The major objective of this proposal is to test the hypotheses that genetic differences in the activation of arylamine carcinogens are important determinants of DNA damage and the formation of DNA-carcinogen adducts, and that DNA-adduct formation seen after short-term exposures to arylamine carcinogens is a valid indicator of susceptibility to carcinogenesis in a genetically defined animal model. To test the first hypothesis intact inbred and congenic mice of defined metabolic genotype will be exposed to 2-aminofluorene under a number of exposure conditions and the formation of 2-AF-DNA adducts in the target tissues (liver and bladder) will be measured. The second hypothesis will be tested by a separate in vivo study of the development of tumors in target tissues in acetylator congenic mice exposed to 2-AF. Additional objectives include determining if a polymorphism in N-oxidation of arylamines exists in mice and it is an important determinant of tissue and DNA damage from these compounds. The role of other enzymes of arylamine metabolism in modulating the risk of damage by this ubiquitous class of chemicals will also be examined. An important goal of this proposal is to establish inbred acetylator congenic mice as models for human colo-rectal cancer related to heterocyclic arylamine food mutagens. The inbred acetylator congenic mouse strains provide a unique resource for the investigations proposed because they enable a study of this hereditary trait isolated from other polymorphic traits affecting the disposition of and response to arylamines. The analysis of the consequences of arylamine exposure using this animal model should enable a more accurate assessment of the effects attributable to acetylator genes in relation to other genes than heretofore possible, and may also facilitate the acquisition of information about differences in susceptibility to human cancers of environmental origin that is stymied because of the ethical constraints and methodological difficulties that prevail.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039018-07
Application #
3177646
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-01-01
Project End
1995-11-30
Budget Start
1991-12-01
Budget End
1992-11-30
Support Year
7
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
de Leon, J H; Vatsis, K P; Weber, W W (2000) Characterization of naturally occurring and recombinant human N-acetyltransferase variants encoded by NAT1. Mol Pharmacol 58:288-99
Dhaini, H R; Levy, G N (2000) Arylamine N-acetyltransferase 1 (NAT1) genotypes in a Lebanese population. Pharmacogenetics 10:79-83
Estrada, L; Kanelakis, K C; Levy, G N et al. (2000) Tissue- and gender-specific expression of N-acetyltransferase 2 (Nat2*) during development of the outbred mouse strain CD-1. Drug Metab Dispos 28:139-46
Weber, W W (1999) Populations and genetic polymorphisms. Mol Diagn 4:299-307
Liu, Y; Levy, G N (1998) Activation of heterocyclic amines by combinations of prostaglandin H synthase-1 and -2 with N-acetyltransferase 1 and 2. Cancer Lett 133:115-23
Estrada-Rodgers, L; Levy, G N; Weber, W W (1998) Characterization of a hormone response element in the mouse N-acetyltransferase 2 (Nat2*) promoter. Gene Expr 7:13-24
Estrada-Rodgers, L; Levy, G N; Weber, W W (1998) Substrate selectivity of mouse N-acetyltransferases 1, 2, and 3 expressed in COS-1 cells. Drug Metab Dispos 26:502-5
Liu, Y; Levy, G N; Weber, W W (1997) Induction of human prostaglandin endoperoxide H synthase-2 (PHS-2) mRNA by TCDD. Prostaglandins 53:1-10
Levy, G N (1997) Prostaglandin H synthases, nonsteroidal anti-inflammatory drugs, and colon cancer. FASEB J 11:234-47
Levy, G N; Rodgers, L; Weber, W W (1996) Effects of heredity on response to drugs and environmental chemicals: construction of rodent models. Chem Res Toxicol 9:1215-24

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