Pharmacogenetic Analysis of CYP450 SNP Enzymes

描述(由申请人提供)：编码细胞色素P450(CYP)基因的遗传多态已被证明是药物反应和药物处置中个体间差异的决定因素。这些基因多态性在人群中以不同的频率发生，通过基因分型预测药物不良反应有可能优化药物选择和剂量，从而更有效地治疗，避免严重的不良反应，并降低医疗成本。目前，制药公司在药物代谢评价中只使用了少数几种CYP酶。这一阶段研究的具体目的是开发和验证一组广泛的CYP多态酶，用于研究发生在CYP的2C19、2D6和3A4亚家族的104个非同义多态的表型效应。这些Cyps代谢了大部分处方药，而导致变异酶催化性质丢失或改变的多态可能对药物的代谢轨迹产生重大影响。在这个项目中，与这104个多态相对应的酶将以重组的形式表达，并将被鉴定为产生40种处方药的Km、Vmax、内源性清除量和KI值。由于所选择的大多数多态还没有在任何水平上被表征，这个项目的结果将产生功能信息，关于哪些多态产生活性或非活性酶，哪些多态导致酶适合性改变，以及哪些酶变体对药物具有改变的行为。这种药物遗传学工具的最终应用将是在药物开发的临床前和临床阶段对这组酶进行常规筛选，以剔除当与某些CYP基因多态性配合使用时可能产生有害影响的化合物和候选药物。此外，当与多路CYP基因分型设备一起使用时，使用该技术产生的药物遗传学信息可以用于预测不相容的药物与基因类型的配对，以减少患者潜在的药物不良反应。 人细胞色素P450酶在药物代谢中起着重要作用。细胞色素P450酶的大量遗传变异(或单核苷酸多态)已在人类群体中被发现，其中许多已被证明是患者不良药物反应的重要决定因素。这个第一阶段的SBIR应用程序建议开发一组与这些遗传多态相对应的蛋白质，以研究它们的功能和表型。这一药物遗传学工具将为预测具有P450基因多态性的药物的不良配对提供重要的第一步，以实现个性化用药。

DESCRIPTION (provided by applicant): Genetic polymorphisms in genes encoding cytochrome P450s (CYP) have been shown to be determinants of inter-individual variability in drug response and drug disposition. These polymorphisms occur in human populations at variable rates, and predicting adverse drug reactions by genotyping of these polymorphisms has the potential to optimize drug choice and doses for more effective therapy, to avoid serious adverse effects, and to decrease medical costs. Currently, only a handful of CYP enzymes are used by pharmaceutical companies in their drug metabolism evaluations. The specific aim of this Phase 1 study is to develop and validate a comprehensive panel of polymorphic CYP enzymes with which to study the phenotypic effects of 104 non-synonymous polymorphisms occurring in 2C19, 2D6, and 3A4 subfamilies of CYP. These CYPs metabolize the bulk of prescription drugs, and the polymorphisms which cause loss or alterations in the catalytic property of the variant enzymes may likely have significant impact in the metabolic trajectory of drugs. In this project, the enzymes corresponding to these 104 polymorphisms will be expressed in recombinant form and will be characterized to generate Km, Vmax, intrinsic clearance, and Ki values to 40 prescription drugs. Since the majority of the selected polymorphisms have not been characterized at any level, the outcome of this project will produce functional information as to which polymorphisms produce active or inactive enzymes, which polymorphisms cause altered enzyme fitness, and which enzyme variants possess modified behaviors to drugs. The ultimate applications of this pharmacogenetic tool will be in routine screening of this panel of enzymes in pre-clinical and clinical stages of drug development to weed out compounds and drug candidates which could have harmful effect when paired with certain CYP polymorphisms. In addition, when applied together with multiplexed CYP genotyping devices, the pharmacogenetic information generated using this technology can be used to prognosticate incompatible pairing of drugs with genotypes to reduce potential adverse drug responses in patients. Human cytochrome P450 enzymes play a major role in drug metabolism. Numerous genetic variations (or single nucleotide polymorphisms) in cytochrome P450 enzymes have been identified in human populations, and many of them have been shown to be important determinants of adverse drug responses in patients. This Phase 1 SBIR application proposes to develop a panel of proteins corresponding to these genetic polymorphisms in order to study their functionality and phenotypes. This pharmacogenetic tool will provide important first step toward predicting adverse pairing of drugs with P450 polymorphisms for personalized medicine.