Expression in Mice of Human Xenobiotic Drug Metabolizing

描述(由申请人提供)：加州大学圣迭戈分校SBRP的前提是，暴露在环境毒物中导致的中毒事件源于基因控制的改变。二恶英或AhR的激活在选择性细胞事件的协调中起着重要作用，这些事件通过依赖于细胞色素P450(CYP)的第一阶段机制导致毒物的生物激活，同时通过诱导第二阶段UGT1葡萄糖醛酸化途径确保适当的细胞保护。在过去的资助期间，我们的实验室已经鉴定了全长的人类CYP1A1基因以及UGT1基因座。为了了解这些基因在定义AhR激活后的毒性事件中的作用，我们开发了携带和表达整个人类CYP1A1基因和UGT1基因座的转基因小鼠系。随着UCSD SBRP的重点是开发可以用于识别毒物的模型，正在设计新的小鼠品系，这些品系表达可检测到的CYP1A1或UGT1发光和荧光标记，这些标记是对激活AhR的毒物做出反应而诱导的。此外，已经在该应用程序中启动了实验，使用Superfund核心服务提供的资源来实现人性化。对小鼠的细胞色素P4501A1基因和UGT1基因座进行研究，目的是让我们深入了解这些基因的表达与毒性相关的调节和体液反应。在这些研究过程中，预计将开发一些重要的生物工具，可用作 生物标志物或资源，以检查AhR直接毒物对基因激活和毒性的贡献。这些资源将由研究翻译核心利用，并由该计划使用，以确定将这些生物工具用作检测选择性环境毒物的生物标记物的可行性。研究人员希望，这些努力和未来的合作将进一步了解AhR在毒物引起的疾病中的作用。

DESCRIPTION (provided by applicant): The premise of the UCSD SBRP states that a toxic episode resulting from exposure to environmental toxicants stems from altered gene control. Activation of the dioxin or AhR plays an important role in the coordination of selective cellular events that lead to bioactivation of toxicants through Phase I cytochrome P450 (CYP)-dependent mechanisms while assuring appropriate cellular protection by induction of Phase II UGT1 glucuronidation pathways. During the past funding period, our laboratory has characterized the full length human CYP1A1 gene as well as the UGT1 locus. To understand the contribution of these genes in defining a toxic event following activation of the AhR, we have developed transgenic mouse lines that carry and express the entire human CYP1A1 gene and the UGT1 locus. With an emphasis in the UCSD SBRP to develop models that can used to identify toxicants, novel mouse strains are being designed that express detectable CYP1A1 or UGT1 luminescent and fluorescent markers that are induced in response to toxicants that activate the AhR. In addition, experiments have been initiated in this application using resources available through the Superfund Core services to .humanize. the CYP1A1 gene and the UGT1 locus in mice with the intention that we will gain valuable insight into the regulatory and humoral responses that link expression of these genes to toxicity. During the course of these studies, it is anticipated that a number of significant biological tools will be developed that can be utilized as biomarkers or resources to examine the contribution of AhR directed toxicants toward gene activation and toxicity. These resources will be exploited by the Research Translation Core and used by this program to determine the feasibility of applying these biological tools as biomarkers for the detection of selective environmental toxicants. The investigators are hopeful that these efforts and future collaborations will further an understanding for the role of the AhR in toxicant induced illnesses.