Pharmacogenomics of Human P450 Oxidoreductase

描述（由申请人提供）：药物基因组学领域旨在描述一个种族群体中个体之间和人群群体之间导致药物反应变异的遗传因素。 迄今为止，药物基因组学的大部分努力都集中在药物代谢肝细胞色素P450（CYP）酶的多态性变体上。 该提案将解决以前未探索的药物代谢变化的潜在基础，NADPH依赖性P450氧化还原酶（POR）。 对于微粒体细胞色素P450的POR是实现催化所必需的电子的唯一来源。 POR从NADPH接受电子并将其转移到P450。 尽管POR基因敲除小鼠的表型是胚胎致死的，但令人惊讶的是，我们最近发现，人类POR错义突变是导致广泛人类疾病的原因，从闭经的正常女性表型到患有Antley-Bixler综合征（ABS）的严重畸形婴儿。 其他数据表明，POR突变破坏胎儿药物代谢，显然使其他良性药物（氟康唑）致畸。 POR错义突变的频率、严重程度和种族分布尚不清楚，无论是那些严重到足以引起疾病的突变，还是那些可能在表型上沉默的突变。 为了评估POR序列变异体在药物反应变化中的潜在作用，我们提出了以下四个具体目的：目的1。识别和表征导致可识别人类疾病的POR突变谱。 目标2.描述正常人群中POR序列变异和多态性的谱。 目标3：评估POR错义突变体或变体对8种最重要的肝脏P450酶（CYP 1A 2、2A 6、2C 8、2C 9、2C 19、2D 6、2 E1和3A 4）的影响。 目标4。确定单独具有最小活性损失的POR和PPO的序列变体组合是否会导致这些酶的活性显著降低。 这些目标的成功实现将大大增加对导致药物反应变异的遗传因素的了解。

DESCRIPTION (provided by applicant): The field of Pharmacogenomics seeks to delineate the genetic factors responsible for variations in drug response, both among individuals in one ethnic group and between population groups. To date, most effort in pharmacogenomics has focused on polymorphic variants in drug-metabolizing hepatic cytochrome P450 (CYP) enzymes. This proposal will address a previously unexplored potential basis for variation in drug metabolism, NADPH-dependent P450 oxidoreductase (POR). For microsomal cytochrome P450's POR is the only source of the electrons necessary to achieve catalysis. POR accepts electrons from NADPH and transfers them to the P450. Although the phenotype of POR knockout mice is an embryonic lethal, surprisingly we recently found that human POR missense mutations are responsible for a broad spectrum of human disease, ranging from a normal female phenotype with amenorrhea, to severely malformed infants with the Antley-Bixler syndrome (ABS). Other data suggest that POR mutations disrupt fetal drug metabolism, apparently rendering an otherwise benign drug (fluconazole) teratogenic. The frequency, severity and ethnic distribution of POR missense mutations, either those severe enough to cause disease or those that may be phenotypically silent, is unknown. To assess the potential role of POR sequence variants in variations in drug response, we propose the following four Specific Aims: Aim 1. Identify and characterize the spectrum of POR mutations causing identifiable human disease. Aim 2. Delineate the spectrum of POR sequence variants and polymorphisms in the normal human population. Aim 3. Assess the impact of POR missense mutants or variants on the eight most important hepatic P450 enzymes (CYP1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4). Aim 4. Determine whether sequence variants of POR and CYP enzymes that have minimal loss of activity individually can, in combination, lead to significant diminution in the activity of these enzymes. Successful completion of these aims will substantially increase knowledge about the genetic factors leading to variations in drug response.