Chronic alcohol and tobacco use have been positively associated with increased risk for head and neck cancers in man. The precise mechanism(s) which account for this increased risk are not known. Our working hypothesis is that chronic alcohol consumption alters one or more components of the microsomal mixed function oxygenase system resulting in enhanced rates of metabolic e=activation of tobacco-associated carcinogens. Our studies have shown that ethanol consumption by hamsters results in enhanced liver and target tissue (trachea) metabolism, enhanced post-mitochondrial supernatant-mediated mutagenicity and carcinogenicity (tracheal and nasal cavity) of N-nitrosopyrrolidine (NPYR). The proposed series of studies are designed to directly test the hypothesis that enhanced metabolic activation of NPYR in target tissues results in enhanced carcinogenicity in Syrian golden hamsters and to critically examine the respective roles of alpha- and Beta-hydroxylation, and denitrosation in the target site specificity of NPYR by examining both target and non-target tissues for the alpha-hydroxylation of NPYR as well as the induction of the isozyme of cytochrome P450 induced by ethanol that is believed to participate in the metabolic activation of the N- nitrosamines. The link between ethanol consumption, metabolism, metabolic activity and enhanced tumor incidence will be clearly delineated. In addition, since the microsomal metabolism of nicotine results in the formation of reactive intermediates (iminium ion species) which have also been suggested as intermediates for the clinical nitrosation of nicotine, we plan to determine if in situ nitrosation of nicotine can be catalyzed by isolated microsomes. This pathway for nitrosamine formation would result in the intracellular generation of N'-nitrosonornicotine (NNN), 4- (methynitrosamino)-4-(3-pyridyl)butanone (NNK), and 4'- (methylnitrosamino)-4-(3-pyridyl)butanol (NNA) from nicotine. These tobacco-specific nitrosamines can be found in both unburned tobacco as well as mainstream and sidestream tobacco smoke and are known to cause head and neck tumors as well as lung tumors in experimental animals.
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