CoChat
Sign Up
Cited by 281

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4)

ZELCER, Noam, REID, Glen, WIELINGA, Peter, KUIL, Annemieke, van der HEIJDEN, Ingrid, SCHUETZ, John D., BORST, Piet·2003·Biochemical Journal
DOI 10.1042/bj20021886
Open this paper in CoChat — free account

Abstract

Human multidrug-resistance protein (MRP) 4 transports cyclic nucleotides and when overproduced in mammalian cells mediates resistance to some nucleoside analogues. Recently, it has been shown that Mrp4 is induced in the livers of Fxr(-/-) mice, which have increased levels of serum bile acids. Since MRP4, like MRP1–3, also mediates transport of a model steroid conjugate substrate, oestradiol 17-β-d-glucuronide (E217βG), we tested whether MRP4 may be involved in the transport of steroid and bile acid conjugates. Bile salts, especially sulphated derivatives, and cholestatic oestrogens inhibited the MRP4-mediated transport of E217βG. Inhibition by oestradiol 3,17-disulphate and taurolithocholate 3-sulphate was competitive, suggesting that these compounds are MRP4 substrates. Furthermore, we found that MRP4 transports dehydroepiandrosterone 3-sulphate (DHEAS), the most abundant circulating steroid in humans, which is made in the adrenal gland. The ATP-dependent transport of DHEAS by MRP4 showed saturable kinetics with Km and Vmax values of 2μM and 45pmol/mg per min, respectively (at 27°C). We further studied the possible involvement of other members of the MRP family of transporters in the transport of DHEAS. We found that MRP1 transports DHEAS in a glutathione-dependent manner and exhibits Km and Vmax values of 5μM and 73pmol/mg per min, respectively (at 27°C). No transport of DHEAS was observed in membrane vesicles containing MRP2 or MRP3. Our findings suggest a physiological role for MRP1 and MRP4 in DHEAS transport and an involvement of MRP4 in transport of conjugated steroids and bile acids.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1042/bj20021886

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • ABCC4 protein is highly conserved between humans and mice, with 100% sequence identity.

    “Notably, ABCC4 protein is highly conserved between humans and mice, with 100% sequence identity, suggesting functional conservation across species39,41,42.”

    From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [39]

    The available copy shows a “Full Text” notice pointing to a PDF and selected references, but no passage comparing human and mouse ABCC4 protein sequences. Searches for “100%,” “sequence identity,” and human–mouse conservation found no support for the claimed 100% identity; the decisive text may be in the unavailable PDF. (LLM, conf=0.73)

    Experimental — accuracy not yet measured

  • ABCC4 is expressed in various tissues, including liver, brain, kidney, colon, lung and placenta.

    “ABCC4, the top-ranking putative negative regulator of LDLR identified in our screens, is expressed in various tissues, including the liver, brain, kidney, colon, lung and placenta38,39.”

    From ABCC4 impairs the clearance of plasma LDL cholesterol through suppressing LDLR expression in the liver (2025) · cites this paper as [39]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Flagged first, then by citations

