title: Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1: estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1.
abstract: 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 microM. 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 microM. This value is not comparable with the Michaelis-Menten constant for digoxin uptake by OATP4C1 (7.8 microM) 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.
authors.affiliation: Department of Pharmaceutical Sciences, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Misa
authors.initials: M
authors.lastname: Sugie
authors.forename: Masahiro
authors.initials: M
authors.lastname: Okada
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Mikkaichi
authors.forename: Takafumi
authors.initials: T
authors.lastname: Toyohara
authors.forename: Takaaki
authors.initials: T
authors.lastname: Abe
authors.forename: Junichi
authors.initials: J
authors.lastname: Goto
authors.forename: Takanori
authors.initials: T
authors.lastname: Hishinuma
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects*; D002460:Cell Line; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D016572:Cyclosporine / Q000378:metabolism; D004077:Digoxin / Q000378:metabolism*; D004285:Dogs; D004847:Epithelial Cells; D004970:Estrone / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010042:Ouabain / Q000378:metabolism; D010599:Pharmacokinetics; D013448:Sulfobromophthalein / Q000378:metabolism; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D027361:Organic Anion Transporters; C484530:SLCO4C1 protein, human; D014284:Triiodothyronine; D013448:Sulfobromophthalein; D002635:Chenodeoxycholic Acid; D004970:Estrone; D010042:Ouabain; D004077:Digoxin; D016572:Cyclosporine; C017296:estrone sulfate