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（如饮食选择）对这种差异也有重要影响。然而，在人类研究中，很难研究暴露-基因相互作用，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联系的，往往会产生多种有益或有害的习惯。为了模拟一个遗传异质性的人类群体，创建了协作交叉（CC）小鼠来代表一个完整的混合小鼠群体，涵盖了所有可能的基因型。在我们提出的研究中，我们假设通过将CC模型与1,3 -丁二烯（BD）暴露模型相结合，可以在小鼠中建立完全由遗传多样性引起的易感性变异模型。之所以选择双酚d作为模型化合物，是因为它可以形成几种蛋白质加合物，这些蛋白质加合物是双酚d摄取、代谢激活和解毒的生物标志物。这些n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 2e1活性，因此我们进一步假设BD衍生的蛋白加合物与P450 2e1活性相关。为了验证这些假设，我们在目标1中提出了来自遗传多样性的致癌物代谢的范围，在目标2中提出了确定致癌物代谢的差异是否通过调节P450 2e1活性来介导。因此，我们建议将CC小鼠暴露于BD，并确定仅由遗传多样性引起的代谢激活与解毒的相对效力。代谢激活的相对效力

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.