3-Amino-3-methylimidazo (4,5-f)quinoline (IQ) is a heterocyclic amine which can be isolated from cooked beef and broiled sardines. It is both a potent bacterial mutagen and a carcinogen in Fischer-344 rats and CDF1 mice. In the rat the main target organs of IQ are the liver and the small and large intestine, while in the CDF1 mouse, the liver, forestomach and the lungs are affected. Because of the exposure through the diet, IQ may be a good candidate etiologic agent in human cancer, particularly in that of the colon. Because it is generally accepted that the covalent interaction of a chemical with DNA is a necessary prerequisite for its carcinogenicity to be expressed, the proposed studies will examine the dynamics of this interaction by isolating and quantitating specific IO-DNA adducts in target organs of the Fischer-344 rat and the CDF1 mouse, using the 32P-postlabeling technique as the principal analytical tool. Because persistence of specific carcinogen-DNA adducts has been linked to a mutational event, and to subsequent triggering of the carcinogenic process, persistence of IQ-DNA adducts in target organs will be examined. Since susceptibility to IQ carcinogenesis appears to depend on the sex of the animal, persistence of IQ-DNA adducts will be examined in both males and females. In related studies, using both rodent species, the genotoxicity of IQ (as measured by unscheduled DNA synthesis) as well as its in vitro metabolic activation by isolated hepatocytes and intestinal cells, will be evaluated. Both epidemiological and experimental evidence indicates that dietary fat may affect susceptibility to tumor formation. In addition, there is good experimental evidence that dietary fat affects rates of carcinogen metabolism. Therefore, the effects of diets with varying fat contents on IQ-DNA adduct formation in target organs will be examined in both species. In addition, using a newborn mouse liver tumor model, rates of formation and removal of IQ-DNA adducts in the liver will be correlated with the liver tumor response in a long-term bioassay. In both these latter studies the effects of diets containing high levels (20%) of either safflower oil (rich in omega-6 polyunsaturated fatty acids) or menhaden oil (rich in omega-3 polyunsaturated fatty acids) will be examined and compared to a control diet containing 5% corn oil.
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