Pharmacogenetic Analysis in Mice (II)

缺乏关于可用于药物和剂量选择的遗传变量的知识 是药物基因组信息临床利用的主要障碍。要启用该例程 药物基因组检测在临床实践中的应用--识别遗传变量的有效策略 影响药物代谢的药物，其作用机制或毒性必须开发和利用。我们将进一步 开发一种实验系统，使影响常用药物代谢的因素成为可能 在小鼠身上高效、快速地识别药物。一种能够实现不同步骤的体外系统 将建立在体外进行有效分析的药物处置(阶段1、11和III)。特定菌株 药代动力学药效学反应数据将使用基于单倍型的计算来评估 方法确定引起药物反应变异的遗传基因座。作为对 计算遗传分析对了解药物毒性的作用，我们将确定遗传因素 有助于抵抗扑热息痛引起的肝脏毒性。这是一个非常重要的问题 人类健康。扑热息痛中毒已成为本病急性肝功能衰竭的头号原因。 国家；在三级医疗中心治疗的急性肝功能衰竭病例中有42%是由对乙酰氨基酚引起的 毒性。 将完成以下具体目标：1)实现计算药物遗传学分析， 导致药物生物转化的500多个小鼠基因的多态性 将在20个近亲交配的小鼠品系中进行鉴定和等位基因特征。2)实现快速识别 处方药的I相和II相生物转化反应的介导酶的体外研究 将开发药物遗传学分析系统。体外孵育后产生的代谢物 从15个近交系菌株制备的含有肝脏提取物的微滴定板形式的药物将被定量 通过基于单倍型的计算遗传作图对其进行表征和分析。3)示范 计算药物遗传学还可以确定调节药物诱导毒性的机制， 对扑热息痛诱导的小鼠肝毒性产生抵抗力的遗传基础将被确定。4)体外培养 将开发药物遗传学分析系统，使鉴定转运体能够 第三阶段生物转化反应。

The lack of knowledge about the genetic variables that could be used for medication and dosage selection represents a major barrier to the clinical utilization of pharmacogenomic information. To enable the routine use of pharmacogenomic testing in clinical practice, efficient strategies for identifying the genetic variables that affect drug metabolism, mechanism of action ortoxicity must be developed and utilized. We will further develop an experimental system that will enable the factors affecting the metabolism of commonly used medications to be efficiently and rapidly identified in mice. An in vitro system that enables distinct steps (phase 1,11 and III) in drug disposition to be efficiently analyzed in vitro will be established. Strain-specific pharmcokinetic pharmacodynamic response data will evaluated using a haplotype-based computational method to identify genetic loci responsible for variation in response to the drugs. As a demonstration of utility of computational genetic analysis for understanding drug toxicty, we will identify the genetic factors contributing to resistance to acetaminophen-induced liver toxicity. This is a very important problem for human health. Acetaminophen toxicity has become the number one cause of acute liver failure in this country; 42% of acute liver failure cases treated in tertiary medical centers result from acetaminophen toxicity. The following specific goals will be completed: 1) To enable computational pharmacogenetic analysis, polymorphisms in over 500 murine genes that are responsible for phase I, II and III drug biotransformation will be identified and alleles characterized across 20 inbred mouse strains. 2) To enable rapid identification of the enzymes mediating phase I and II biotransformation reactions for prescribed medications, an in vitro pharmacogenetic analysis system will be developed. The metabolites produced after in vitro incubation of drugs in a microtiter plate format with liver extracts prepared from 15 inbred strains will be quantitatively characterized, and then analyzed by computational haplotype-based genetic mapping. 3) To demonstrate that computational pharmacogenetics can also identify mechanisms mediating drug-induced toxicity, the genetic basis for resistance to acetaminophen-induced liver toxicity in mice will be defined. 4) An in vitro pharmacogenetic analysis system will be developed that enables the identification of transporters mediating phase III biotransformation reactions.