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Volume 272, Number 30,
Issue of July 25, 1997
pp. 18526-18529
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.
COMMUNICATION:
Expression Cloning and Characterization of a Novel Multispecific
Organic Anion Transporter
(Received for publication, April 15, 1997, and in revised form, June 3, 1997)
Takashi
Sekine
,
Nobuaki
Watanabe
,
Makoto
Hosoyamada
,
Yoshikatsu
Kanai
and
Hitoshi
Endou
From the Department of Pharmacology and Toxicology, Kyorin
University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo
181, Japan
Numerous drugs and endogenous compounds are
efficiently excreted from the renal proximal tubule via
carrier-mediated pathways. Transepithelial excretion of organic anions
occurs via their accumulative transport from the blood into the
proximal tubule cells across the basolateral membrane and subsequent
secretion into the urine through the apical membrane. Here we report on
the isolation of a novel complementary DNA from rat kidney that encodes
a 551-amino acid residue protein (OAT1) with 12 putative
membrane-spanning domains. When expressed in Xenopus laevis
oocytes, OAT1 mediated sodium-independent para-aminohippurate (PAH)
uptake (Km = 14.3 ± 2.9 µM).
The uptake rate of PAH was increased by the outwardly directed
dicarboxylate gradient, consisting with the idea that OAT1 is an
organic anion/dicarboxylate exchanger. OAT1 displayed remarkably wide
substrate selectivity, covering endogenous substrates such as cyclic
nucleotides, a prostaglandin and uric acid, and a variety of drugs
with different structures (e.g. antibiotics, a nonsteroidal
anti-inflammatory drug, diuretics, an antineoplastic drug, and a
uricosuric drug). The Northern blot analysis and in situ
hybridization revealed that OAT1 is exclusively expressed in the
particular segment of the proximal tubule in the kidney. These data
suggest that OAT1 is a multispecific organic anion transporter at the
basolateral membrane of the proximal tubule. Isolation of OAT1 will
facilitate elucidation of the molecular basis of drug kinetics and the
development of new drugs lacking unwanted side effects.

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C. Sauvant, H. Holzinger, and M. Gekle
Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular Opossum Kidney Cells: Prostaglandin E2 Acts via Receptor-Mediated Activation of Protein Kinase A
J. Am. Soc. Nephrol.,
December 1, 2003;
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[Abstract]
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E. Babu, Y. Kanai, A. Chairoungdua, D. K. Kim, Y. Iribe, S. Tangtrongsup, P. Jutabha, Y. Li, N. Ahmed, S. Sakamoto, et al.
Identification of a Novel System L Amino Acid Transporter Structurally Distinct from Heterodimeric Amino Acid Transporters
J. Biol. Chem.,
October 31, 2003;
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[Abstract]
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E. Beery, P. Middel, A. Bahn, H. S. Willenberg, Y. Hagos, H. Koepsell, S. R. Bornstein, G. A. Muller, G. Burckhardt, and J. Steffgen
Molecular Evidence of Organic Ion Transporters in the Rat Adrenal Cortex with Adrenocorticotropin-Regulated Zonal Expression
Endocrinology,
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144(10):
4519 - 4526.
[Abstract]
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A. Aslamkhan, Y.-H. Han, R. Walden, D. H. Sweet, and J. B. Pritchard
Stoichiometry of organic anion/dicarboxylate exchange in membrane vesicles from rat renal cortex and hOAT1-expressing cells
Am J Physiol Renal Physiol,
October 1, 2003;
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[Abstract]
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N. Mizuno, T. Niwa, Y. Yotsumoto, and Y. Sugiyama
Impact of Drug Transporter Studies on Drug Discovery and Development
Pharmacol. Rev.,
September 1, 2003;
55(3):
425 - 461.
