ACETYLATION PHARMACOGENETICS--ARYLAMINES AND DNA DAMAGE

这项提议的主要目标是检验基因的假设 芳胺类致癌物质的活性差异是重要的 DNA损伤和DNA致癌加合物形成的决定因素，以及 短期接触芳胺后DNA加合物的形成 致癌物是一种有效的癌症易感性的指标。 基因定义的动物模型。要完整地检验第一个假设 具有特定代谢基因的近交系和同源基因小鼠将暴露于 2-氨基荧烯在若干暴露条件下的形成及 靶组织(肝脏和膀胱)中的2-AF-DNA加合物将是 量过了。第二个假设将通过一项单独的体内研究进行验证。 乙酰化同源基因小鼠靶组织肿瘤发生发展的研究 暴露在2-AF环境中。 其他目标包括确定N-氧化中的多态 在小鼠体内存在，它是组织的重要决定因素 以及这些化合物造成的DNA损伤。其他酶的作用 芳胺代谢调节由这种无处不在的 还将检查化学品的类别。 这项提议的一个重要目标是建立近交系乙酰化 同源基因小鼠作为人结直肠癌相关模型的研究 杂环芳胺食品诱变剂。 近亲交配的乙酰化同源小鼠品系为 之所以提出调查，是因为它们使对这种遗传病的研究成为可能 从影响性格的其他多态性状中分离出来的特征 以及对芳香胺的反应。芳香胺的后果分析 使用这种动物模型的暴露应该能够更准确地评估 乙酰化基因的作用与其他基因的关系 比到目前为止更有可能，还可以促进收购 关于人类癌症易感性差异的信息 环境起源由于伦理限制和 普遍存在的方法上的困难。

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.