TY - JOUR
T1 - Transport of estrone 3-sulfate mediated by organic anion transporter OATP4C1
T2 - Estrone 3-sulfate binds to the different recognition site for digoxin in OATP4C1
AU - Yamaguchi, Hiroaki
AU - Sugie, Misa
AU - Okada, Masahiro
AU - Mikkaichi, Tsuyoshi
AU - Toyohara, Takafumi
AU - Abe, Takaaki
AU - Goto, Junichi
AU - Hishinuma, Takanori
AU - Shimada, Miki
AU - Mano, Nariyasu
N1 - Funding Information:
**Present address: Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan. This work was supported in part by a grant from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
KW - Digoxin
KW - Estrone 3-sulfate
KW - Mutual inhibition
KW - OATP4C1
KW - Recognition site
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U2 - 10.2133/dmpk.25.314
DO - 10.2133/dmpk.25.314
M3 - Article
C2 - 20610891
AN - SCOPUS:77954289040
SN - 1347-4367
VL - 25
SP - 314
EP - 317
JO - Drug Metabolism and Pharmacokinetics
JF - Drug Metabolism and Pharmacokinetics
IS - 3
ER -