Effects of Genetic Diversity on Carcinogen Metabolism

描述（由申请人提供）：个体易感性在地区、种族和文化群体之间存在差异，通常认为，除了环境和职业暴露外，遗传背景和生活方式（例如饮食选择）也会显著导致这种变异性。然而，在人类研究中，很难研究暴露与基因的相互作用，因为人类群体包含复杂的亚结构，这些亚结构是社会、种族和地区差异的产物。此外，不同的生活方式是相互关联的，往往会产生多种有益或有害的习惯。为了模拟遗传异质性的人类群体，创建了协作杂交（CC）小鼠以代表涵盖所有可能基因型的完整混合小鼠群体。在拟议的工作中，我们假设，在易感性的变异性，仅来自遗传多样性，可以在小鼠中建模的CC模型与1，3-丁二烯（BD）暴露模型相结合。选择BD作为模型化合物，因为它形成几种蛋白加合物，这些蛋白加合物是BD摄取、代谢活化和解毒的生物标志物。这些N-末端缬氨酸加合物将用于评估CC人群的易感性。BD代谢依赖于P450 2 e1活性，因此我们进一步假设BD衍生的蛋白加合物与P450 2 e1活性相关。为了验证这些假设，我们提出在目标1，以证明来自遗传多样性的致癌物质代谢的范围，并在目标2，以确定是否通过调节P450 2 E1活性介导的致癌物质代谢的差异。因此，我们建议将CC小鼠暴露于BD，并确定代谢活化与仅来自遗传多样性的解毒的相对效力。代谢活化的相对效价 通过应用最近建立的倍增风险模型，从BD衍生的蛋白加合物计算RPoMA。由于90%的BD由P450 2 e1代谢，因此将测定CC小鼠肝组织中的酶活性，以专门研究P450 2 e1在BD代谢中的作用，因为它与易感性有关。如果成功的话，这一提议将显示遗传背景对致癌物代谢的相对贡献，并揭示P450 2 e1在各种遗传背景中的重要性。

DESCRIPTION (provided by applicant): Individual susceptibility varies between regional, racial, and cultural groups, and it is commonly assumed that, in addition to environmental and occupational exposures, genetic background and lifestyle (e.g. diet selection) significantly contribute to this variability. In human studies, however, it is difficult to study exposure- gene interactions because human populations contain complex substructures that are the product of social, racial, and regional differences. In addition, different lifestyles are interconnected and often create multiple beneficial or adverse habits. To model a genetically heterogeneous human population, the Collaborative Cross (CC) mice were created to represent a complete intermixed mouse population covering all possible genotypes. In the proposed work, we hypothesize that the variability in susceptibility derived solely from genetic diversity can be modeled in mice by combining the CC model with the 1, 3-butadiene (BD) exposure model. BD was chosen as a model compound because it forms several protein adducts that are biomarkers for BD uptake, metabolic activation, and detoxification. These N-terminal valine adducts will be used to assess susceptibility of the CC population. BD metabolism is dependent on P450 2e1 activity, and therefore we further hypothesize that BD-derived protein adducts correlate with P450 2e1 activity. To test these hypotheses we propose in aim 1 to demonstrate the range of carcinogen metabolism derived from genetic diversity and in aim 2 to determine whether differences in carcinogen metabolism are mediated via regulation of P450 2e1 activity. Therefore, we propose to expose CC mice to BD and determine relative potency for metabolic activation versus detoxification derived solely from genetic diversity. The Relative potency for metabolic activation (RPoMA) will be calculated from BD-derived protein adducts by applying a recently established multiplicative risk model. Because 90% of BD is metabolized by P450 2e1, its enzymatic activity in liver tissues from CC mice will be determined to specifically investigate the role of P450 2e1 in BD metabolism as it relates to susceptibility. If successful, this proposal will show the relatie contributions of genetic background on carcinogen metabolism and reveal the importance of P450 2e1 across various genetic backgrounds.