ACETYLATION PHARMACOGENETICS: ARYLAMINES AND DNA DAMAGE

这项提案的主要目的是检验遗传学的假设， 芳胺致癌物活化的差异是重要的 DNA损伤和DNA致癌物加合物形成的决定因素， 在短期暴露于芳胺后观察到的DNA加合物形成 致癌物是一个有效的指标，易感性致癌， 基因定义的动物模型。 为了完整地检验第一个假设 具有确定代谢基因型的近交系和同类系小鼠将暴露于 2-氨基芴在许多曝光条件下， 靶组织（肝脏和膀胱）中的2-AF-DNA加合物将被 测定了 第二个假设将通过单独的体内研究进行检验 乙酰化同源小鼠靶组织肿瘤发生的研究 暴露于2-AF。 其他目的包括确定是否在N-氧化多态性 芳香胺在小鼠体内的存在，是一个重要的决定因素， 和DNA损伤 其他酶的作用 芳胺代谢在调节这种普遍存在的 化学品也将被检查。 该建议的一个重要目标是建立近交乙酰化器 同种小鼠作为人结肠直肠癌相关模型 杂环芳胺食品诱变剂。 近交乙酰化同源小鼠品系提供了独特的资源， 这项研究之所以提出，是因为它们能够研究这种遗传性的 与其他多态性性状分离的性状， 和对芳胺的反应。 芳胺的危害性分析 使用这种动物模型的暴露应该能够进行更准确的评估 乙酰化基因相对于其他基因的影响 比迄今为止可能的，也可以促进收购 关于人类癌症易感性差异的信息， 由于伦理约束而受到阻碍的环境起源， 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.