Many of the transporters involved in the transport of bile acids in the enterohepatic circulation have been characterized. The basolateral bile-acid transporter of ileocytes and cholangiocytes remains an exception. It has been suggested that rat multidrug resistance protein 3 (Mrp3) fulfills this function. Here we analyse bile-salt transport by human MRP3. Membrane vesicles from insect (Spodoptera frugiperda) cells expressing MRP3 show time-dependent uptake of glycocholate and taurocholate. Furthermore, sulphated bile salts were high-affinity competitive inhibitors of etoposide glucuronide transport by MRP3 (IC5010μM). Taurochenodeoxycholate, taurocholate and glycocholate inhibited transport at higher concentrations (IC50100, 250 and 500μM respectively). We used mouse fibroblast-like cell lines derived from mice with disrupted Mdr1a, Mdr1b and Mrp1 genes to generate transfectants that express the murine apical Na+-dependent bile-salt transporter (Asbt) and MRP3. Uptake of glycocholate by these cells is Na+-dependent, with a Km and Vmax of 29±7μM and 660±63pmol/min per mg of protein respectively and is inhibited by several organic-aniontransport inhibitors. Expression of MRP3 in these cells limits the accumulation of glycocholate and increases the efflux from cells preloaded with taurocholate or glycocholate. In conclusion, we find that MRP3 transports both taurocholate and glycocholate, albeit with low affinity, in contrast with the high-affinity transport by rat Mrp3. Our results suggest that MRP3 is unlikely to be the principal basolateral bile-acid transporter of ileocytes and cholangiocytes, but that it may have a role in the removal of bile acids from the liver in cholestasis.
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January 2003
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Research Article|
January 01 2003
Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal Na+-dependent bile-acid transporter
Noam ZELCER;
Noam ZELCER
Division of Molecular Biology and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Tohru SAEKI;
Tohru SAEKI
1
Division of Molecular Biology and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Ilse BOT;
Ilse BOT
Division of Molecular Biology and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Annemieke KUIL;
Annemieke KUIL
Division of Molecular Biology and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Piet BORST
Piet BORST
2
Division of Molecular Biology and Centre of Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
2To whom correspondence should be addressed (e-mail p.borst@nki.nl).
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Publisher: Portland Press Ltd
Received:
July 09 2002
Revision Received:
September 04 2002
Accepted:
September 10 2002
Accepted Manuscript online:
September 10 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 369 (1): 23–30.
Article history
Received:
July 09 2002
Revision Received:
September 04 2002
Accepted:
September 10 2002
Accepted Manuscript online:
September 10 2002
Citation
Noam ZELCER, Tohru SAEKI, Ilse BOT, Annemieke KUIL, Piet BORST; Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal Na+-dependent bile-acid transporter. Biochem J 1 January 2003; 369 (1): 23–30. doi: https://doi.org/10.1042/bj20021081
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