A ACETYLATION PHARMACOGENETICS:ARYLAMINES AND DNA DAMAGE

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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.