Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney
Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney
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DOI：
10.1073/pnas.0304987101
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发表时间：
2004-03-09
影响因子：
11.1
通讯作者：
Abe, T
中科院分区：
文献类型：
--
作者：
Mikkaichi, T;Suzuki, T;Abe, T
地高辛是治疗心力衰竭最常用的处方药之一，它主要通过肾脏从血液循环中排出。p -糖蛋白被认为是肾元顶膜上的地高辛泵。然而，对基底外侧膜的转运机制知之甚少。我们从人体肾脏中分离出一种有机阴离子转运蛋白（OATP4C1）。人OATP4C1是在人体肾脏中表达的有机阴离子转运多肽（OATP）家族的第一个成员。分离的cDNA编码一个724aa的多肽，具有12个跨膜结构域。基因组组织由位于染色体5q21上的13个外显子组成。它在大鼠中的对应物Oatp4c1也从大鼠肾脏中分离出来。人OATP4C1以不依赖钠的方式转运心脏糖苷（地高辛，K-m = 7.8 muM和乌阿巴因，K-m = 0.38 muM）、甲状腺激素（三碘甲状腺原氨酸，k = 5.9 muM和甲状腺素）、cAMP和甲氨蝶呤。大鼠Oatp4c1也运输地高辛（Km = 8.0 muM）和三氯甲状腺原氨酸（Km = 1.9 muM）。免疫组化分析显示，大鼠的Oatp4c1蛋白定位于肾近端小管细胞的基底外膜。这些数据表明，人OATP40/大鼠Oatp4c1可能是地高辛和各种化合物通过肾脏进入尿液的第一步。
Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, K-m = 7.8 muM and ouabain, K-m = 0.38 muM), thyroid hormone (triiodothyronine, K. = 5.9 muM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (Km = 8.0 muM) and triioclothyronine (Km = 1.9 muM). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP40/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.