Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney.
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 microM and ouabain, K(m) = 0.38 microM), thyroid hormone (triiodothyronine, K(m) = 5.9 microM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin (K(m) = 8.0 microM) and triiodothyronine (K(m) = 1.9 microM). 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.
Mikkaichi
Tsuyoshi
T
Department of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8575, Japan.
Suzuki
Takehiro
T
Onogawa
Tohru
T
Tanemoto
Masayuki
M
Mizutamari
Hiroya
H
Okada
Masahiro
M
Chaki
Tatsuji
T
Masuda
Satohiro
S
Tokui
Taro
T
Eto
Nobuaki
N
Abe
Michiaki
M
Satoh
Fumitoshi
F
Unno
Michiaki
M
Hishinuma
Takanori
T
Inui
Ken-Ichi
K
Ito
Sadayoshi
S
Goto
Junichi
J
Abe
Takaaki
T
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000235:genetics / Q000302:isolation & purification; D004077:Digoxin / Q000378:metabolism*; D004285:Dogs; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000235:genetics* / Q000302:isolation & purification* / Q000378:metabolism; D010802:Phylogeny; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D051437:Renal Insufficiency / Q000235:genetics / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014018:Tissue Distribution; D014162:Transfection
D018076:DNA, Complementary; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D011994:Recombinant Proteins; C484530:SLCO4C1 protein, human; C484531:organic anion transporting polypeptide 4C1, rat; D004077:Digoxin