Research works printed but not linked: 47

  1. Bakos E., Evers R., Sinkó E., Váradi A., Borst P., Sarkadi B. Interactions of the human multidrug resistance proteins MRP1 and MRP2 with organic anions. Mol Pharmacol. 2000 Apr;57(4):760–768. doi: 10.1124/mol.57.4.760. [DOI] [PubMed] [Google Scholar] · DOI
  2. Borst P., Elferink R. Oude. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2001 Nov 9;71:537–592. doi: 10.1146/annurev.biochem.71.102301.093055. [DOI] [PubMed] [Google Scholar] · DOI
  3. Borst P., Evers R., Kool M., Wijnholds J. A family of drug transporters: the multidrug resistance-associated proteins. J Natl Cancer Inst. 2000 Aug 16;92(16):1295–1302. doi: 10.1093/jnci/92.16.1295. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  4. Chen Z. S., Lee K., Kruh G. D. Transport of cyclic nucleotides and estradiol 17-beta-D-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. J Biol Chem. 2001 Jul 10;276(36):33747–33754. doi: 10.1074/jbc.M104833200. [DOI] [PubMed] [Google Scholar] · DOI
  5. Chen Zhe-Sheng, Lee Kun, Walther Susan, Raftogianis Rebecca Blanchard, Kuwano Michihiko, Zeng Hao, Kruh Gary D. Analysis of methotrexate and folate transport by multidrug resistance protein 4 (ABCC4): MRP4 is a component of the methotrexate efflux system. Cancer Res. 2002 Jun 1;62(11):3144–3150. [PubMed] [Google Scholar]
  6. Cui Y., König J., Keppler D. Vectorial transport by double-transfected cells expressing the human uptake transporter SLC21A8 and the apical export pump ABCC2. Mol Pharmacol. 2001 Nov;60(5):934–943. doi: 10.1124/mol.60.5.934. [DOI] [PubMed] [Google Scholar] · DOI
  7. Dean M., Rzhetsky A., Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 2001 Jul;11(7):1156–1166. doi: 10.1101/gr.184901. [DOI] [PubMed] [Google Scholar] · DOI
  8. Donner M. G., Keppler D. Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology. 2001 Aug;34(2):351–359. doi: 10.1053/jhep.2001.26213. [DOI] [PubMed] [Google Scholar] · DOI
  9. Eckhardt U., Schroeder A., Stieger B., Höchli M., Landmann L., Tynes R., Meier P. J., Hagenbuch B. Polyspecific substrate uptake by the hepatic organic anion transporter Oatp1 in stably transfected CHO cells. Am J Physiol. 1999 Apr;276(4 Pt 1):G1037–G1042. doi: 10.1152/ajpgi.1999.276.4.G1037. [DOI] [PubMed] [Google Scholar] · DOI
  10. Evers R., de Haas M., Sparidans R., Beijnen J., Wielinga P. R., Lankelma J., Borst P. Vinblastine and sulfinpyrazone export by the multidrug resistance protein MRP2 is associated with glutathione export. Br J Cancer. 2000 Aug;83(3):375–383. doi: 10.1054/bjoc.2000.1262. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  11. Flens M. J., Zaman G. J., van der Valk P., Izquierdo M. A., Schroeijers A. B., Scheffer G. L., van der Groep P., de Haas M., Meijer C. J., Scheper R. J. Tissue distribution of the multidrug resistance protein. Am J Pathol. 1996 Apr;148(4):1237–1247. [PMC free article] [PubMed] [Google Scholar]
  12. Gurnell E. M., Chatterjee V. K. Dehydroepiandrosterone replacement therapy. Eur J Endocrinol. 2001 Aug;145(2):103–106. doi: 10.1530/eje.0.1450103. [DOI] [PubMed] [Google Scholar] · DOI
  13. Higgins C. F. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. doi: 10.1146/annurev.cb.08.110192.000435. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  14. Hsiang B., Zhu Y., Wang Z., Wu Y., Sasseville V., Yang W. P., Kirchgessner T. G. A novel human hepatic organic anion transporting polypeptide (OATP2). Identification of a liver-specific human organic anion transporting polypeptide and identification of rat and human hydroxymethylglutaryl-CoA reductase inhibitor transporters. J Biol Chem. 1999 Dec 24;274(52):37161–37168. doi: 10.1074/jbc.274.52.37161. [DOI] [PubMed] [Google Scholar] · DOI
  15. Ito K., Suzuki H., Sugiyama Y. Single amino acid substitution of rat MRP2 results in acquired transport activity for taurocholate. Am J Physiol Gastrointest Liver Physiol. 2001 Oct;281(4):G1034–G1043. doi: 10.1152/ajpgi.2001.281.4.G1034. [DOI] [PubMed] [Google Scholar] · DOI
