A ACETYLATION PHARMACOGENETICS:ARYLAMINES AND DNA DAMAGE

我们已经提议对芳胺类药物进行药物遗传学研究， 致癌物质和其他环境化学物质在基因上定义 动物模型，以及从动物模型中分离出来的组织和细胞。在这项研究中， 我们将确定造成核DNA损伤的程度和意义 通过将细胞和组织暴露在多态乙酰化模型中 芳胺类致癌物质，2-氨基荧烯。我们将培育出同基因小鼠 具有不同乙酰化和AH诱导组合的品系 用于这一目的的表型。我们将检测分离出的DNA损伤 肝细胞和尿路上皮细胞通过检测程序外DNA合成和 DNA加合物；我们还将通过检测DNA来确定体内DNA损伤 短时间内小鼠肝脏和膀胱DNA加合物的合成及作用 2-氨基荧烯的长期给药。此外，我们将确定 2-氨基荧烯在分离细胞和正常小鼠体内的代谢特征。 我们的目标是评估这些遗传性代谢的重要性 芳胺所致DNA损伤的基因多态性。

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.