scholarly journals Enhanced Expression of the Human Multidrug Resistance Protein 3 by Bile Salt in Human Enterocytes

2001 ◽  
Vol 276 (50) ◽  
pp. 46822-46829 ◽  
Author(s):  
Akihiko Inokuchi ◽  
Eiji Hinoshita ◽  
Yukihide Iwamoto ◽  
Kimitoshi Kohno ◽  
Michihiko Kuwano ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Bile Salt ◽  
Bile Salts ◽  
Promoter Activity ◽  
Enterohepatic Circulation ◽  
Basolateral Membrane ◽  
Mrna Levels ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 3 ◽  
Resistance Protein

The enterohepatic circulation is essential for the maintenance of bile acids and cholesterol homeostasis. The ileal bile acid transporter on the apical membrane of enterocytes mediates the intestinal uptake of bile salts, but little is known about the bile salt secretion from the basolateral membrane of enterocytes into blood. In the basolateral membrane of enterocytes, an ATP-binding cassette transporter, multidrug resistance protein 3 (MRP3), is expressed, which has the ability to transport bile salts. We hypothesized that MRP3 might play a role in the enterohepatic circulation of bile salts by transporting them from enterocytes into circulating blood through the up-regulation ofMRP3expression, so we investigated the transcriptional control ofMRP3in response to bile salts.MRP3mRNA levels were increased about 3-fold in human colon cells by chenodeoxycholic acid (CDCA), in a dose- and time-dependent manner. In the promoter assay, the promoter activity ofMRP3was increased about 3-fold over the basal promoter activity when treated with CDCA, and the putative bile salt-responsive elements exist in the region −229/−138 including two α-1 fetoprotein transcription factor (FTF)-like elements. Constructs with a specific mutation in the consensus sequence of FTF elements showed no increase in basal transcriptional activity following CDCA treatment. In electrophoretic mobility shift assay with nuclear extracts, specific binding of FTF to FTF-like elements was observed when treated with CDCA. The expression ofFTFmRNA levels were also markedly enhanced in response to CDCA, and overexpression of FTF specifically activated theMRP3promoter activity about 4-fold over the basal promoter activity. FTF thus might play a key role not only in the bile salt synthetic pathway in hepatocytes but also in the bile salt excretion pathway in enterocytes through the regulation ofMRP3expression. MRP3 may contribute as a plausible bile salt-exporting transporter to the enterohepatic circulation of bile salts.

scholarly journals Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal Na+-dependent bile-acid transporter

2003 ◽  
Vol 369 (1) ◽  
pp. 23-30 ◽  
Author(s):  
Noam ZELCER ◽  
Tohru SAEKI ◽  
Ilse BOT ◽  
Annemieke KUIL ◽  
Piet BORST
Keyword(s):  
Multidrug Resistance ◽  
Bile Acid ◽  
Bile Salt ◽  
Bile Acids ◽  
Multidrug Resistance Protein ◽  
High Affinity ◽  
Multidrug Resistance Protein 3 ◽  
Bile Acid Transporter ◽  
Resistance Protein ◽  
Acid Transporter

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 (IC5010μM). Taurochenodeoxycholate, taurocholate and glycocholate inhibited transport at higher concentrations (IC50100, 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.

scholarly journals Involvement of the Multidrug Resistance Protein 3 in Drug Sensitivity and Its Expression in Human Glioma

2001 ◽  
Vol 92 (2) ◽  
pp. 211-219 ◽  
Author(s):  
Sei Haga ◽  
Eiji Hinoshita ◽  
Kiyonobu Ikezaki ◽  
Masashi Fukui ◽  
George L. Scheffer ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Drug Sensitivity ◽  
Multidrug Resistance Protein ◽  
Human Glioma ◽  
Multidrug Resistance Protein 3 ◽  
Resistance Protein

Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver

2003 ◽  
Vol 304 (2) ◽  
pp. 524-530 ◽  
Author(s):  
Monika Hitzl ◽  
Kathrin Klein ◽  
Ulrich M. Zanger ◽  
Peter Fritz ◽  
Andreas K. Nüssler ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Human Liver ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 3 ◽  
Resistance Protein

Multidrug resistance protein 3 loss promotes tumor formation by inducing senescence escape

