Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney

Tsuyoshi Mikkaichi, Takehiro Suzuki, Tohru Onogawa, Masayuki Tanemoto, Hiroya Mizutamari, Masahiro Okada, Tatsuji Chaki, Satohiro Masuda, Taro Tokui, Nobuaki Eto, Michiaki Abe, Fumitoshi Satoh, Michiaki Unno, Takanori Hishinuma, Ken Ichi Inui, Sadayoshi Ito, Junichi Goto, Takaaki Abe

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Abstract

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.

Original languageEnglish
Pages (from-to)3569-3574
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number10
DOIs
Publication statusPublished - Mar 9 2004

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Digoxin
Kidney
Triiodothyronine
Membranes
Organic Anion Transporters
Cardiac Glycosides
Peptides
Renal Circulation
Nephrons
P-Glycoprotein
Ouabain
Treatment Failure
Thyroxine
Thyroid Hormones
Methotrexate
Anions
Exons
Heart Failure
Complementary DNA
Chromosomes

All Science Journal Classification (ASJC) codes

  • General

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Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. / Mikkaichi, Tsuyoshi; Suzuki, Takehiro; Onogawa, Tohru; Tanemoto, Masayuki; Mizutamari, Hiroya; Okada, Masahiro; Chaki, Tatsuji; Masuda, Satohiro; Tokui, Taro; Eto, Nobuaki; Abe, Michiaki; Satoh, Fumitoshi; Unno, Michiaki; Hishinuma, Takanori; Inui, Ken Ichi; Ito, Sadayoshi; Goto, Junichi; Abe, Takaaki.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 101, No. 10, 09.03.2004, p. 3569-3574.

Research output: Contribution to journalArticle

Mikkaichi, T, Suzuki, T, Onogawa, T, Tanemoto, M, Mizutamari, H, Okada, M, Chaki, T, Masuda, S, Tokui, T, Eto, N, Abe, M, Satoh, F, Unno, M, Hishinuma, T, Inui, KI, Ito, S, Goto, J & Abe, T 2004, 'Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney', Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 10, pp. 3569-3574. https://doi.org/10.1073/pnas.0304987101
Mikkaichi, Tsuyoshi ; Suzuki, Takehiro ; Onogawa, Tohru ; Tanemoto, Masayuki ; Mizutamari, Hiroya ; Okada, Masahiro ; Chaki, Tatsuji ; Masuda, Satohiro ; Tokui, Taro ; Eto, Nobuaki ; Abe, Michiaki ; Satoh, Fumitoshi ; Unno, Michiaki ; Hishinuma, Takanori ; Inui, Ken Ichi ; Ito, Sadayoshi ; Goto, Junichi ; Abe, Takaaki. / Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney. In: Proceedings of the National Academy of Sciences of the United States of America. 2004 ; Vol. 101, No. 10. pp. 3569-3574.
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AU - Mikkaichi, Tsuyoshi

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AU - Mizutamari, Hiroya

AU - Okada, Masahiro

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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

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