Pharmacogenetic Analysis of CYP450 SNP Enzymes

描述（由申请方提供）：已证明编码细胞色素P450（CYP）的基因中的遗传多态性是药物应答和药物处置中个体间变异性的决定因素。 这些多态性在人群中以可变的比率发生，并且通过这些多态性的基因分型来预测药物不良反应具有优化药物选择和剂量以获得更有效治疗、避免严重不良反应和降低医疗成本的潜力。目前，制药公司在药物代谢评估中只使用了少数几种酶。这项1期研究的具体目的是开发和验证一组全面的多态性β-内酰胺酶，用于研究β-内酰胺酶2C 19、2D 6和3A 4亚家族中104种非同义多态性的表型效应。这些CYP代谢大部分处方药物，并且导致变体酶的催化性质的损失或改变的多态性可能对药物的代谢轨迹具有显著影响。在该项目中，对应于这104种多态性的酶将以重组形式表达，并将被表征为产生40种处方药的Km、Vmax、固有清除率和Ki值。由于大多数选定的多态性尚未在任何水平上进行表征，因此本项目的结果将产生功能信息，即哪些多态性产生活性或非活性酶，哪些多态性导致酶适应性改变，以及哪些酶变体对药物具有修饰行为。 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，以剔除与某些α-多态性配对时可能产生有害影响的化合物和候选药物。 此外，当与多重PCR基因分型装置一起应用时，使用该技术产生的药物遗传学信息可用于证实药物与基因型的不相容配对，以减少患者中潜在的药物不良反应。 人细胞色素P450酶在药物代谢中起主要作用。 已在人群中发现细胞色素P450酶的许多遗传变异（或单核苷酸多态性），其中许多已被证明是患者药物不良反应的重要决定因素。该SBIR申请的第1阶段提出开发一组对应于这些遗传多态性的蛋白质，以研究其功能和表型。 这种药物遗传学工具将为预测具有P450多态性的药物的不良配对提供重要的第一步，以用于个性化药物。

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.