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J Biol Chem, Vol. 275, Issue 6, 4507-4512, February 11, 2000

Molecular Cloning and Characterization of Multispecific Organic Anion Transporter 4 Expressed in the Placenta*

Seok Ho ChaDagger , Takashi SekineDagger , Hiroyuki KusuharaDagger §, Erkang YuDagger , Ju Young KimDagger , Do Kyung KimDagger , Yuichi Sugiyama§, Yoshikatsu KanaiDagger , and Hitoshi EndouDagger

From the Dagger  Department of Pharmacology and Toxicology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611 and § Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan

A cDNA encoding a novel multispecific organic anion transporter, OAT4, was isolated from a human kidney cDNA library. The OAT4 cDNA consisted of 2210 base pairs that encoded a 550-amino acid residue protein with 12 putative membrane-spanning domains. The amino acid sequence of OAT4 showed 38 to 44% identity to those of other members of the OAT family. Northern blot analysis revealed that OAT4 mRNA is abundantly expressed in the placenta as well as in the kidney. When expressed in Xenopus oocytes, OAT4 mediated the high affinity transport of estrone sulfate (Km = 1.01 µM) and dehydroepiandrosterone sulfate (Km = 0.63 µM) in a sodium-independent manner. OAT4 also mediated the transport of ochratoxin A. OAT4-mediated transport of estrone sulfate was inhibited by several sulfate conjugates, such as p-nitrophenyl sulfate, alpha -naphthyl sulfate, beta -estradiol sulfate, and 4-methylumbelliferyl sulfate. By contrast, glucuronide conjugates showed little or no inhibitory effect on the OAT4-mediated transport of estrone sulfate. OAT4 interacted with chemically heterogeneous anionic compounds, such as nonsteroidal anti-inflammatory drugs, diuretics, sulfobromophthalein, penicillin G, and bile salts, whereas tetraethylammonium, an organic cation, did not. OAT4 is the first member of the multispecific organic anion transporter family, which is expressed abundantly in the placenta. OAT4 might be responsible for the elimination and detoxification of harmful anionic substances from the fetus.

* This work was supported in part by grants from the Japanese Ministry of Education Science, Sports, and Culture, (grants-in-aid for scientific research and High Tech Research Center), the Science Research Promotion Fund of the Japan Private School Promotion Foundation, the Uehara Memorial Foundation, and CREST (Core Research for Evolutional Science and Technology) of the Japan Science and Technology Corporation (JST).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AB026198.

To whom correspondence should be addressed. Tel.: 81-422-47-5511 (ext. 3451); Fax: 81-422-79-1321.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 534 - 539.
[Abstract] [Full Text] [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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 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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 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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 J. Clin. Endocrinol. Metab.Home page
M. V. St-Pierre, B. Hagenbuch, B. Ugele, P. J. Meier, and T. Stallmach
Characterization of an Organic Anion-Transporting Polypeptide (OATP-B) in Human Placenta
J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1856 - 1863.
[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. 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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 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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 Pharmacol. Rev.Home page
G. Lee, S. Dallas, M. Hong, and R. Bendayan
Drug Transporters in the Central Nervous System: Brain Barriers and Brain Parenchyma Considerations
Pharmacol. Rev., December 1, 2001; 53(4): 569 - 596.
[Abstract] [Full Text] [PDF]

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 J. Am. Soc. Nephrol.Home page
N. A. WOLFF, B. GRUNWALD, B. FRIEDRICH, F. LANG, S. GODEHARDT, and G. BURCKHARDT
Cationic Amino Acids Involved in Dicarboxylate Binding of the Flounder Renal Organic Anion Transporter
J. Am. Soc. Nephrol., October 1, 2001; 12(10): 2012 - 2018.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Renal Physiol.Home page
D. H. Sweet, K. T. Bush, and S. K. Nigam
The organic anion transporter family: from physiology to ontogeny and the clinic
Am J Physiol Renal Physiol, August 1, 2001; 281(2): F197 - F205.
[Abstract] [Full Text] [PDF]

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 Mol. Pharmacol.Home page
S. H. Cha, T. Sekine, J.-i. Fukushima, Y. Kanai, Y. Kobayashi, T. Goya, and H. Endou
Identification and Characterization of Human Organic Anion Transporter 3 Expressing Predominantly in the Kidney
Mol. Pharmacol., April 16, 2001; 59(5): 1277 - 1286.
[Abstract] [Full Text]

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 J. Pharmacol. Exp. Ther.Home page
A. S. Mulato, E. S. Ho, and T. Cihlar
Nonsteroidal Anti-Inflammatory Drugs Efficiently Reduce the Transport and Cytotoxicity of Adefovir Mediated by the Human Renal Organic Anion Transporter 1
J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 10 - 15.
[Abstract] [Full Text]

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 J. Pharmacol. Exp. Ther.Home page
S. Wada, M. Tsuda, T. Sekine, S. H. Cha, M. Kimura, Y. Kanai, and H. Endou
Rat Multispecific Organic Anion Transporter 1 (rOAT1) Transports Zidovudine, Acyclovir, and Other Antiviral Nucleoside Analogs
J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 844 - 849.
[Abstract] [Full Text]

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 EndocrinologyHome page
D. Chamoun, M. D. DeMoura, E. Levitas, C. E. Resnick, S. E. Gargosky, R. G. Rosenfeld, T. Matsumoto, and E. Y. Adashi
Transcriptional and Posttranscriptional Regulation of Intraovarian Insulin-Like Growth Factor-Binding Proteins by Interleukin-1{beta} (IL-1{beta}): Evidence for IL-1{beta} as an Antiatretic Principal
Endocrinology, August 1, 1999; 140(8): 3488 - 3495.
[Abstract] [Full Text]

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 J. Biol. Chem.Home page
Y.-M. Qian, W.-C. Song, H. Cui, S. P. C. Cole, and R. G. Deeley
Glutathione Stimulates Sulfated Estrogen Transport by Multidrug Resistance Protein 1
J. Biol. Chem., February 23, 2001; 276(9): 6404 - 6411.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Cell Physiol.Home page
A. Emoto, F. Ushigome, N. Koyabu, H. Kajiya, K. Okabe, S. Satoh, K. Tsukimori, H. Nakano, H. Ohtani, and Y. Sawada
H+-linked transport of salicylic acid, an NSAID, in the human trophoblast cell line BeWo
Am J Physiol Cell Physiol, May 1, 2002; 282(5): C1064 - C1075.
[Abstract] [Full Text] [PDF]


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