNs) are involved in the metabolic activation of pulmonary carcinogens. Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants and like many xenobiotics, the metabolism of PAHs to reactive intermediates appears to be an essential component in their mechanism of cell death, mutagenicity and carcinogenicity. The activation of benzo(a)pyrene, a PAH, by cellular enzyme systems results in the formation of an ultimate carcinogenic bay region diol-epoxide that covalently binds to tissue constituents. Mice exposed to Proteus mirabilis will be utilized as a source of pulmonary PMNs and the interaction of BP-7,8-dihydrodiol, a proximate carcinogenic metabolite of BP, with isolated PMNs will be assessed by the generation of chemiluminescence from BP-7,8-dihydrodiol, by covalent binding to nucleic acids, by the induction of sister chromatid exchanges in mammalian cells and by characterizing products of this interaction by HPLC. Total covalent binding to DNA and carcinogen-DNA adduct profiles will be used as indices to demonstrate the occurrence of this carcinogen-cell interaction in vivo. It is likely that the extent of BP-7,8-dihydrodiol binding to DNA mediated by PMN activation will be influenced by host factors. This issue will be addressed by modulating pulmonary toxification and detoxification systems (for example, decreasing cellular glutathione levels) prior to bacterial exposure. Two additional factors whose influence on this response will be examined are genetic responsiveness at the Ah locus and route of carcinogen administration. The results of these experiments should provide new insights as to how inflammation could be a predisposing or an enhancing factor in the induction of lung cancer by environmental toxicants. Moreover, on the basis of these experiments, it may be possible to propose a role for PMNs in toxicologic processes that is not presently appreciated.
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