HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kramer, W. Articles by Weyland, C. Search for Related Content PubMed PubMed Citation Articles by Kramer, W. Articles by Weyland, C. Social Bookmarking                      What's this?

Journal of Lipid Research, Vol. 40, 1604-1617, September 1999
Copyright © 1999 by Lipid Research, Inc.

Original Article

Substrate specificity of the ileal and the hepatic Na⁺/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters

Correspondence to: Werner Kramer

The substrate specificity of the ileal and the hepatic Na⁺/bile acid cotransporters was determined using brush border membrane vesicles and CHO cell lines permanently expressing the Na⁺/bile acid cotransporters from rabbit ileum or rabbit liver. The hepatic transporter showed a remarkably broad specificity for interaction with cholephilic compounds in contrast to the ileal system. The anion transport inhibitor diisothiocyanostilbene disulfonate (DIDS) is a strong inhibitor of the hepatic Na⁺/bile acid cotransporter, but does not show any affinity to its ileal counterpart. Inhibition studies and uptake measurements with about 40 different bile acid analogues differing in the number, position, and stereochemistry of the hydroxyl groups at the steroid nucleus resulted in clear structure;–activity relationships for the ileal and hepatic bile acid transporters. The affinity to the ileal and hepatic Na⁺/bile acid cotransport systems and the uptake rates by cell lines expressing those transporters as well as rabbit ileal brush border membrane vesicles is primarily determined by the substituents on the steroid nucleus. Two hydroxy groups at position 3, 7, or 12 are optimal whereas the presence of three hydroxy groups decreased affinity. Vicinal hydroxy groups at positions 6 and 7 or a shift of the 7-hydroxy group to the 6-position significantly decreased the affinity to the ileal transporter in contrast to the hepatic system. 6-Hydroxylated bile acid derivatives are preferred substrates of the hepatic Na⁺/bile acid cotransporter. Surprisingly, the 3-hydroxy group being present in all natural bile acids is not essential for high affinity interaction with the ileal and the hepatic bile acid transporter.

The 3-hydroxy group seems to be necessary for optimal transport of a bile acid across the hepatocyte canalicular membrane. A modification of bile acids at the 3-position therefore conserves the bile acid character thus determining the 3-position of bile acids as the ideal position for drug targeting strategies using bile acid transport pathways.—Kramer, W., S. Stengelin, K-H. Baringhaus, A. Enhsen, H. Heuer, W. Becker, D. Corsiero, F. Girbig, R. Noll, and C. Weyland. Substrate specificity of the ileal and the hepatic Na⁺/bile acid cotransporters of the rabbit. I. Transport studies with membrane vesicles and cell lines expressing the cloned transporters. J. Lipid Res. 1999. 40: 1604;–1617.

Supplementary key words: bile acids, Na⁺/bile acid cotransporters, substrate specificity, molecular recognition, structure–activity relationships, cloned transporters, transport studies, ileum, liver

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Geyer, B. Doring, K. Meerkamp, B. Ugele, N. Bakhiya, C. F. Fernandes, J. R. Godoy, H. Glatt, and E. Petzinger Cloning and Functional Characterization of Human Sodium-dependent Organic Anion Transporter (SLC10A6) J. Biol. Chem., July 6, 2007; 282(27): 19728 - 19741. [Abstract] [Full Text] [PDF]

				N. Hussainzada, A. Banerjee, and P. W. Swaan Transmembrane Domain VII of the Human Apical Sodium-Dependent Bile Acid Transporter ASBT (SLC10A2) Lines the Substrate Translocation Pathway Mol. Pharmacol., November 1, 2006; 70(5): 1565 - 1574. [Abstract] [Full Text] [PDF]

				A.-Q. Sun, N. Balasubramaniyan, H. Chen, M. Shahid, and F. J. Suchy Identification of Functionally Relevant Residues of the Rat Ileal Apical Sodium-dependent Bile Acid Cotransporter J. Biol. Chem., June 16, 2006; 281(24): 16410 - 16418. [Abstract] [Full Text] [PDF]