Oncogene ◽  
2015 ◽  
Vol 35 (12) ◽  
pp. 1596-1601 ◽  
Author(s):  
C Wiel ◽  
B Gras ◽  
D Vindrieux ◽  
M Warnier ◽  
D Gitenay ◽  
...  
Keyword(s):  
Multidrug Resistance ◽  
Tumor Formation ◽  
Multidrug Resistance Protein ◽  
Multidrug Resistance Protein 3 ◽  
Resistance Protein

The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane

1999 ◽  
Vol 112 (3) ◽  
pp. 415-422 ◽  
Author(s):  
R.J. Raggers ◽  
A. van Helvoort ◽  
R. Evers ◽  
G. van Meer
Keyword(s):  
Plasma Membrane ◽  
Multidrug Resistance ◽  
Abc Transporter ◽  
Basolateral Membrane ◽  
Brefeldin A ◽  
Apical Plasma Membrane ◽  
Multidrug Resistance Protein ◽  
Vesicular Traffic ◽  
P Glycoprotein ◽  
Resistance Protein

Recently, we have provided evidence that the ABC-transporter MDR1 P-glycoprotein translocates analogs of various lipid classes across the apical plasma membrane of polarized LLC-PK1 cells transfected with MDR1 cDNA. Here, we show that expression of the basolateral ABC-transporter MRP1 (the multidrug resistance protein) induced lipid transport to the exoplasmic leaflet of the basolateral plasma membrane of LLC-PK1 cells at 15 degreesC. C6-NBD-glucosylceramide synthesized on the cytosolic side of the Golgi complex, but not C6-NBD-sphingomyelin synthesized in the Golgi lumen, became accessible to depletion by BSA in the basal culture medium. This suggests the absence of vesicular traffic and direct translocation of C6-NBD-glucosylceramide by MRP1 across the basolateral membrane. In line with this, transport of the lipid to the exoplasmic leaflet depended on the intracellular glutathione concentration and was inhibited by the MRP1-inhibitors sulfinpyrazone and indomethacin, but not by the MDR1 P-glycoprotein inhibitor PSC 833. In contrast to the broad substrate specificity of the MDR1 P-glycoprotein, MRP1 selectively transported C6-NBD-glucosylceramide and C6-NBD-sphingomyelin, the latter only when it was released from the Golgi lumen by brefeldin A. This shows the specific nature of the lipid translocation. We conclude that the transport activity of MDR1 P-glycoprotein and MRP1 must be taken into account in studies on the transport of lipids to the cell surface.

Substitution of Trp1242 of TM17 alters substrate specificity of human multidrug resistance protein 3

2003 ◽  
Vol 284 (2) ◽  
pp. G280-G289 ◽  
Author(s):  
Curtis J. Oleschuk ◽  
Roger G. Deeley ◽  
Susan P. C. Cole
Keyword(s):  
Multidrug Resistance ◽  
Substrate Specificity ◽  
Multidrug Resistance Protein ◽  
Wild Type ◽  
Multidrug Resistance Protein 3 ◽  
17Β Estradiol ◽  
Resistance Protein ◽  
Estradiol 17Β ◽  
Taurocholate Transport

Multidrug resistance protein 3 (MRP3) is an ATP-dependent transporter of 17β-estradiol 17β(d-glucuronide) (E217βG), leukotriene C4 (LTC4), methotrexate, and the bile salts taurocholate and glycocholate. In the present study, the role of a highly conserved Trp residue at position 1242 on MRP3 transport function was examined by expressing wild-type MRP3 and Ala-, Cys-, Phe-, Tyr-, and Pro-substituted mutants in human embryonic kidney 293T cells. Four MRP3-Trp1242 mutants showed significantly increased E217βG uptake, whereas transport by the Pro mutant was undetectable. Similarly, the Pro mutant did not transport LTC4. By comparison, LTC4transport by the Ala, Cys, Phe, and Tyr mutants was reduced by ∼35%. The Ala, Cys, Phe, and Tyr mutants all showed greatly reduced methotrexate and leucovorin transport, except the Tyr mutant, which transported leucovorin at levels comparable with wild-type MRP3. In contrast, the MRP3-Trp1242 substitutions did not significantly affect taurocholate transport or taurocholate and glycocholate inhibition of E217βG uptake. Thus Trp1242 substitutions markedly alter the substrate specificity of MRP3 but leave bile salt binding and transport intact.

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