TY - JOUR
T1 - Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney
AU - Mikkaichi, Tsuyoshi
AU - Suzuki, Takehiro
AU - Onogawa, Tohru
AU - Tanemoto, Masayuki
AU - Mizutamari, Hiroya
AU - Okada, Masahiro
AU - Chaki, Tatsuji
AU - Masuda, Satohiro
AU - Tokui, Taro
AU - Eto, Nobuaki
AU - Abe, Michiaki
AU - Satoh, Fumitoshi
AU - Unno, Michiaki
AU - Hishinuma, Takanori
AU - Inui, Ken Ichi
AU - Ito, Sadayoshi
AU - Goto, Junichi
AU - Abe, Takaaki
PY - 2004/3/9
Y1 - 2004/3/9
N2 - 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, Km = 7.8 μM and ouabain, Km = 0.38 μM), thyroid hormone (triiodothyronine, Km = 5.9 μM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (Km = 8.0 μM) and triiodothyronine (Km = 1.9 μM). 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 OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.
AB - 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, Km = 7.8 μM and ouabain, Km = 0.38 μM), thyroid hormone (triiodothyronine, Km = 5.9 μM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (Km = 8.0 μM) and triiodothyronine (Km = 1.9 μM). 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 OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.
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U2 - 10.1073/pnas.0304987101
DO - 10.1073/pnas.0304987101
M3 - Article
C2 - 14993604
AN - SCOPUS:12144288563
SN - 0027-8424
VL - 101
SP - 3569
EP - 3574
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 10
ER -