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Journal of Lipid Research, Vol. 47, 1196-1202, June 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Transport of fluorescent chenodeoxycholic acid via the human organic anion transporters OATP1B1 and OATP1B3

Hiroaki Yamaguchi^*,, Masahiro Okada^*, Shou Akitaya^*, Hiroshi Ohara^*, Tsuyoshi Mikkaichi^*, Haruna Ishikawa^*, Mayumi Sato, Masaki Matsuura, Toshihide Saga, Michiaki Unno, Takaaki Abe^**,, Nariyasu Mano, Takanori Hishinuma^*, and Junichi Goto^1,*,

^* Division of Clinical Pharmacy, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan
Division of Gastroenterological Surgery, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
^** Division of Nephrology, Endocrinology, and Vascular Medicine, Department of Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Japan; Japan Science and Technology Corporation, Kawaguchi, Japan
Division of Bio-Analytical Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan

Published, JLR Papers in Press, March 13, 2006.

¹ To whom correspondence should be addressed. e-mail: jun-goto{at}pharm.med.tohoku.ac.jp

This study sought to clarify the contributions of organic anion-transporting polypeptide (OATP) 1B1 and 1B3 to the liver uptake of chenodeoxycholic acid (CDCA). We synthesized a fluorescent version of CDCA, chenodeoxychilyl-(N-NBD)-lysine (CDCA-NBD), to characterize transporter-mediated uptake. CDCA-NBD is efficiently transported by OATP1B1 and OATP1B3 with high affinities. The Michaelis-Menten constants for CDCA-NBD uptake by OATP1B1 and OATP1B3 were 1.45 ± 0.39 µM and 0.54 ± 0.09 µM, respectively. By confocal laser scanning microscopy, CDCA-NBD, which is taken up by OATP1B1 and OATP1B3, was observed to localize to the cytosol. We also examined the transport of newly synthesized fluorescent bile acids. NBD-labeled bile acids, including cholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, were all transported by OATP1B1 and OATP1B3. CDCA-NBD exhibited the highest rate of transport of the five NBD-labeled bile acids examined in OATP1B1- and OATP1B3-expressing cells. Our results suggest that OATP1B1 and OATP1B3 play important roles in CDCA uptake into the liver. Fluorescent bile acids are useful tools to characterize the uptake properties of membrane transporters.

Supplementary key words nitrobenz-2-oxa-1,3-diazole • organic anion-transporting polypeptide 1B1 • organic anion-transporting polypeptide 1B3 • visualization

Abbreviations: BSP, bromosulfophtalein; CA, cholic acid; CDCA, chenodeoxycholic acid; CDCA-NBD, chenodeoxychilyl-(N-NBD)-lysine; CsA, cyclosporin A; DCA, deoxycholic acid; E3S, estrone-3-sulfate; FXR, farnesoid X receptor; LCA, lithocholic acid; NBD, 7-nitrobenz-2-oxa-1,3-diazole; OATP, organic anion-transporting polypeptide; T₃, triiodothyronine; UDCA, ursodeoxycholic acid

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