				H. Li, F. Chen, Q. Shang, L. Pan, B. L. Shneider, J. Y. L. Chiang, B. M. Forman, M. Ananthanarayanan, G. S. Tint, G. Salen, et al. FXR-activating ligands inhibit rabbit ASBT expression via FXR-SHP-FTF cascade Am J Physiol Gastrointest Liver Physiol, January 1, 2005; 288(1): G60 - G66. [Abstract] [Full Text] [PDF]

				R. H. Ho, B. F. Leake, R. L. Roberts, W. Lee, and R. B. Kim Ethnicity-dependent Polymorphism in Na+-taurocholate Cotransporting Polypeptide (SLC10A1) Reveals a Domain Critical for Bile Acid Substrate Recognition J. Biol. Chem., February 20, 2004; 279(8): 7213 - 7222. [Abstract] [Full Text] [PDF]

				S. Hata, P. Wang, N. Eftychiou, M. Ananthanarayanan, A. Batta, G. Salen, K. S. Pang, and A. W. Wolkoff Substrate specificities of rat oatp1 and ntcp: implications for hepatic organic anion uptake Am J Physiol Gastrointest Liver Physiol, November 1, 2003; 285(5): G829 - G839. [Abstract] [Full Text] [PDF]

				M. Trauner and J. L. Boyer Bile Salt Transporters: Molecular Characterization, Function, and Regulation Physiol Rev, April 1, 2003; 83(2): 633 - 671. [Abstract] [Full Text] [PDF]

				M. E. Mendoza, M. J. Monte, M. A. Serrano, M. Pastor-Anglada, B. Stieger, P. J. Meier, M. Medarde, and J. J. G. Marin Physiological characteristics of allo-cholic acid J. Lipid Res., January 1, 2003; 44(1): 84 - 92. [Abstract] [Full Text] [PDF]

				G. Rzewuski and M. Sauter The novel rice (Oryza sativa L.) gene OsSbf1 encodes a putative member of the Na+/bile acid symporter family J. Exp. Bot., September 1, 2002; 53(376): 1991 - 1993. [Abstract] [Full Text] [PDF]

				D. Schwab, A. W. Herling, H. Hemmerle, G. Schubert, B. Hagenbuch, and H.-J. Burger Hepatic Uptake of Synthetic Chlorogenic Acid Derivatives by the Organic Anion Transport Proteins J. Pharmacol. Exp. Ther., January 1, 2001; 296(1): 91 - 98. [Abstract] [Full Text]

				K.-H. Baringhaus, H. Matter, S. Stengelin, and W. Kramer Substrate specificity of the ileal and the hepatic Na+/bile acid cotransporters of the rabbit. II. A reliable 3D QSAR pharmacophore model for the ileal Na+/bile acid cotransporter J. Lipid Res., December 1, 1999; 40(12): 2158 - 2168. [Abstract] [Full Text] [PDF]

				W. Kramer, K. Sauber, K.-H. Baringhaus, M. Kurz, S. Stengelin, G. Lange, D. Corsiero, F. Girbig, W. Konig, and C. Weyland Identification of the Bile Acid-binding Site of the Ileal Lipid-binding Protein by Photoaffinity Labeling, Matrix-assisted Laser Desorption Ionization-Mass Spectrometry, and NMR Structure J. Biol. Chem., March 2, 2001; 276(10): 7291 - 7301. [Abstract] [Full Text] [PDF]

				W. Kramer, F. Girbig, H. Glombik, D. Corsiero, S. Stengelin, and C. Weyland Identification of a Ligand-binding Site in the Na+/Bile Acid Cotransporting Protein from Rabbit Ileum J. Biol. Chem., September 14, 2001; 276(38): 36020 - 36027. [Abstract] [Full Text] [PDF]