[Abstract]
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G.-H. Kim, K. Y. Na, S.-Y. Kim, K. W. Joo, Y. K. Oh, S.-W. Chae, H. Endou, and J. S. Han
Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney
Nephrol. Dial. Transplant.,
August 1, 2003;
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[Abstract]
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G.-H. Kim, K. Y. Na, S.-Y. Kim, K. W. Joo, Y. K. Oh, S.-W. Chae, H. Endou, and J. S. Han
Up-regulation of organic anion transporter 1 protein is induced by chronic furosemide or hydrochlorothiazide infusion in rat kidney
Nephrol. Dial. Transplant.,
August 1, 2003;
18(88):
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[Abstract]
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P. Jutabha, Y. Kanai, M. Hosoyamada, A. Chairoungdua, D. K. Kim, Y. Iribe, E. Babu, J. Y. Kim, N. Anzai, V. Chatsudthipong, et al.
Identification of a Novel Voltage-driven Organic Anion Transporter Present at Apical Membrane of Renal Proximal Tubule
J. Biol. Chem.,
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[Abstract]
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R. Kikuchi, H. Kusuhara, D. Sugiyama, and Y. Sugiyama
Contribution of Organic Anion Transporter 3 (Slc22a8) to the Elimination of p-Aminohippuric Acid and Benzylpenicillin across the Blood-Brain Barrier
J. Pharmacol. Exp. Ther.,
July 1, 2003;
306(1):
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[Abstract]
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M. Hasegawa, H. Kusuhara, H. Endou, and Y. Sugiyama
Contribution of Organic Anion Transporters to the Renal Uptake of Anionic Compounds and Nucleoside Derivatives in Rat
J. Pharmacol. Exp. Ther.,
June 1, 2003;
305(3):
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[Abstract]
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S. C. N. Buist, N. J. Cherrington, and C. D. Klaassen
Endocrine Regulation of Rat Organic Anion Transporters
Drug Metab. Dispos.,
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559 - 564.
[Abstract]
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F. Van Bambeke, J.-M. Michot, and P. M. Tulkens
Antibiotic efflux pumps in eukaryotic cells: occurrence and impact on antibiotic cellular pharmacokinetics, pharmacodynamics and toxicodynamics
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May 1, 2003;
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D. H. Sweet, L. M. S. Chan, R. Walden, X.-P. Yang, D. S. Miller, and J. B. Pritchard
Organic anion transporter 3 (Slc22a8) is a dicarboxylate exchanger indirectly coupled to the Na+ gradient
Am J Physiol Renal Physiol,
April 1, 2003;
284(4):
F763 - F769.
[Abstract]
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S. Ohtsuki, T. Takizawa, H. Takanaga, N. Terasaki, T. Kitazawa, M. Sasaki, T. Abe, K.-i. Hosoya, and T. Terasaki
In Vitro Study of the Functional Expression of Organic Anion Transporting Polypeptide 3 at Rat Choroid Plexus Epithelial Cells and Its Involvement in the Cerebrospinal Fluid-to-Blood Transport of Estrone-3-Sulfate
Mol. Pharmacol.,
March 1, 2003;
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[Abstract]
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A. G. Aslamkhan, Y.-H. Han, X.-P. Yang, R. K. Zalups, and J. B. Pritchard
Human Renal Organic Anion Transporter 1-Dependent Uptake and Toxicity of Mercuric-Thiol Conjugates in Madin-Darby Canine Kidney Cells
Mol. Pharmacol.,
March 1, 2003;
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[Abstract]
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C. E. Groves, L. Munoz, A. Bahn, G. Burckhardt, and S. H. Wright
Interaction of Cysteine Conjugates with Human and Rabbit Organic Anion Transporter 1
J. Pharmacol. Exp. Ther.,
February 1, 2003;
304(2):
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[Abstract]
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P. T. Ronaldson and R. Bendayan
Renal Drug Transport and Drug-Drug Interactions
Journal of Pharmacy Practice,
December 1, 2002;
15(6):
490 - 503.
[Abstract]
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Y. Tsutsumi, T. Deguchi, M. Takano, A. Takadate, W. E. Lindup, and M. Otagiri
Renal Disposition of a Furan Dicarboxylic Acid and Other Uremic Toxins in the Rat
J. Pharmacol. Exp. Ther.,
November 1, 2002;
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A. Bahn, M. Knabe, Y. Hagos, M. Rodiger, S. Godehardt, D. S. Graber-Neufeld, K. K. Evans, G. Burckhardt, and S. H. Wright
Interaction of the Metal Chelator 2,3-Dimercapto-1-propanesulfonate with the Rabbit Multispecific Organic Anion Transporter 1 (rbOAT1)
Mol. Pharmacol.,
November 1, 2002;
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[Abstract]
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F. Knauf, B. Rogina, Z. Jiang, P. S. Aronson, and S. L. Helfand
Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy
PNAS,
October 29, 2002;
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14315 - 14319.
