Analysis of multiplicity and polymorphism of drug transporters expressed in the liver.

肝脏中表达的药物转运蛋白的多样性和多态性分析。

• 批准号: 09470501
• 负责人: SUGIYAMA Yuichi
• 金额: $ 8.51万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470501/
• 关键词: biliary excretion; MRP; cMOAT; Ntcp; oatp; ABC transpoter; organic anions; induction; 輸送担体; 遺伝子クローニング; 遺伝的多型

Liver, along with kidney, plays an important role in the detoxification of xenobiotics. It is well established that drugs in the circulating blood are taken up into the liver via transporters on the basal membrane, and then excreted into the bile via transporters on the bile canalicular membrane. Concerning the transporters responsible for the uptake, Na^+-dependent bile acid transporter (Ntcp) and organic anion transporter 1 (oatp1) have been identified. However, no quantitative studies have been performed on the contribution of these transporters to the hepatic uptake of drugs. In the present study, we determined the contribution of each transporter in hepatic drug uptake, by comparing the ability to take up drugs into hepatocytes and into cDNA-transfected mammalian cells. The results suggested the presence of multiplicity for both Na^+-dependent and independent transport systems. Studies are under way to determine the contribution of homologous transporters (such as oatp2 and oat 3) … More . Concerning the transport across the bile canalicular membrane, the transport properties of organic anions has been identified by using the isolated bile canalicular membrane vesicles isolated from rats and humans. In addition, we have characterized the transport properties of canalicular multispecific organic anion transporter (cMOAT) using the membrane vesicles isolated from cDNA-transfected cells. Moreover, as a homologue of cMOAT, we have cloned rat and human MRP3 (multidrug resistance associated protein 3). Studies with isolated membrane vesicles from mammalian cells transfected with MRP3 cDNA, it was demonstrated that MRP3 accepts glucuronides, but not glutathione-conjugates, as good substrates. Thus, the difference in the transport characteristics was demonstrated between MRP1/2 and 3. In rats and HepG2 cells in culture, MRP3 was induced by phenobarbital, suggesting that the difference in the expression level of MRP3 may result in the interindividual difference in the ability to excrete xenobiotics and/or their conjugates into the bile in humans. Less

肝脏与肾脏沿着，在外源性物质的解毒过程中起着重要作用。已经确定，循环血液中的药物通过基底膜上的转运蛋白被摄取到肝脏中，然后通过胆小管膜上的转运蛋白排泄到胆汁中。关于负责吸收的转运蛋白，已确定了Na^+依赖性胆汁酸转运蛋白（Ntcp）和有机阴离子转运蛋白1（oatp 1）。然而，尚未对这些转运蛋白对药物肝摄取的贡献进行定量研究。在本研究中，我们通过比较药物进入肝细胞和cDNA转染的哺乳动物细胞的能力，确定了每种转运蛋白在肝脏药物摄取中的贡献。结果表明，Na^+依赖性和非依赖性转运系统都存在多重性。目前正在进行研究，以确定同源转运蛋白（如oatp 2和oat 3）的作用。 ...更多信息 .关于跨胆小管膜的转运，已通过使用从大鼠和人类分离的胆小管膜囊泡鉴定了有机阴离子的转运特性。此外，我们已经使用从cDNA转染细胞分离的膜囊泡的小管多特异性有机阴离子转运蛋白（cMOAT）的运输特性的特点。此外，作为cMOAT的同源物，我们已经克隆了大鼠和人MRP 3（多药耐药相关蛋白3）。研究与分离的膜囊泡从哺乳动物细胞转染与MRP 3 cDNA，它被证明，MRP 3接受葡萄糖醛酸，但不是谷胱甘肽结合物，作为良好的底物。因此，证明了MRP 1/2和3之间的转运特性差异。在大鼠和培养的HepG 2细胞中，MRP 3被苯巴比妥诱导，这表明MRP 3表达水平的差异可能导致人类将外源性物质和/或其缀合物排泄到胆汁中的能力的个体间差异。少

项目成果

H.Kouzuki: "Contribution of sodium taurocholate co-transporting polypeptide to the uptake of its possible substrates into rat hepatocytes." J.Pharmacol.Exp.Ther.286. 1043-1050 (1998)

H.Kouzuki：“牛磺胆酸钠共转运多肽对其可能的底物摄取到大鼠肝细胞中的贡献。”

H.Kouzuki: "Contribution of organic anion transporting polypeptide to the uptake of ligands into rat hepatocytes." J.Pharmacol.Exp.Ther.(in press).

H.Kouzuki：“有机阴离子转运多肽对大鼠肝细胞摄取配体的贡献。”

鈴木洋史: "肝臓病学の最前線" (中外医学社)山中、滝川編, (1997)

铃木宏：“肝脏疾病的最前沿”（中外医学社）山中伸弥和泷川，（1997）

鈴木洋史: "肝臓病学の最前線" (中外医学社)中山、滝川編, (1997)

铃木宏：《肝病前沿》（中外医学社），中山和泷川编辑，（1997 年）

M.Yamazaki: "Biliary excretion of pravaststin in rats:contribution of the excretion pathway mediated by canalicular multispecific organic anion transporter(cMOAT)" Drug Metabolismsm and Disposition. 25・10. 1123-11129 (1997)

M. Yamazaki：“大鼠中普伐他汀的胆汁排泄：小管多特异性有机阴离子转运蛋白（cMOAT）介导的排泄途径的贡献”药物代谢和处置 1123-11129（1997）。