Multispecific substrate recognition of kidney-specific organic anion transporters OAT-K1 and OAT-K2

Ayako Takeuchi, Satohiro Masuda, Hideyuki Saito, Takaaki Abe, Ken Ichi Inui

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

We characterized the interactions of various compounds with OAT-K1 and OAT-K2, kidney-specific organic anion transporters. By using Madin-Darby canine kidney cells stably transfected with OAT-K1 or OAT-K2 cDNA, the antitumor drug methotrexate, the mycotoxin ochratoxin A, endogenous organic anions (thyroid hormones, taurocholic acid, and conjugated steroids), and the antiretroviral drug zidovudine were shown to be substrates for these transporters. Although the apparent Michaelis constant (Km) values of methotrexate for OAT-K1 and OAT-K2 were 2.1 and 1.8 μM, respectively, 2.5 mM methotrexate inhibited only 20% of the 125l-thyroid hormones uptake via these transporters, In addition, 100 μM methotrexate did not have any effect on [3H]zidovudine uptake via OAT-K1 or OAT-K2. Similarly, several substrates caused little or no mutual inhibition at concentrations much higher than their Km values for these transporters. Moreover, intracellular methotrexate trans-stimulated the OAT-K1- and OAT-K2-mediated uptake of [3H]folic acid, but not that of other compounds. Organic anion-transporting polypeptide 2 (oatp2), a liver-type homolog of OAT-K1 and OAT-K2, showed similar events. The inhibition constant values of triiodothyronine and taurocholic acid for [3H]digoxin uptake in oatp2-expressing oocytes resulted in 50.4 and 1.48 mM, respectively, which were about 9- and 40-fold higher than their Km values for oatp2, respectively. These findings suggested that several substrates interact with these transporters at different amino acid residue(s). Taken together, these observations suggested that OAT-K1 and OAT-K2 could serve as multispecific transporters, mediating transport of a wide variety of endogenous substances, xenobiotics, and their metabolites in the kidney, presumably via several interaction sites in their molecules.

Original languageEnglish
Pages (from-to)261-267
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume299
Issue number1
Publication statusPublished - Oct 9 2001
Externally publishedYes

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Organic Anion Transporters
Methotrexate
Anions
Kidney
Taurocholic Acid
Zidovudine
Thyroid Hormones
Peptides
Madin Darby Canine Kidney Cells
Mycotoxins
Digoxin
Triiodothyronine
Xenobiotics
Folic Acid
Antineoplastic Agents
Oocytes
Complementary DNA
Steroids
Amino Acids
Liver

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Multispecific substrate recognition of kidney-specific organic anion transporters OAT-K1 and OAT-K2. / Takeuchi, Ayako; Masuda, Satohiro; Saito, Hideyuki; Abe, Takaaki; Inui, Ken Ichi.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 299, No. 1, 09.10.2001, p. 261-267.

Research output: Contribution to journalArticle

Takeuchi, Ayako ; Masuda, Satohiro ; Saito, Hideyuki ; Abe, Takaaki ; Inui, Ken Ichi. / Multispecific substrate recognition of kidney-specific organic anion transporters OAT-K1 and OAT-K2. In: Journal of Pharmacology and Experimental Therapeutics. 2001 ; Vol. 299, No. 1. pp. 261-267.
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