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

基于遗传多态性的 ABC 转运蛋白的体内功能表征

• 批准号: 13357020
• 负责人: IEIRI Ichiro
• 金额: $ 23.38万
• 依托单位: Tottori University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2001
• 资助国家: 日本
• 起止时间: 2001 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-13357020/
• 关键词: ABC transporters; P-glycoprotein; MDR1; BCRP; Basic research; Clinical Study; 4MU; 胎盤; hapolotype; diplotype; タクロリムス; 部分肝移植; SNPs; 中枢毒性; MDR1遺伝子; MRPs遺伝子; 薬物脳移行; 遺伝子多型; モルヒネ; ジゴキシン; オーダーメイド医療

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.

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。

项目成果

Yamauchi A, Ieiri I, Kataoka Y. et al.: "Neurotoxicity induced by tacrolimus after liver transplantation : relation to genetic polymorphisms of the ABCB1 (MDR1) gene."Transplantation. 74. 571-578 (2002)

Yamauchi A、Ieiri I、Kataoka Y. 等人：“肝移植后他克莫司诱导的神经毒性：与 ABCB1 (MDR1) 基因的遗传多态性的关系。”移植。

Ieiri I, Takane H, Otsubo K. et al.: "The MDR1 (ABCB1) gene polymorphism and its clinical implications."Clin Pharmacokinet. (印刷中). (2004)

Ieiri I、Takane H、Otsubo K. 等人：“MDR1 (ABCB1) 基因多态性及其临床意义。”Clin Pharmacokinet（出版中）。

Ieiri I., Takane H., Otsubo K.: "The MDR1 (ABCB1) gene polymorphism and its clinical implications"Clin Pharmacokinet. (In press). (2004)

Ieiri I.、Takane H.、Otsubo K.：“MDR1 (ABCB1) 基因多态性及其临床意义”Clin Pharmacokinet。

Takane H, Ieiri I, Otsubo K.et al.: "Genetic polymorphism of organic anion and cation transporters : Pharmacokinetic and pharmacodynamic consequences in pharmacotherapy."Curr Pharmacogemonics. 1. 245-257 (2003)

Takane H、Ieiri I、Otsubo K.等人：“有机阴离子和阳离子转运蛋白的遗传多态性：药物治疗中的药代动力学和药效学后果。”Curr Pharmacogemonics。

Honda T, Dan Y, Koyabu N, Ieiri I, et al.: "Polymorphism of MDR1 gene in healthy Japanese subjects : a novel SNP with an amino acid substitution"Drug Metabolism and Pharmacokinetics. 17. 479-481 (2002)

Honda T、Dan Y、Koyabu N、Ieiri I 等人：“健康日本受试者中 MDR1 基因的多态性：具有氨基酸取代的新型 SNP”药物代谢和药代动力学。