摘要
体内外研究证明,人体中p-gp在药物的吸收、分布、代谢和排泄(ADME)过程中发挥了非常重要的作用。多药耐药基因MDR1(ABCB1)是p-gp的编码基因。药物基因组学和遗传药理学研究发现在不同个体中MDR1基因多态性与P-gp表达和功能的改变密切相关,而且这些多态位点存在基因型分布和等位基因频率的种族差异性。近几年,己陆续发现在MDR1基冈中有50处单核苷酸多态性(SNPs)和3处插入与缺失多态性。随后,大量文献报道某些位点的SNPs如C3435T会使个体患病的易感性增加。因此人们相信,深入研究MDR1基因多态性与P-gp的生理和生化方面的相关性将对个体医疗有着非常深远的意义。文章总结了国外最新的研究进展并结合本实验室的工作着重讨论了4个方面：1)P-gp对药代动力学性质的影响；2)MDR1基因多态性及其对遗传药理学性质的影响;3)MDR1C3435T的单核苷酸多态性与P-gp表达和功能之间的相关性；4)MDR1基因多态性与人类某些疾病之间的相关性。
In vivo and in vitro studies have demonstrated that P-glycoprotein （P-gp） plays a very significant role in the ADME processes （absorption, distribution, metabolism, excretion） and drug-drug interaction （DDI） of drugs in humans. P-gp is the product of multidrug resistance gene （MDR I/ABCBI）. Pharmacogenomics and pharmacogenetics studies have revealed that genetic polymorphisms of MDR1 are associated with alteration in P-gp expression and function in different ethnicities and subjects. By now, 50 single nucleotide polymorphisms （SNPs） and 3 insertion/deletion polymorphisms have been found in the MDR1 gene. Some of them, such as C3435T, have been identified to be a risk factor for numerous diseases. It is believed that further understanding of the physiology and biochemistry of P-gp with respect to its genetic variations may be important for individualized pharmacotherapy. Therefore, based on the latest public information and our studies, this review focuses on the following four aspects： 1 ） the impact of P-gp on pharmacokinetics; 2） MDR1 genetic polymorphisms and their impacts on pharmacogenetics; 3） relationship between altered P-gp expression and function and the MDR1^C3435T SNP, and 4） relevance of MDR1 polymorphisms to certain human diseases.
基金
This work was supported by the 973 Program (No.2003CCA03400) and the 863 Program (No.2003AA223061) of Ministry of Sci-ence and Technology of China
关键词
P糖蛋白
MDR1
遗传多态性
遗传药理学
P-glycoprotein （P-gp）
MDR1
genetic polymorphism
pharmacogenetics
