Abstract

We have proposed a pharmacogenetic investigation of arylamine drugs, carcinogens, and other environmental chemicals in genetically defined animal models, and in tissues and cells isolated from them. In this study, we will determine the extent and significance of nuclear DNA damage caused by exposure of cells and tissues to the polymorphically acetylated model arylamine carcinogen, 2-aminofluorene. We will develop congenic mouse lines that possess different combinations of acetylator and Ah-inducible phenotypes for this purpose. We will determine DNA damage in isolated hepatocytes and urothelial cells by examining unscheduled DNA synthesis and DNA adducts; we will also determine DNA damage in vivo by examining DNA synthesis and DNA adducts in liver and urinary bladder of mice after short term administration of 2-aminofluorene. Furthermore, we will determine the metabolic profiles of 2-aminofluorene in isolated cells and intact mice. Our objective is to assess the importance of these hereditary metabolic polymorphisms to arylamine-induced DNA damage.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA039018-03
Application #
3177643
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1985-01-01
Project End
1989-12-31
Budget Start
1987-01-01
Budget End
1987-12-31
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost

  Institution

Name
University of Michigan Ann Arbor
Department
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109

  Publications

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

Showing the most recent 10 out of 27 publications