【作者】 李芹；

【导师】 王睿；

【作者基本信息】 中国海洋大学 ， 水产品加工与贮藏， 2006， 博士

【摘要】 细胞色素P4502D6(CYP2D6)是一种重要的药物代谢酶,参与临床近百种重要药物的代谢,而且对药物的代谢呈现出明显的个体差异和种族差异,这是造成临床用药个体差异的重要原因。CYP2D6是最具有基因多态性的药物代谢酶,目前已发现有七十多个变异位点。本研究拟制备基因芯片,测定中国人群CYP2D6基因多态性的分布频率,并研究不同基因型的中国健康志愿者体内曲马多和美托洛尔的代谢特点及其对两药相互作用的影响。1.基因芯片法测定中国人群CYP2D6基因多态性根据CYP2D6基因序列的多态性分布特点,针对在中国人群药物代谢中具有潜在作用的突变位点C188T和G4268C(CYP2D6*2和CYP2D6*10),设计寡核苷酸探针,制备寡核苷酸芯片,测定312例中国健康志愿者CYP2D6的基因型,并使用直接测序法对分型结果进行验证,探讨基因芯片技术应用于CYP2D6基因分型的可行性。结果312例中国健康志愿者中CYP2D6*2和CYP2D6*10的变异频率分别为CYP2D6*2W*10W 8.3%, *2H*10W 13.5%, *2M*10W 10.6%, *2M*10H 17.0%, *2M*10M 34.6%, *2H*10H 9.6%, *2H*10M 6.4%。对部分样本采用直接测序的方法进行进一步确证,结果完全吻合。说明本研究建立的基因芯片适用于中国人群CYP2D6基因分型研究。2.中国人群CYP2D6基因多态性对曲马多药代动力学的影响按照变异位点,筛选40例健康志愿者,分为四组进行试验,每组10人。第一组:CYP2D6*2W*10W,第二组:CYP2D6*2H*10W和CYP2D6*2M*10W,更多还原

【Abstract】 Cytochrome P450 2D6 (CYP2D6) is an important drug-metabolizing enzyme, which metabolizes nearly 100 drugs. CYP2D6 was first identified as the polymorphic enzyme involved in debrisoquine hydroxylation and sparteine oxidation. Currently more than 70 different alleles have been described. In this study, gene chips are created to evaluate the allelic frequency of CYP2D6 and investigate the influence of genetic polymorphism of CYP2D6 on pharmacokinetic interactions between tramadol and metoprolol in a Chinese population.1. Screening the genetic polymorphism of CYP2D6 in a Chinese population by gene chipsAccording to the distributing feature of the polymorphisms in CYP2D6 gene, specially aimed to C188T and G4268C, the two mutant sites reported to have the potent effects in the drug metabolism of Chinese people, gene chips are created with a set of designed oligonuceotides probes. 312 DNA samples from Chinese healthy volunteers were genotyped and parts of samples were validated by direct sequencing. The results of these two genotyping methods are in concordance which indicates that the gene chips established in this study can be applied to screen the genotypes of CYP2D6 in a Chinese population. The allelic frequencies of CYP2D6 were 8.3% (CYP2D6*2W*10W), 13.5% (CYP2D6*2H*10W), 10.6% (CYP2D6*2M*10W),更多还原