Characterization and chemical modification of the Na+-dependent bile-acid transport system in brush-border membrane vesicles from rabbit ileum

Kramer, Werner; Nicol, Sven-Boris; Girbig, Frank; Gutjahr, Ulrike; Kowalewski, Simone; Fasold, H.

doi:10.1016/0005-2736(92)90278-t

Cited by 50 publications

(48 citation statements)

References 44 publications

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“…DTT) that are able to reduce S-S bridges Petzinger 1990, 1993). Similar results were obtained by Kramer and coworkers for the Na + -dependent bile acid uptake in the ileum from rabbit small intestine (Kramer et al 1992). From these studies, it was suggested that cysteine residues in the hitherto unidentified bile acid carrier proteins are important for substrate binding and translocation.…”

Section: Structure-activity Relationships Of the Slc10 Memberssupporting

confidence: 84%

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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Section: Structure-activity Relationships Of the Slc10 Memberssupporting

confidence: 84%

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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“…Since glycerol uptake was also inhibited by pCMBS, a thiol-modifying reagent, cysteine residues, which have a thiol group, seem to play an important role in the function of the carrier, as suggested for Na ϩ -dependent D-glucose transporter 1 (SGLT1) 8) and several other carriers. [9][10][11][12][13] At the higher concentration of 40 mM (Tables 1, 2), glycerol uptake was not altered by NaCl substitution or DNP, consistent with the suggestion that the contribution of passive transport is predominant.…”

Section: Time-courses Of Glycerol Uptakesupporting

confidence: 83%

Functional Characterization of the Carrier-Mediated Transport System for Glycerol in Everted Sacs of the Rat Small Intestine

Kato

Hayashi

Inoue

et al. 2004

Biological & Pharmaceutical Bulletin

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The mechanism of intestinal glycerol transport was investigated by using the in vitro everted sac method involving the rat small intestine. The uptake of glycerol into everted sacs was saturable with a Michaelis constant (K m ) of 0.77 mM and a maximum transport rate (J max ) of 11.5 nmol/min/100 mg wet tissue weight (wtw), suggesting the involvement of carrier-mediated transport, and was accompanied by unsaturable transport (passive transport) with a membrane permeability clearance (CL m,d ) of 4.9 m ml/min/100 mg wtw. The carrier-mediated uptake of glycerol was inhibited by the removal of Na ؉ and also by the addition of 2,4-dinitrophenol (DNP) and sodium azide (NaN 3 ), which are metabolic inhibitors. These results suggest that the carrier-mediated glycerol transport is Na ؉ -dependent and secondary active. Since glycerol uptake was also inhibited by p-chloromercuribenzene sulfonate (pCMBS), a thiol-modifying reagent, cysteine residues, which have a thiol group, seem to play an important role in the function of the carrier. We further found that glycerol uptake was selectively inhibited by glycerol-3-phosphate, chloramphenicol and voglibose, which are alcohol-related compounds analogous to glycerol. Several other compounds that did not inhibit glycerol uptake included D-glucose and 5-fluorouracil, which are known to be transported by specific carriers, and none of the selective inhibitors of glycerol uptake inhibited the uptake of D-glucose and 5-fluorouracil. Therefore, the carriers for these two compounds do not seem to be involved in glycerol uptake. It is likely that the carrier-mediated transport system involved in glycerol uptake is specific to glycerol and, possibly, some analogous compounds with hydroxyl groups. It would be interesting to examine the possibility that the carrier-mediated glycerol transport system might be involved in drug absorption and also that it might be used for oral drug delivery.

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“…Sodium-dependent bile acid uptake by ileocytes or hepatocytes has been reported to be sensitive to thiolgroup modiˆers [1][2][3] suggesting either involvement of cysteine in the function or location of cysteine close to the functional center of ISBT and NTCP. It is thus thought that cysteine could be a reasonable target for site-directed mutagenesis to investigate structurefunction relationships of these transporters.…”

mentioning

confidence: 99%

Effects of Cys Mutation on Taurocholic Acid Transport by Mouse Ileal and Hepatic Sodium-dependent Bile Acid Transporters

Saeki

Kuroda

Matsumoto

et al. 2002

Bioscience, Biotechnology, and Biochemistry

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All cysteines of mouse ileal and hepatic sodiumdependent bile acid transporters (Isbt and Ntcp, respectively) were individually replaced by alanine. Replacement of Cys 106 in Isbt and Cys 96 in Ntcp, which are located closely in alignment, decreased taurocholate uptake. Although Cys 51 in Isbt is conserved in Ntcp, the replacement spoiled Isbt only. Both similarity and diŠerence in the arrangement of functional sites are suggested.

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Characterization and chemical modification of the Na+-dependent bile-acid transport system in brush-border membrane vesicles from rabbit ileum

Cited by 50 publications

References 44 publications

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

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

Functional Characterization of the Carrier-Mediated Transport System for Glycerol in Everted Sacs of the Rat Small Intestine

Effects of Cys Mutation on Taurocholic Acid Transport by Mouse Ileal and Hepatic Sodium-dependent Bile Acid Transporters

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