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 是药物基因组学信息临床应用的主要障碍。要启用例程， 在临床实践中使用药物基因组学检测，识别遗传变量的有效策略 影响药物代谢、作用机制或毒性的因素必须加以研究和利用。我们将进一步 开发一个实验系统，使影响代谢的因素， 在小鼠中有效和快速地识别药物。一种体外系统， （1期、11期和III期）的药物分布进行有效的体外分析。菌株特异 药代动力学药效学反应数据将使用基于单体型的计算方法进行评价。 方法，以确定遗传基因座负责响应于药物的变化。为了表明 利用计算遗传分析来了解药物毒性，我们将确定遗传因素 有助于抵抗对乙酰氨基酚诱导的肝毒性。这是一个非常重要的问题， 人体健康对乙酰氨基酚毒性已成为急性肝衰竭的头号原因， 国家;在三级医疗中心治疗的急性肝衰竭病例中有42%是由对乙酰氨基酚引起的 毒性 将完成以下具体目标：1）为了实现计算药物遗传学分析， 在超过500个鼠基因中的多态性，负责I、II和III期药物生物转化 将在20个近交系小鼠品系中鉴定和表征等位基因。2)为了能够快速识别 介导处方药物的I相和II相生物转化反应的酶，体外 将开发药物遗传学分析系统。体外孵育后产生的代谢产物 将用从15个近交系制备的肝提取物定量测定微量滴定板形式中的药物， 表征，然后通过基于计算单体型的遗传作图进行分析。3)证明 计算药物遗传学也可以识别介导药物诱导毒性的机制， 将确定对乙酰氨基酚诱导的小鼠肝毒性的抗性的遗传基础。4)体外 将开发药物遗传学分析系统，该系统能够鉴定介导 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.