大约15%的临床药物经CYP2C9代谢,基因型的差异是造成部分患者用药剂量个体差异大的重要因素之一。最近我们对2127例汉族人群进行基因扫描,共发现21种新等位基因（*36-*56）。利用C0S-7细胞发现,17种变异体对非甾体抗炎药物双氯芬酸的代谢特性发生了明显改变。为明确新变异是否会影响CYP2C9酶对其他药物的代谢活性,本研究拟开展以下3个层次的系统研究：首先体外大量表达各变异体，利用昆虫微粒体系统研究其对10种以上临床常用药物及抑制剂的体外代谢活性,筛选药代特性发生明显改变的有效突变体；其次招募健康人群开展药理实验加以验证和分析；最后招募900例以上华法林（CYP2C9典型探针底物药）长期服药病人进行遗传学分析，寻找新突变的携带者并考察其与药物使用剂量间的关系。旨在系统阐明CYP2C9新变异体的主要药物代谢特性及临床意义,为有效指导临床用药,从真正意义上实现个体化用药提供理论依据。

About 15 percent of therapeutically important drugs are metabolized by cytochrome P450 2C9(CYP2C9).CYP2C9 exhibits marked interindividual variability in its expression and catalytic activity due to functionally significant genetic variations, which is the main reason for the diverse clicinal medicican dosages in some patients. Recently, we detected 22 novel non-synonymous mutations in CYP2C9 after a sytematic genetic screen in 2127 Chinese Han population, in which, 21 new muation types have been nominated as new alleles *36-*56 by the Human CYP Allele Nomenclature Committee. in vitro functional analysis revealed that 17 new alleles showed different catalyitic activity toward the non-steroidal anti-inflammatory drug diclofenac compared to which of wild type *1 in transfected COS-7 cells. To elucidate whether these novel muations could affect the biological function of CYP2C9 protein toward other cilinical drugs, here we plan to perform the following studies at three different levels: First, highly express all the acquired variants in insect cells and systemically assesse the in vitro catalytic character of each variant toward at least 10 CYP2C9 specific drug substrates and some inhibitor drugs. Second,perform the clinical pharmacological study in some representative allelic healthy carriers in order to investigate their demic effects in vivo. Third,perform the association study of CYP2C9 genetic polymorhism and the drug oral dose of 900 patients who use the anticoagulant drug wafarin, an typical CYP2C9 phenotyping probe substrate, for at least 1 month. Our systematic clinical and functional studys of these new CYP2C9 alleles will pave the theoretical foundation for the therapeutic recommendations and personalized medicine in the Chinese population.