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Research ArticleArticle

Molecular Identification and Functional Characterization of Rat Multidrug and Toxin Extrusion Type Transporter 1 as an Organic Cation/H+ Antiporter in the Kidney

Kin-ya Ohta, Katsuhisa Inoue, Yayoi Hayashi and Hiroaki Yuasa
Drug Metabolism and Disposition November 2006, 34 (11) 1868-1874; DOI: https://doi.org/10.1124/dmd.106.010876
Kin-ya Ohta
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Katsuhisa Inoue
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Yayoi Hayashi
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Hiroaki Yuasa
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Abstract

We have cloned and functionally characterized the rat ortholog of multidrug and toxin extrusion type transporter 1 (rMATE1). The mRNA of rMATE1 was strongly expressed in kidney and detectable in the various tissues such as brain, stomach, colon, lung, liver, spleen, skeletal muscle, and prostate. When stably expressed in HEK293 cells, rMATE1 could mediate the transport of tetraethylammonium (TEA) and cimetidine under the condition where the membrane potential was disrupted by a high concentration of potassium ion and intracellular pH was reduced by NH4Cl pretreatment. When extracellular pH was changed from 5.5 to 8.5, the transport of TEA by rMATE1 was greatest at pH 7.5. Kinetic analyses showed that the transports of TEA and cimetidine mediated by rMATE1 were both saturable with a Km of 260 ± 10 and 3.01 ± 0.21 μM, respectively. It was found that cimetidine is the most potent inhibitor of rMATE1, and many other organic cations, such as 1-methyl-4-phenylpyridinium, amiloride, imipramine, and quinidine, are also effective as inhibitors. Pretreatment of the cells expressing rMATE1 with p-chloromercuribenzene sulfonate significantly reduced TEA transport, but this effect was totally reversed by subsequent treatment with dithiothreitol. These results indicate that the functional nature of rMATE1 is consistent with that of the hypothetical organic cation/H+ antiporter system in the brush-border membrane of the renal tubular epithelial cells. Accordingly, these results suggest that rMATE1 is an electroneutral and multispecific organic cation transporter energized by the trans-proton gradient, and plays a physiological role in renal secretion of organic cations, including clinically used cationic drugs.

Footnotes

  • This work was supported in part by a Grant-in-Aid for Young Scientists (B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (#18790125), a Grant-in-Aid from the Nakatomi Foundation, and a Grant-in-Aid for Research in Nagoya City University.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010876.

  • ABBREVIATIONS: TEA, tetraethylammonium; OCT, organic cation transporter; OCTN, novel organic cation transporter; BCECF, 2′,7′-bis-(carboxyethyl)-carboxyfluorescein; AM, acetoxymethyl ester; MPP, 1-methyl-4-phenylpyridinium; MATE, multidrug and toxin extrusion; hMATE1, human MATE transporter 1; mMATE1, mouse MATE transporter 1; rMATE1, rat MATE transporter 1; Mes, 4-morpholineethanesulfonic acid; RT-PCR, reverse transcription-polymerase chain reaction; NMN, N1-methylnicotinamide; pCMBS, p-chloromercuribenzene sulfonate; NHE, Na+/H+ exchanger.

    • Received May 1, 2006.
    • Accepted August 21, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (11)
Drug Metabolism and Disposition
Vol. 34, Issue 11
1 Nov 2006
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Research ArticleArticle

Molecular Identification and Functional Characterization of Rat Multidrug and Toxin Extrusion Type Transporter 1 as an Organic Cation/H+ Antiporter in the Kidney

Kin-ya Ohta, Katsuhisa Inoue, Yayoi Hayashi and Hiroaki Yuasa
Drug Metabolism and Disposition November 1, 2006, 34 (11) 1868-1874; DOI: https://doi.org/10.1124/dmd.106.010876

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Research ArticleArticle

Molecular Identification and Functional Characterization of Rat Multidrug and Toxin Extrusion Type Transporter 1 as an Organic Cation/H+ Antiporter in the Kidney

Kin-ya Ohta, Katsuhisa Inoue, Yayoi Hayashi and Hiroaki Yuasa
Drug Metabolism and Disposition November 1, 2006, 34 (11) 1868-1874; DOI: https://doi.org/10.1124/dmd.106.010876
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