Specific Inhibitors of Ileal Bile Acid Transport

Wess, Guenther; Kramer, Werner; Enhsen, Alfons; Glombik, Heiner; Baringhaus, Karl‐Heinz; Boeger, Georg; Urmann, Matthias; Bock, Klaus; Kleine, H.

doi:10.1021/jm00033a001

Cited by 45 publications

(37 citation statements)

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“…Therefore, it is desirable to develop a hypocholesterolemic agent that interrupts the reabsorption of bile acids, resulting in increased cholesterol catabolism at more reasonable therapeutic doses. Inhibitors of ASBT have been reported with IC 50 values in the micromolar range, and some of these have been shown to reduce total cholesterol in various animal models (20)(21)(22)(23)(24)(25). Development of potent agents that specifically inhibit intestinal uptake of bile acids by ASBT are likely to be more efficacious than the bile acid binding resins (26).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Bhat

Rapp

Beaudry

et al. 2003

Journal of Lipid Research

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Section: Discussionmentioning

confidence: 99%

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Bhat

Rapp

Beaudry

et al. 2003

Journal of Lipid Research

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“…Potent inhibitors of the ileal apical sodium bile acid transporter have been developed as potential therapies for hypercholesterolemia ( 248,(260)(261)(262). Because the same transporter is expressed in the kidney, these inhibitors could be used to block renal reclamation of bile acids and increase urinary bile acid output.…”

Section: Future Researchmentioning

confidence: 99%

Bile acid transporters

Dawson

Lan

Rao

2009

Journal of Lipid Research

582

456

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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

158

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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Specific Inhibitors of Ileal Bile Acid Transport

Cited by 45 publications

References 1 publication

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Inhibition of ileal bile acid transport and reduced atherosclerosis in apoE−/− mice by SC-435

Bile acid transporters

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

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