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First published on May 19, 2006; DOI: 10.1124/dmd.106.009530

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Received for publication January 31, 2006.
Revised May 11, 2006.
Accepted for publication May 17, 2006.

Predominant Contribution of Organic Anion Transporting Polypeptide OATP-B (OATP2B1) to Apical Uptake of Estrone-3-sulfate by Human Intestinal Caco-2 Cells

Yoshimichi Sai 1, Yosuke Kaneko 1, Satsuki Ito 1, Keisuke Mitsuoka 1, Yukio Kato 1, Ikumi Tamai 2*, Per Artursson 3, Akira Tsuji 1

1 Kanazawa University 2 Tokyo University of Science 3 Uppsala University

* Address correspondence to: E-mail: tamai{at}rs.noda.tus.ac.jp

Abstract

Human organic anion transporting polypeptide OATP-B (OATP2B1) is a pH-sensitive transporter expressed in the apical membranes of small intestinal epithelial cells. In this study, we have examined the contribution of OATP-B to the uptake of [3H]estrone-3-sulfate in Caco-2 cells in comparison with those of its homologues OATP-D (OATP3A1) and OATP-E (OATP4A1). Immunocytochemical study revealed that OATP-B is expressed in the apical membranes of Caco-2 cells. The uptake of [3H]estrone-3-sulfate by Caco-2 cells was Na+-independent and inhibited by several organic anions. It showed biphasic saturation kinetics, the Km values being 1.81 µM and 1.40 mM. The uptake of [3H]estrone-3-sulfate by HEK293 cells stably expressing OATP-B (HEK293/OATP-B), was also Na+-independent and inhibited by several organic anions. The Km value for estrone-3-sulfate uptake by OATP-B (1.56 µM) was close to that for the high-affinity component observed in Caco-2 cells. The mRNA expression level of OATP-B was higher than that of OATP-D or OATP-E in Caco-2 cells and in human jejunum biopsies from health volunteers. The values of [3H]estrone-3-sulfate uptake normalized to OATP-B mRNA expression were similar in Caco-2 cells and HEK293/OATP-B cells. The specific activity of OATP-B per mRNA expression was much higher than that of OATP-D and OATP-E. [3H]Estrone-3-sulfate uptake by membrane vesicles prepared from HEK293/OATP-B cells exhibited an overshoot phenomenon in the presence of an inwardly directed H+ gradient, suggesting that an H+ gradient is the driving force of estrone-3-sulfate transport by OATP-B. These results suggest that OATP-B is predominantly responsible for the apical uptake of estrone-3-sulfate in Caco-2 cells.


Key words: absorption, active transport, cellular transport, drug absorption, intestinal transport, membrane transport, transporters


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