1. Transport of Estrone 3-sulfate Mediated by Organic Anion Transporter OATP4C1: Estrone 3-sulfate binds to the Different Recognition Site for Digoxin in OATP4C1
- Author
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Masahiro Okada, Takanori Hishinuma, Nariyasu Mano, Tsuyoshi Mikkaichi, Takafumi Toyohara, Junichi Goto, Miki Shimada, Hiroaki Yamaguchi, Takaaki Abe, and Misa Sugie
- Subjects
Organic Anion Transporters/antagonists & inhibitors ,Organic anion transporter 1 ,Digoxin ,Organic Anion Transporters ,Dogs ,Pharmaceutical Science ,Kidney ,Chenodeoxycholic Acid/metabolism ,Ouabain ,Sulfobromophthalein ,chemistry.chemical_compound ,Kidney/metabolism ,Triiodothyronine/metabolism ,Chenodeoxycholic acid ,polycyclic compounds ,Digoxin/metabolism ,Pharmacology (medical) ,Kidney/cytology ,Cell Line ,biology ,Estrone/analogs & derivatives ,Sulfobromophthalein/metabolism ,mutual inhibition ,estrone 3-sulfate ,digoxin ,Estrone/metabolism ,Biochemistry ,Cyclosporine/metabolism ,Cyclosporine ,Triiodothyronine ,medicine.drug ,Biological Transport/drug effects ,medicine.medical_specialty ,Estrone ,OATP4C1 ,Humans ,Chenodeoxycholic Acid ,Binding, Competitive ,Estrone sulfate ,Internal medicine ,medicine ,Animals ,Pharmacokinetics ,Pharmacology ,Biological Transport ,Epithelial Cells ,Organic Anion Transporters/metabolism ,Ouabain/metabolism ,Endocrinology ,chemistry ,recognition site ,Renal physiology ,biology.protein - Abstract
Summary: Human organic anion transporter OATP4C1 is a member of the OATP family predominantly expressed 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 transported by OATP4C1. The Michaelis-Menten constant for estrone 3-sulfate uptake by OATP4C1 was 26.6 ± 4.9 μ M. 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 IC 50 value of digoxin for OATP4C1-mediated estrone 3-sulfate transport was 119 μ M. This value is not comparable with the Michaelis-Menten constant for digoxin uptake by OATP4C1 (7.8 μ M) 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.
- Published
- 2010