IDENTIFICATION & FUNCTIONAL CHARACTERIZATION OF SNPS IN RXRA GENE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 细胞色素-P450(CYP)超家族的药物代谢酶基因，如细胞色素P450(CYP)超家族的酶基因，如细胞色素P450(CyP)D6、细胞色素P450(CyP)C9和细胞色素P450(CyP)C19，已发现基因多态性，这可能有助于解释多种药物代谢率的显著差异。在负责代谢50%以上处方药的细胞色素P3A4基因中，尚未发现这种基因多态。迫切需要阐明控制这一重要蛋白质的可变基因表达和酶功能的遗传多态。CYP3A4的基因表达是由核受体介导的网络在转录水平上调节的，其中关键的转录调节因子是孕烷-x受体(PXR)、构成性雄烷受体(CAR)和维甲酸x受体(RXR)的核受体。CYP3A4的酶功能需要辅酶P450氧化还原酶(POR)为氧化反应提供电子。本应用的目的是确定PXR、CAR、RXRpha和POR基因的遗传多态对肝脏中不同的CYP3A4介导的药物代谢率的表现的贡献。我们建议系统地检测核受体介导的网络中基因的遗传多态对CYP3A4基因表达和酶活性的功能影响。鉴定这些基因的遗传多态，并将这些基因多态与CYP3A4酶活性相关联，将为进一步评价该酶代谢的40%处方药的个体差异提供有力的科学依据。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Genetic polymorphisms have been identified in drug-metabolizing enzyme genes of cytochrome-P450 (CYP) superfamily, such as CYP2D6, CYP2C9, and CYP2C19, which may help to explain significant differences in the metabolic rates for a variety of drugs. Such genetic polymorphisms have not been identified in CYP3A4 which is responsible for metabolizing more than 50% of prescription drugs. There is a critical need to elucidate the genetic polymorphisms that control variable gene expression and enzyme functions of this important protein. Gene expression of CYP3A4 is regulated at transcriptional level by a nuclear receptor mediated network, in which key transcriptional regulatory factors are nuclear receptors of pregnane-x-receptor (PXR), constitutive androstane receptor (CAR), and retinoid x receptor (RXR). Enzyme functions of CYP3A4 required a coenzyme, P450 oxidoreductase (POR), to provide electrons for oxidation reactions. The objective of this application is to determine the contribution of genetic polymorphisms in the PXR, CAR, RXRalpha, and POR genes to the manifestations of differential CYP3A4-mediated drug metabolic rates in liver. We propose to systematically exam functional influence of genetic polymorphisms in genes in the nuclear receptor mediated network on CYP3A4 gene expression and enzyme activity. The identification of genetic polymorphisms among these genes and to correlate these genetic polymorphisms with CYP3A4 enzyme activity, will provide a strong scientific foundation for further evaluation of inter-individual differences of drug metabolism for the 40% of prescription drugs metabolized by this enzyme.