Bile acid transport systems as pharmaceutical targets

Kramer, Werner; Wess, G.

doi:10.1111/j.1365-2362.1996.tb02383.x

Cited by 77 publications

(51 citation statements)

References 67 publications

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“…The following competitive inhibition model was applied to cis inhibition studies of taurocholate uptake by individual bile acids 10 : (3) where I is the concentration of inhibitor (i.e. CDCA conjugate) and S is the concentration of taurocholate (i.e.…”

Section: Discussionmentioning

confidence: 99%

Influence of Charge and Steric Bulk in the C-24 Region on the Interaction of Bile Acids with Human Apical Sodium-Dependent Bile Acid Transporter

et al. 2006

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The human Apical Sodium-dependent Bile Acid Transporter (hASBT) is a potential target for drug delivery, but an understanding of hASBT substrate requirements is limited. The objective of this study was to evaluate the influence of ionic character and steric bulk in the C-24 region of bile acid conjugates in governing interaction with hASBT. Ionic character was studied using chenodeoxycholate (CDCA) conjugates of glutamic acid and lysine, which varied in charge (monoanionic, dianionic, cationic, neutral, and zwitterionic) and location of charge (proximal or distal to C-24). Steric effects were evaluated using ester conjugates that varied in ester substituent size (methyl, benzyl, and t-butyl) and location (proximal and/or distal). Conjugate interaction with hASBT was assessed via transport and inhibition studies, using a hASBT-MDCK monolayer. Monoanionic, cationic, and neutral conjugates of CDCA exhibited high inhibitory potency (Ki < 10 μM). High inhibition potency of neutral and cationic conjugates indicated a negative charge is not essential for hASBT binding. Dianionic conjugates exhibited low inhibition potency (Ki > 100 μM).Conjugates with a single bulky ester substituent proximal or distal to C-24 region exhibited high inhibition potency. However, two bulky substituents practically abolished interaction. In transport studies, monoanionic conjugates were high affinity hASBT substrates. Meanwhile, cationic and zwitterionic conjugates were not substrates for hASBT. Overall, C-24 ionic character influenced interaction with hASBT. Although the presence of a single negative charge was not essential for interaction with hASBT, monoanionic conjugates were favored for hASBT-mediated transport compared to cationic and zwitterionic conjugates.

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Section: Discussionmentioning

confidence: 99%

Influence of Charge and Steric Bulk in the C-24 Region on the Interaction of Bile Acids with Human Apical Sodium-Dependent Bile Acid Transporter

et al. 2006

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“…The first class of compounds comprised dimeric bile acid analogues where two bile acid molecules were coupled via spacer. These compounds were able to block simultaneously ligand binding sites of two ASBT molecules from the cell surface without being translocated (Wess et al 1994;Kramer and Wess 1996;Baringhaus et al 1999). A second class of ASBT inhibitors contains several benzothiazepine derivatives.…”

Section: Pharmacological Inhibition Of the Asbtmentioning

confidence: 99%

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

Geyer

Wilke

Petzinger

2006

Naunyn Schmied Arch Pharmacol

159

138

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The solute carrier family 10 (SLC10) comprises two sodium-dependent bile acid transporters, i.e. the Na + / taurocholate cotransporting polypeptide (NTCP; SLC10A1) and the apical sodium-dependent bile acid transporter (ASBT; SLC10A2). These carriers are essentially involved in the maintenance of the enterohepatic circulation of bile acids mediating the first step of active bile acid transport through the membrane barriers in the liver (NTCP) and intestine (ASBT). Recently, four new members of the SLC10 family were described and referred to as P3 (SLC10A3), P4 (SLC10A4), P5 (SLC10A5) and sodium-dependent organic anion transporter (SOAT; SLC10A6). Experimental data supporting carrier function of P3, P4, and P5 is currently not available. However, as demonstrated for SOAT, not all members of the SLC10 family are bile acid transporters. SOAT specifically transports steroid sulfates such as oestrone-3-sulfate and dehydroepiandrosterone sulfate in a sodium-dependent manner, and is considered to play an important role for the cellular delivery of these prohormones in testes, placenta, adrenal gland and probably other peripheral tissues. ASBT and SOAT are the most homologous members of the SLC10 family, with high sequence similarity (∼70%) and almost identical gene structures. Phylogenetic analyses of the SLC10 family revealed that ASBT and SOAT genes emerged from a common ancestor gene. Structure-activity relationships of NTCP, ASBT and SOAT are discussed at the amino acid sequence level.Based on the high structural homology between ASBT and SOAT, pharmacological inhibitors of the ASBT, which are currently being tested in clinical trials for cholesterollowering therapy, should be evaluated for their crossreactivity with SOAT.

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“…Similar studies by Dawson [16] and others have also contributed to our understanding of the role of intestinal transporters in the so-called enterohepatic circulation of bile acids. Advances in the research of substrate-transporter interactions by many important groups, including several mentioned above in addition to those of Sugiyama [19] , Klaassen [20] and Petzinger [21] , has lead to Kramer [22] and others, including our own laboratory [23,24] to undertake the development of promising new drugs based on the substrate selectivity of plasma membrane transporters and the possibility of either blocking their function or targeting bile acid derivatives toward healthy liver tissue or toward tumours located in the enterohepatic circuit. Over the last few years the novel concept of bile acids as signalling molecules in several cell types has emerged.…”

Section: Introductionmentioning

confidence: 99%

How we have learned about the complexity of physiology, pathobiology and pharmacology of bile acids and biliary secretion

Marin¹

2008

WJG

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During the last decades the concept of bile secretion as merely a way to add detergent components to the intestinal mixture to facilitate fat digestion/absorption and to eliminate side products of heme metabolism has evolved considerably. In the series of mini-reviews that the World Journal of Gastroenterology is to publish in its section of "Highlight Topics", we will intend to give a brief but updated overview of our knowledge in this field. This introductory letter is intended to thank all scientists who have contributed to the development of this area of knowledge in gastroenterology.© 2008 The WJG Press. All rights reserved.Key words: Bile flow; Cholestasis; Hepatocyte; Liver; Transport Marin JJG. How we have learned about the complexity of physiology, pathobiology and pharmacology of bile acids and biliary secretion.

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Bile acid transport systems as pharmaceutical targets

Cited by 77 publications

References 67 publications

Influence of Charge and Steric Bulk in the C-24 Region on the Interaction of Bile Acids with Human Apical Sodium-Dependent Bile Acid Transporter

Influence of Charge and Steric Bulk in the C-24 Region on the Interaction of Bile Acids with Human Apical Sodium-Dependent Bile Acid Transporter

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

How we have learned about the complexity of physiology, pathobiology and pharmacology of bile acids and biliary secretion

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