[Abstract]
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A. S. Koh, T. A. Simmons-Willis, J. B. Pritchard, S. M. Grassl, and N. Ballatori
Identification of a Mechanism by Which the Methylmercury Antidotes N-Acetylcysteine and Dimercaptopropanesulfonate Enhance Urinary Metal Excretion: Transport by the Renal Organic Anion Transporter-1
Mol. Pharmacol.,
October 1, 2002;
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F. Pizzagalli, B. Hagenbuch, B. Stieger, U. Klenk, G. Folkers, and P. J. Meier
Identification of a Novel Human Organic Anion Transporting Polypeptide as a High Affinity Thyroxine Transporter
Mol. Endocrinol.,
October 1, 2002;
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[Abstract]
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S. M. Grassl
Urate/alpha -ketoglutarate exchange in avian basolateral membrane vesicles
Am J Physiol Cell Physiol,
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C1144 - C1154.
[Abstract]
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A. Enomoto, M. F. Wempe, H. Tsuchida, H. J. Shin, S. H. Cha, N. Anzai, A. Goto, A. Sakamoto, T. Niwa, Y. Kanai, et al.
Molecular Identification of a Novel Carnitine Transporter Specific to Human Testis. INSIGHTS INTO THE MECHANISM OF CARNITINE RECOGNITION
J. Biol. Chem.,
September 20, 2002;
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[Abstract]
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Y. Kato, K. Kuge, H. Kusuhara, P. J. Meier, and Y. Sugiyama
Gender Difference in the Urinary Excretion of Organic Anions in Rats
J. Pharmacol. Exp. Ther.,
August 1, 2002;
302(2):
483 - 489.
[Abstract]
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M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, M. Hosoyamada, S. H. Cha, T. Sekine, and H. Endou
Characterization of Methotrexate Transport and Its Drug Interactions with Human Organic Anion Transporters
J. Pharmacol. Exp. Ther.,
August 1, 2002;
302(2):
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[Abstract]
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C. Sauvant, H. Holzinger, and M. Gekle
Short-Term Regulation of Basolateral Organic Anion Uptake in Proximal Tubular OK cells: EGF Acts via MAPK, PLA2, and COX1
J. Am. Soc. Nephrol.,
August 1, 2002;
13(8):
1981 - 1991.
[Abstract]
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D. H. Sweet, D. S. Miller, J. B. Pritchard, Y. Fujiwara, D. R. Beier, and S. K. Nigam
Impaired Organic Anion Transport in Kidney and Choroid Plexus of Organic Anion Transporter 3 (Oat3 (Slc22a8)) Knockout Mice
J. Biol. Chem.,
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26934 - 26943.
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Y. Kobayashi, N. Ohshiro, A. Shibusawa, T. Sasaki, S. Tokuyama, T. Sekine, H. Endou, and T. Yamamoto
Isolation, Characterization and Differential Gene Expression of Multispecific Organic Anion Transporter 2 in Mice
Mol. Pharmacol.,
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A. Enomoto, M. Takeda, A. Tojo, T. Sekine, S. H. Cha, S. Khamdang, F. Takayama, I. Aoyama, S. Nakamura, H. Endou, et al.
Role of Organic Anion Transporters in the Tubular Transport of Indoxyl Sulfate and the Induction of its Nephrotoxicity
J. Am. Soc. Nephrol.,
July 1, 2002;
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[Abstract]
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J. Alcorn and P. J. McNamara
Acyclovir, Ganciclovir, and Zidovudine Transfer into Rat Milk
Antimicrob. Agents Chemother.,
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[Abstract]
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A. Enomoto, M. Takeda, M. Shimoda, S. Narikawa, Y. Kobayashi, Y. Kobayashi, T. Yamamoto, T. Sekine, S. H. Cha, T. Niwa, et al.