  16. Jedlitschky G., Burchell B., Keppler D. The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. J Biol Chem. 2000 Sep 29;275(39):30069–30074. doi: 10.1074/jbc.M005463200. [DOI] [PubMed] [Google Scholar] · DOI
  17. Kroboth P. D., Salek F. S., Pittenger A. L., Fabian T. J., Frye R. F. DHEA and DHEA-S: a review. J Clin Pharmacol. 1999 Apr;39(4):327–348. doi: 10.1177/00912709922007903. [DOI] [PubMed] [Google Scholar] · DOI
  18. Kullak-Ublick G. A., Fisch T., Oswald M., Hagenbuch B., Meier P. J., Beuers U., Paumgartner G. Dehydroepiandrosterone sulfate (DHEAS): identification of a carrier protein in human liver and brain. FEBS Lett. 1998 Mar 13;424(3):173–176. doi: 10.1016/s0014-5793(98)00168-9. [DOI] [PubMed] [Google Scholar] · DOI
  19. König J., Nies A. T., Cui Y., Leier I., Keppler D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta. 1999 Dec 6;1461(2):377–394. doi: 10.1016/s0005-2736(99)00169-8. [DOI] [PubMed] [Google Scholar] · DOI
  20. Laatikaninen T., Peltokallio P., Vihko R. Steroid sulfates in human bile. Steroids. 1968 Sep;12(3):407–421. doi: 10.1016/0039-128x(68)90031-7. [DOI] [PubMed] [Google Scholar] · DOI
  21. Lai Liqi, Tan Theresa M. C. Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)-mediated efflux of cAMP and resistance to purine analogues. Biochem J. 2002 Feb 1;361(Pt 3):497–503. doi: 10.1042/0264-6021:3610497. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  22. Lee K., Belinsky M. G., Bell D. W., Testa J. R., Kruh G. D. Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Res. 1998 Jul 1;58(13):2741–2747. [PubMed] [Google Scholar]
  23. Lee K., Klein-Szanto A. J., Kruh G. D. Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells. J Natl Cancer Inst. 2000 Dec 6;92(23):1934–1940. doi: 10.1093/jnci/92.23.1934. [DOI] [PubMed] [Google Scholar] · DOI
  24. Leslie E. M., Ito K., Upadhyaya P., Hecht S. S., Deeley R. G., Cole S. P. Transport of the beta -O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1). Requirement for glutathione or a non-sulfur-containing analog. J Biol Chem. 2001 May 25;276(30):27846–27854. doi: 10.1074/jbc.M102453200. [DOI] [PubMed] [Google Scholar] · DOI
  25. Li L., Meier P. J., Ballatori N. Oatp2 mediates bidirectional organic solute transport: a role for intracellular glutathione. Mol Pharmacol. 2000 Aug;58(2):335–340. doi: 10.1124/mol.58.2.335. [DOI] [PubMed] [Google Scholar] · DOI
  26. Loe D. W., Deeley R. G., Cole S. P. Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res. 1998 Nov 15;58(22):5130–5136. [PubMed] [Google Scholar]
  27. Meier Peter J., Stieger B. Bile salt transporters. Annu Rev Physiol. 2002;64:635–661. doi: 10.1146/annurev.physiol.64.082201.100300. [DOI] [PubMed] [Google Scholar] · DOI
  28. Ogawa K., Suzuki H., Hirohashi T., Ishikawa T., Meier P. J., Hirose K., Akizawa T., Yoshioka M., Sugiyama Y. Characterization of inducible nature of MRP3 in rat liver. Am J Physiol Gastrointest Liver Physiol. 2000 Mar;278(3):G438–G446. doi: 10.1152/ajpgi.2000.278.3.G438. [DOI] [PubMed] [Google Scholar] · DOI
  29. Orentreich N., Brind J. L., Rizer R. L., Vogelman J. H. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab. 1984 Sep;59(3):551–555. doi: 10.1210/jcem-59-3-551. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  30. Qian Y. M., Song W. C., Cui H., Cole S. P., Deeley R. G. Glutathione stimulates sulfated estrogen transport by multidrug resistance protein 1. J Biol Chem. 2000 Dec 1;276(9):6404–6411. doi: 10.1074/jbc.M008251200. [DOI] [PubMed] [Google Scholar] · DOI
  31. Radominska A., Comer K. A., Zimniak P., Falany J., Iscan M., Falany C. N. Human liver steroid sulphotransferase sulphates bile acids. Biochem J. 1990 Dec 15;272(3):597–604. doi: 10.1042/bj2720597. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  32. Renes Johan, de Vries Elisabeth G. E., Jansen Peter L. M., Müller Michael. The (patho)physiological functions of the MRP family. Drug Resist Updat. 2000 Oct;3(5):289–302. doi: 10.1054/drup.2000.0156. [DOI] [PubMed] [Google Scholar] · DOI
