A ACETYLATION PHARMACOGENETICS:ARYLAMINES AND DNA DAMAGE

我们提出了芳胺类药物的遗传药理学研究， 致癌物质和其他环境化学物质在基因定义 动物模型，以及从它们分离的组织和细胞中。 在本研究中， 我们将确定核DNA损伤的程度和意义， 通过将细胞和组织暴露于多晶型乙酰化模型 芳胺致癌物2-氨基芴。 我们将开发同类小鼠 具有不同乙酰化和AH诱导组合的品系 表型为此目的。 我们将确定DNA损伤在孤立的 通过检查非程序性DNA合成， DNA加合物;我们还将通过检查DNA来确定体内DNA损伤 小鼠肝、膀胱DNA加合物合成及DNA加合物的变化 2-氨基芴长期给药。 此外，我们将确定 2-氨基芴在分离细胞和完整小鼠中的代谢谱。 我们的目标是评估这些遗传代谢的重要性， 多态性对芳胺诱导的DNA损伤的影响。

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.