Interaction of Human Organic Anion Transporters 2 and 4 with Organic Anion Transport Inhibitors
J. Pharmacol. Exp. Ther.,
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Y. L. Zhao, X. B. Cen, M. Ito, K. Yokoyama, K. Takagi, K. Kitaichi, M. Nadai, M. Ohta, K. Takagi, and T. Hasegawa
Shiga-Like Toxin II Derived from Escherichia coli O157:H7 Modifies Renal Handling of Levofloxacin in Rats
Antimicrob. Agents Chemother.,
May 1, 2002;
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[Abstract]
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Y. Nagata, H. Kusuhara, H. Endou, and Y. Sugiyama
Expression and Functional Characterization of Rat Organic Anion Transporter 3 (rOat3) in the Choroid Plexus
Mol. Pharmacol.,
May 1, 2002;
61(5):
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S. C. N. Buist, N. J. Cherrington, S. Choudhuri, D. P. Hartley, and C. D. Klaassen
Gender-Specific and Developmental Influences on the Expression of Rat Organic Anion Transporters
J. Pharmacol. Exp. Ther.,
April 1, 2002;
301(1):
145 - 151.
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H. Kimura, M. Takeda, S. Narikawa, A. Enomoto, K. Ichida, and H. Endou
Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Transport of Prostaglandins
J. Pharmacol. Exp. Ther.,
April 1, 2002;
301(1):
293 - 298.
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R. Kojima, T. Sekine, M. Kawachi, S. H. Cha, Y. Suzuki, and H. Endou
Immunolocalization of Multispecific Organic Anion Transporters, OAT1, OAT2, and OAT3, in Rat Kidney
J. Am. Soc. Nephrol.,
April 1, 2002;
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848 - 857.
[Abstract]
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H. Motohashi, Y. Sakurai, H. Saito, S. Masuda, Y. Urakami, M. Goto, A. Fukatsu, O. Ogawa, and K.-i. Inui
Gene Expression Levels and Immunolocalization of Organic Ion Transporters in the Human Kidney
J. Am. Soc. Nephrol.,
April 1, 2002;
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866 - 874.
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M. Hasegawa, H. Kusuhara, D. Sugiyama, K. Ito, S. Ueda, H. Endou, and Y. Sugiyama
Functional Involvement of Rat Organic Anion Transporter 3 (rOat3; Slc22a8) in the Renal Uptake of Organic Anions
J. Pharmacol. Exp. Ther.,
March 1, 2002;
300(3):
746 - 753.
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M. Takeda, S. Khamdang, S. Narikawa, H. Kimura, Y. Kobayashi, T. Yamamoto, S. H. Cha, T. Sekine, and H. Endou
Human Organic Anion Transporters and Human Organic Cation Transporters Mediate Renal Antiviral Transport
J. Pharmacol. Exp. Ther.,
March 1, 2002;
300(3):
918 - 924.
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R. A. M. H. van Aubel, P. H. E. Smeets, J. G. P. Peters, R. J. M. Bindels, and F. G. M. Russel
The MRP4/ABCC4 Gene Encodes a Novel Apical Organic Anion Transporter in Human Kidney Proximal Tubules: Putative Efflux Pump for Urinary cAMP and cGMP
J. Am. Soc. Nephrol.,
March 1, 2002;
13(3):
595 - 603.
[Abstract]
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C. S. Wilcox
New Insights into Diuretic Use in Patients with Chronic Renal Disease
J. Am. Soc. Nephrol.,
March 1, 2002;
13(3):
798 - 805.
[Abstract]
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G. Hill, T. Cihlar, C. Oo, E. S. Ho, K. Prior, H. Wiltshire, J. Barrett, B. Liu, and P. Ward
The Anti-Influenza Drug Oseltamivir Exhibits Low Potential to Induce Pharmacokinetic Drug Interactions via Renal Secretion---Correlation of in Vivo and in Vitro Studies
Drug Metab. Dispos.,
January 1, 2002;
30(1):
13 - 19.
[Abstract]
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Copyright © 1997 by the American Society for Biochemistry and Molecular Biology.
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