SLCO1B1与CYP2C9之间的相互作用机理及在个体化用药中的应用

综合考虑代谢酶与转运体基因多态性对个体化用药十分重要。我们前期工作发现SLCO1B1和CYP2C9存在某种联系，而两者的相互作用机理尚不清楚。本项目应用OATP1B1转基因细胞研究一系列CYP2C9底物经OATP1B1转运的性质，探究CYP2C9底物与OATP1B1相互作用方式和构效关系。建立OATP1B1-CYP2C9双转染细胞模型，探索CYP2C9底物经OATP1B1的转运与经细胞内CYP2C9代谢的内在清除率之间的关系。开展人体试验，揭示SLCO1B1基因多态性对CYP2C9活性影响以及CYP2C9基因多态性对OATP1B1活性影响。利用临床肝脏样本，研究CYP2C9、OATP1B1在基因多态性、mRNA和蛋白水平的相关性，以及相关核受体因子在CYP2C9和OATP1B1相互关系中的作用。揭示SLCO1B1与CYP2C9相互作用的分子机理，为指导个体化合理用药提供科学依据。

It is very important to comprehensively consider genetic polymorphism in drug metabolism enzymes and drug transporters in personlized medicine. Our previous work indicates that there may be some relations between SLCO1B1 and CYP2C9. However, study of interaction between SLCO1B1 and CYP2C9 has not been available in literature. Our project is to invetigate transport of series of CYP2C9 substrates via OATP1B1 by using transgenic OATP1B1 cells, explore the interaction between CYP2C9 substrates and OATP1B1 and quantitative structure activity relationship. A double transfected OATP1B1/CYP2C9 cell line will be established to describe the relationship between transport ability of CYP2C9 substrates via OATP1B1 and intrinsic clearance rate of intracellular drug metabolism via CYP2C9. Clinical studies in volunteers will be conducted to investigate the influence of SLCO1B1 gene polymorphism on CYP2C9 phenotype and single-nucleotide polymorphism of CYP2C9 on OATP1B1 phenotye. Clinical liver samples will be used to study the relations among gene polymorphism, mRNA and protein level of CYP2C9 and SLCO1B1, and the role of nuclear receptor-related factors in interplay of CYP2C9 and SLCO1B1. The molecular mechanism of interation between CYP2C9 and SLCO1B1 will be revealed and thus provide the scientific evidence for personalized medicine and rational drug use.