title: Inhibitory effects of angiotensin II receptor antagonists and leukotriene receptor antagonists on the transport of human organic anion transporter 4.
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 K(m) value of 20.9+/-3.53 microM. 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 microM, 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.
authors.affiliation: Department of Medico-Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Yamashita
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Ohtani
authors.forename: Noriko
authors.initials: N
authors.lastname: Koyabu
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Ushigome
authors.forename: Hiroki
authors.initials: H
authors.lastname: Satoh
authors.forename: Hideyasu
authors.initials: H
authors.lastname: Murakami
authors.forename: Takeshi
authors.initials: T
authors.lastname: Uchiumi
authors.forename: Takanori
authors.initials: T
authors.lastname: Nakamura
authors.forename: Michihiko
authors.initials: M
authors.lastname: Kuwano
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tsujimoto
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D000085:Acetates / Q000737:chemistry / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000737:chemistry / Q000494:pharmacology*; D001562:Benzimidazoles / Q000737:chemistry / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D002460:Cell Line; D002867:Chromones / Q000737:chemistry / Q000494:pharmacology; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles; D020024:Leukotriene Antagonists / Q000737:chemistry / Q000494:pharmacology*; D019808:Losartan / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000502:physiology*; D048448:Phenylcarbamates; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013440:Sulfides; D013449:Sulfonamides; D013777:Tetrazoles / Q000737:chemistry / Q000494:pharmacology; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection; D014316:Tritium; D014633:Valine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D000085:Acetates; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002867:Chromones; D003521:Cyclopropanes; D007093:Imidazoles; D007211:Indoles; D020024:Leukotriene Antagonists; D029362:Organic Anion Transporters, Sodium-Independent; D048448:Phenylcarbamates; D011804:Quinolines; C498886:SLC22A9 protein, human; D013440:Sulfides; D013449:Sulfonamides; D013777:Tetrazoles; D014105:Tosyl Compounds; D014316:Tritium; D004970:Estrone; D000068756:Valsartan; C066026:losartan carboxylic acid; D014633:Valine; D019808:Losartan; C093875:montelukast; C017296:estrone sulfate; C077793:candesartan cilexetil; C081643:candesartan; C047681:pranlukast; C062735:zafirlukast