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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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Am. J. Physiol. Renal Physiol.Home page
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; 285(4): F775 - F783.
[Abstract] [Full Text] [PDF]


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Pharmacol. Rev.Home page
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] [Full Text] [PDF]


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Nephrol Dial TransplantHome page
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(8): 1505 - 1511.
[Abstract] [Full Text] [PDF]


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Nephrol Dial TransplantHome page
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): 1505 - 1511.
[Abstract] [Full Text]


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J. Biol. Chem.Home page
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., July 18, 2003; 278(30): 27930 - 27938.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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): 51 - 58.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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): 1087 - 1097.
[Abstract] [Full Text] [PDF]


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Drug Metab. Dispos.Home page
S. C. N. Buist, N. J. Cherrington, and C. D. Klaassen
Endocrine Regulation of Rat Organic Anion Transporters
Drug Metab. Dispos., May 1, 2003; 31(5): 559 - 564.
[Abstract] [Full Text] [PDF]


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J Antimicrob ChemotherHome page
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
J. Antimicrob. Chemother., May 1, 2003; 51(5): 1067 - 1077.
[Full Text] [PDF]


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Am. J. Physiol. Renal Physiol.Home page
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] [Full Text] [PDF]


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Mol. Pharmacol.Home page
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; 63(3): 532 - 537.
[Abstract] [Full Text] [PDF]


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Mol. Pharmacol.Home page
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; 63(3): 590 - 596.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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): 560 - 566.
[Abstract] [Full Text] [PDF]


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Journal of Pharmacy PracticeHome page
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] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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; 303(2): 880 - 887.
[Abstract] [Full Text] [PDF]


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Mol. Pharmacol.Home page
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; 62(5): 1128 - 1136.
[Abstract] [Full Text] [PDF]


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Proc. Natl. Acad. Sci. USAHome page
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; 99(22): 14315 - 14319.
[Abstract] [Full Text] [PDF]


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Mol. Pharmacol.Home page
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; 62(4): 921 - 926.
[Abstract] [Full Text] [PDF]


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Mol. Endocrinol.Home page
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; 16(10): 2283 - 2296.
[Abstract] [Full Text] [PDF]


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Am. J. Physiol. Cell Physiol.Home page
S. M. Grassl
Urate/alpha -ketoglutarate exchange in avian basolateral membrane vesicles
Am J Physiol Cell Physiol, October 1, 2002; 283(4): C1144 - C1154.
[Abstract] [Full Text] [PDF]


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J. Biol. Chem.Home page
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; 277(39): 36262 - 36271.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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): 666 - 671.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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] [Full Text] [PDF]


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J. Biol. Chem.Home page
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., July 19, 2002; 277(30): 26934 - 26943.
[Abstract] [Full Text] [PDF]


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Mol. Pharmacol.Home page
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., July 1, 2002; 62(1): 7 - 14.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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; 13(7): 1711 - 1720.
[Abstract] [Full Text] [PDF]


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Antimicrob. Agents Chemother.Home page
J. Alcorn and P. J. McNamara
Acyclovir, Ganciclovir, and Zidovudine Transfer into Rat Milk
Antimicrob. Agents Chemother., June 1, 2002; 46(6): 1831 - 1836.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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., June 1, 2002; 301(3): 797 - 802.
[Abstract] [Full Text] [PDF]


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Antimicrob. Agents Chemother.Home page
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; 46(5): 1522 - 1528.
[Abstract] [Full Text] [PDF]


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Mol. Pharmacol.Home page
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): 982 - 988.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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; 13(4): 848 - 857.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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; 13(4): 866 - 874.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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.
[Abstract] [Full Text] [PDF]


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J. Pharmacol. Exp. Ther.Home page
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.
[Abstract] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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] [Full Text] [PDF]


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J. Am. Soc. Nephrol.Home page
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] [Full Text] [PDF]


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Drug Metab. Dispos.Home page
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] [Full Text] [PDF]




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