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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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Interacti