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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA047484-01
Application #
3191151
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1988-04-01
Project End
1991-03-31
Budget Start
1988-04-01
Budget End
1989-03-31
Support Year
1
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Toledo
Department
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Patnaik, Akash; Chau, Vincent; Li, Feng et al. (2002) Budding of equine infectious anemia virus is insensitive to proteasome inhibitors. J Virol 76:2641-7
Schut, H A; Snyderwine, E G (1999) DNA adducts of heterocyclic amine food mutagens: implications for mutagenesis and carcinogenesis. Carcinogenesis 20:353-68
Schut, H A; Cummings, D A; Smale, M H et al. (1997) DNA adducts of heterocyclic amines: formation, removal and inhibition by dietary components. Mutat Res 376:185-94
Schut, H A; Wang, C L; Twining, L M et al. (1997) Formation and persistence of DNA adducts of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in CDF1 mice fed a high omega-3 fatty acid diet. Mutat Res 378:23-30
Schut, H A; Herzog, C R; Cummings, D A (1994) Accumulation of DNA adducts of 2-amino-3-methylimidazo[4,5-f] quinoline (IQ) in tissues and white blood cells of the Fischer-344 rat after multiple oral dosing. Carcinogenesis 15:1467-70
Schut, H A (1994) Dietary modulation of DNA adduct formation of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the male Fischer 344 rat. Environ Health Perspect 102 Suppl 6:57-60
Schut, H A (1993) Effects of dietary menhaden oil on DNA adducts of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) in Fischer-344 rats. Anticancer Res 13:1517-24
Davis, C D; Schut, H A; Adamson, R H et al. (1993) Mutagenic activation of IQ, PhIP and MeIQx by hepatic microsomes from rat, monkey and man: low mutagenic activation of MeIQx in cynomolgus monkeys in vitro reflects low DNA adduct levels in vivo. Carcinogenesis 14:61-5
Schut, H A; Zu, H X (1993) Application of the 32P-postlabelling assay to the inhibition of 2-amino-3-methylimidazo[4,5-f]quinoline (IQ)-DNA adduct formation by dietary fatty acids. IARC Sci Publ :181-8
Herzog, C R; Schut, H A; Maronpot, R R et al. (1993) ras mutations in 2-amino-3-methylimidazo-[4,5-f]quinoline-induced tumors in the CDF1 mouse. Mol Carcinog 8:202-7

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