Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4

Fumiaki Yamashita, Hisakazu Ohtani, Noriko Koyabu, Fumihiko Ushigome, Hiroki Satoh, Hideyasu Murakami, Takeshi Uchiumi, Takanori Nakamura, Michihiko Kuwano, Masayuki Tsujimoto, Yasufumi Sawada

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Human organic anion transporter 4 (OAT4) is the only member of the OAT family that is expressed in the placenta and also expressed in kidney. Although OAT4 has been shown to transport certain organic anions as well as other members of the OAT family, fewer numbers of substrates have been identified for OAT4 compared with OAT1 and OAT3, suggesting that the substrate specificity of OAT4 is greater than other OAT members. However, the substrate specificity of OAT4 remains to be investigated in detail. The aim of this study was to examine the effects of various drugs on the OAT4-mediated transport of estrone-3-sulfate, a typical substrate of OAT4, by using human embryonic kidney cells stably transfected with OAT4 (HEK-OAT4). HEK-OAT4 cells exhibited concentration- dependent uptake of estrone-3-sulfate, with a Km value of 20.9±3.53 μM. Dehydroepiandrosterone sulfate and probenecid potently inhibited estrone-3-sulfate uptake. We also searched for the potential inhibitors of OAT4 and identified candesartan, candesartan cilexetil, losartan, losartan carboxyl (EXP3174) and valsartan as inhibitors of OAT4, with K i values of 88.9, 135.2, 24.8, 13.8 and 19.6 μM, respectively. The above angiotensin II receptor antagonists and leukotriene receptor antagonists share a common structural feature, that is the tetrazole group. Although pranlukast is devoid of anionic motifs other than the tetrazole group, it potently inhibited the OAT4-mediated uptake of estrone-3-sulfate, indicating that a tetrazole group may be one important structural feature in substrate recognition by OAT4.

Original languageEnglish
Pages (from-to)1499-1505
Number of pages7
JournalJournal of Pharmacy and Pharmacology
Volume58
Issue number11
DOIs
Publication statusPublished - 2006 Nov
Externally publishedYes

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Organic Anion Transporters
Leukotriene Antagonists
Angiotensin Receptor Antagonists
Losartan
Valsartan
Substrate Specificity
Kidney
Probenecid
Dehydroepiandrosterone Sulfate

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

Cite this

Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4. / Yamashita, Fumiaki; Ohtani, Hisakazu; Koyabu, Noriko; Ushigome, Fumihiko; Satoh, Hiroki; Murakami, Hideyasu; Uchiumi, Takeshi; Nakamura, Takanori; Kuwano, Michihiko; Tsujimoto, Masayuki; Sawada, Yasufumi.

In: Journal of Pharmacy and Pharmacology, Vol. 58, No. 11, 11.2006, p. 1499-1505.

Research output: Contribution to journalArticle

Yamashita, F, Ohtani, H, Koyabu, N, Ushigome, F, Satoh, H, Murakami, H, Uchiumi, T, Nakamura, T, Kuwano, M, Tsujimoto, M & Sawada, Y 2006, 'Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4', Journal of Pharmacy and Pharmacology, vol. 58, no. 11, pp. 1499-1505. https://doi.org/10.1211/jpp.58.11.0011
Yamashita, Fumiaki ; Ohtani, Hisakazu ; Koyabu, Noriko ; Ushigome, Fumihiko ; Satoh, Hiroki ; Murakami, Hideyasu ; Uchiumi, Takeshi ; Nakamura, Takanori ; Kuwano, Michihiko ; Tsujimoto, Masayuki ; Sawada, Yasufumi. / Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4. In: Journal of Pharmacy and Pharmacology. 2006 ; Vol. 58, No. 11. pp. 1499-1505.
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