OATP1B1及CYP3A4基因多态性对阿托伐他汀转运代谢影响的分子机制  

The molecular mechanism of actin of OATP1B1 and CYP3A4 genetic polymorphism on the metabolism and transport of atorvastatin

作　　者：袁钊[1] 李新华[2] 黄世博[1] 夏春华[1] 熊玉卿[1] 

机构地区：[1]南昌大学医学院临床药理研究所,江西南昌330006 [2]南昌大学校医院,江西南昌330006

出　　处：《中国医院药学杂志》2013年第13期1035-1041,共7页Chinese Journal of Hospital Pharmacy

基　　金：十二五科技重大专项(编号:2011ZX09302-007-03);国家自然基金(编号:H3110)

摘　　要：目的:研究有机阴离子转运多肽1B1(organic anion transporting polypeptide 1B1,OATP1B1)及细胞色素酶3A4(cy-tochrome P3A4,CYP3A4)基因多态性对阿托伐他汀(atorvastatin,ATV)转运及代谢影响的差异及产生差异的分子机制。方法:通过构建野生型及不同位点突变型OATP1B1重组质粒模型,研究ATV在不同OATP1B1基因型个体中药物体外转运的差异及其分子机制;并通过野生型及不同位点突变型CYP3A4重组酶,研究ATV在不同CYP3A4基因型个体中体外代谢的差异及产生差异的分子机制。结果:OATP1B1*5(521T>C)基因型个体对ATV的转运活性低于野生型OATP1B1*1a;而OATP1B1*15(388A>G521T>C)基因型个体与野生型OATP1B1*1a个体对ATV转运活性差异无统计学意义。CYP3A4*3(M445T)及*5(P218R)突变型重组酶代谢ATV的活性大于CYP3A4*1野生型重组酶;CYP3A4*16(T185S)突变型重组酶代谢ATV的活性显著低于野生型;CYP3A4*18(L293P)突变型重组酶代谢ATV的活性与野生型相近。结论:OATP1B1 521位点可能是ATV转运的分子作用点,也是影响OATP1B1对ATV转运能力的关键位点,突变型OATP1B1 521T>C对阿托伐他汀的体内转运活性能力降低;CYP3A4*3、CYP3A4*5、CYP3A4*16位点可能是ATV代谢的分子作用点,也是影响CYP3A4对ATV代谢活性的关键位点。故在临床应用中应结合OATP1B1及CYP3A4突变情况指导ATV用药,将更具合理性。OBJECTIVE To study the molecular mechanism of actin of OATP1B1 and CYP3A4 genetic polymorphism in the metabolism and transport of atorvastatin.METHODS Build OATP1B1＊1a,＊5 and＊15 recombinant plasmid model was established to study differences in transport（in vitro） and its molecular mechanism of atorvastatin in different OATP1B1 genotype mutant;and to study the difference in metaboliem and its molecular mechanism of atorvastatin in wild-type and different points mutant CYP3A4 recombinant enzyme.RESULTS The effects of OATP1B1＊1a and OATP1B1＊5 gene on atorvastatin transport were quite different,OATP1B1＊5 gene reduced the transport capacity of atorvastatin.Compared with OATP1B1＊15,OATP1B1＊5 the transport activity was lower.In our research,the activities of CYP3A4＊3 and CYP3A4＊5 were greater than the the activity of CYP3A4＊16,the activities of CYP3A4＊3 and CYP3A4＊5 were lower than the wild type,the CYP3A4＊18 had the similar activity of wild-type.CONCLUSION Our present results suggest that the OATP1B1 521 site might be the molecular action site of transporting ATV,also be the key affect point of transport capacity of ATV.And CYP3A4＊3,CYP3A4 ＊5,CYP3A4＊16 sites may be the molecular role of point of ATV metabolism,also affect CYP3A4 on the the ATV metabolic activity of key sites.Therefore,in clinic the applications should be based on the mutation of OATP1B1 and CYP3A4 to guide the rational use of ATV.

关 键 词：阿托伐他汀 有机阴离子转运多肽1B1 CYP3A4 基因多态性 分子机制 

分 类 号：R966[医药卫生—药理学]