In vivo functional characterization of the ABC transporters based on the genetic polymorphisms

在ABC转运体中，我们从基础研究和临床研究两个角度对MDR1和BCRP两个转运基因的结构和功能特征进行了研究。在基础研究中，我们分析了位于编码区以及5‘和3’非翻译区的snp，然后使用人类材料（如血液和足月胎盘）评估其对mRNA和/或蛋白质表达的贡献。在临床研究中，我们进行了以下4项临床检查；(i)在基因分型匹配的健康志愿者中，人类MDR1基因多态性在地高辛（p -糖蛋白（PGP）的底物）的生物利用度和相互作用（与典型抑制剂克拉霉素）谱中的作用；（ii）肝移植后他克莫司（PGP的一种底物）引起的神经毒性（如癫痫）：与MDR1基因遗传多态性的关系；（iii）吗啡（PGP的一种底物）治疗期间两例临床结果复杂的癌症患者的序列变异性和候选基因分析；（iv）人BCRP基因多态性在健康受试者体内4-甲基伞形酮及其结合代谢物的药代动力学谱中的作用。可以得到以下观察结果（由于解释空间有限，仅限临床结果）：(1)胃肠道吸收（即生物利用度）和PGP底物的相互作用谱似乎受到PGP基因多态性的影响。凋亡基因。(2)某些药物经血脑渗透也可能受p -糖蛋白的调控。基于这些观察，我们得出结论，MDR1基因多态性对个体化药物治疗是有用的。

Among the ABC transporters, we examined structural and functional characterizations of the two transporter genes, MDR1 and BCRP, from the 2 perspectives including basic and clinical study. In the basic study, we bat analyzed SNPs, which located in the coding region, and 5' and 3' untranslated regions, and then evaluated contributions to mRNA and/or protein expressions using human materials such as blood and full tern placentas. In the clinical study, we conducted following 4 clinical examinations ; (i)role of human MDR1 gene polymorphisms in bioavailability and interaction (with typical inhibiter, clarithromycin) profile of digoxin, a substrate of P-glycoprotein (PGP), in genotyping matched healthy volunteers ; (ii)Neurotoxicity (e-g.,epilepsy) induced by tacrolimus (a substrate of PGP) after liver transplantation : relation to genetic polymorphisms of the MDR1 gene ; (iii)Sequence variability and candidate gene analysis in two cancer patients with complex clinical outcomes during morphine (a substrate of PGP) therapy ; (iv)role of human BCRP gene polymorphisms in the pharmacokinetic profiles of 4-methyl umbelliferone and its conjugated metabolites in healthy subjects.Following observations could be obtained (only clinical consequences due to explanation space)(1)Absorption from the gastrointestinal tracts (ie, bioavailability) and interaction profiles of PGP substrates seem to be influenced by polymorphisms in th. MDR1 gene.(2)Brain penetration from blood of certain drugs may also be regulated by P-glycoprotein.Based on these observations, we concluded that genetic polymorphism in the MDR1 is useful to the individual pharmacotherapy.