Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1: Estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1

Hiroaki Yamaguchi, Misa Sugie, Masahiro Okada, Tsuyoshi Mikkaichi, Takafumi Toyohara, Takaaki Abe, Junichi Goto, Takanori Hishinuma, Miki Simada, Nariyasu Mano

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Human organic anion transporter OATP4C1 is a member of the OATP family predominantly ex-pressed in the kidney, and contributes to the renal secretion of digoxin. However, little is known about the characteristics of OATP4C1-madiated transport. We examined the transport of estrone 3-sulfate, which is known as a substrate for other OATPs, by OATP4C1-expressing cells. Estrone 3-sulfate was efficiently trans-ported by OATP4C1. The Michaelis-Menten constant for estrone 3-sulfate uptake by OATP4C1 was 26.6±4.9 mM. Transport of estrone 3-sulfate was significantly inhibited by triiodothyronine, chenodeoxycholic acid, bromosulfophtalein, and cyclosporine, whereas known substrates of OATP4C1, digoxin and ouabain, did not change OATP4C1-mediated transport. We further examined the mutual inhibition study between estrone 3-sulfate and digoxin. Digoxin partially inhibited the estrone 3-sulfate transport, and estrone 3-sulfate did not significantly inhibit digoxin transport. The estimated IC50 value of digoxin for OATP4C1-mediated estrone 3-sulfate transport was 119 mM. This value is not comparable with the Michaelis-Menten constant for digoxin uptake by OATP4C1 (7.8 mM) reported by Mikkaichi et al.1) In conclusion, we found that estrone 3-sulfate is a novel substrate for OATP4C1. Moreover, our results indicate that estrone 3-sulfate does not bind to the recognition site for digoxin in OATP4C1.

Original languageEnglish
Pages (from-to)314-317
Number of pages4
JournalDrug metabolism and pharmacokinetics
Volume25
Issue number3
DOIs
Publication statusPublished - 2010 Jan 1

Keywords

  • Digoxin
  • Estrone 3-sulfate
  • Mutual inhibition
  • OATP4C1
  • Recognition site

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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