  33. Sakamoto H., Hara H., Hirano K., Adachi T. Enhancement of glucuronosyl etoposide transport by glutathione in multidrug resistance-associated protein-overexpressing cells. Cancer Lett. 1999 Jan 8;135(1):113–119. doi: 10.1016/s0304-3835(98)00285-7. [DOI] [PubMed] [Google Scholar] · DOI
  34. Sasaki Makoto, Suzuki Hiroshi, Ito Kousei, Abe Takaaki, Sugiyama Yuichi. Transcellular transport of organic anions across a double-transfected Madin-Darby canine kidney II cell monolayer expressing both human organic anion-transporting polypeptide (OATP2/SLC21A6) and Multidrug resistance-associated protein 2 (MRP2/ABCC2). J Biol Chem. 2001 Dec 17;277(8):6497–6503. doi: 10.1074/jbc.M109081200. [DOI] [PubMed] [Google Scholar] · DOI
  35. Scheffer George L., Kool Marcel, de Haas Marcel, de Vree J. Marleen L., Pijnenborg Adriana C. L. M., Bosman Diederik K., Elferink Ronald P. J. Oude, van der Valk Paul, Borst Piet, Scheper Rik J. Tissue distribution and induction of human multidrug resistant protein 3. Lab Invest. 2002 Feb;82(2):193–201. doi: 10.1038/labinvest.3780411. [DOI] [PubMed] [Google Scholar] · DOI
  36. Schuetz E. G., Strom S., Yasuda K., Lecureur V., Assem M., Brimer C., Lamba J., Kim R. B., Ramachandran V., Komoroski B. J. Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. J Biol Chem. 2001 Aug 16;276(42):39411–39418. doi: 10.1074/jbc.M106340200. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  37. Schuetz J. D., Connelly M. C., Sun D., Paibir S. G., Flynn P. M., Srinivas R. V., Kumar A., Fridland A. MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 1999 Sep;5(9):1048–1051. doi: 10.1038/12487. [DOI] [PubMed] [Google Scholar] · DOI
  38. Sinal C. J., Tohkin M., Miyata M., Ward J. M., Lambert G., Gonzalez F. J. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000 Sep 15;102(6):731–744. doi: 10.1016/s0092-8674(00)00062-3. [DOI] [PubMed] [Google Scholar] · DOI · Paper page
  39. Song C. S., Echchgadda I., Baek B. S., Ahn S. C., Oh T., Roy A. K., Chatterjee B. Dehydroepiandrosterone sulfotransferase gene induction by bile acid activated farnesoid X receptor. J Biol Chem. 2001 Aug 30;276(45):42549–42556. doi: 10.1074/jbc.M107557200. [DOI] [PubMed] [Google Scholar] · DOI
  40. Wielinga P. R., Reid G., Challa E. E., van der Heijden I., van Deemter L., de Haas M., Mol C., Kuil A. J., Groeneveld E., Schuetz J. D. Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol. 2002 Dec;62(6):1321–1331. doi: 10.1124/mol.62.6.1321. [DOI] [PubMed] [Google Scholar] · DOI
  41. Wijnholds J., Mol C. A., van Deemter L., de Haas M., Scheffer G. L., Baas F., Beijnen J. H., Scheper R. J., Hatse S., De Clercq E. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7476–7481. doi: 10.1073/pnas.120159197. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  42. Yen S. S. Dehydroepiandrosterone sulfate and longevity: new clues for an old friend. Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8167–8169. doi: 10.1073/pnas.161278698. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  43. Zelcer N., Saeki T., Reid G., Beijnen J. H., Borst P. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001 Dec 7;276(49):46400–46407. doi: 10.1074/jbc.M107041200. [DOI] [PubMed] [Google Scholar] · DOI
  44. Zelcer Noam, Saeki Tohru, Bot Ilse, Kuil Annemieke, Borst Piet. Transport of bile acids in multidrug-resistance-protein 3-overexpressing cells co-transfected with the ileal Na+-dependent bile-acid transporter. Biochem J. 2003 Jan 1;369(Pt 1):23–30. doi: 10.1042/BJ20021081. [DOI] [PMC free article] [PubMed] [Google Scholar] · DOI
  45. Zhang D. W., Cole S. P., Deeley R. G. Identification of an amino acid residue in multidrug resistance protein 1 critical for conferring resistance to anthracyclines. J Biol Chem. 2001 Jan 23;276(16):13231–13239. doi: 10.1074/jbc.M010008200. [DOI] [PubMed] [Google Scholar] · DOI
  46. van Aubel Rémon A. M. H., Smeets Pascal H. E., Peters Janny G. P., Bindels René J. M., Russel Frans G. M. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002 Mar;13(3):595–603. doi: 10.1681/ASN.V133595. [DOI] [PubMed] [Google Scholar] · DOI
  47. van Montfoort Jessica E., Schmid Thomas E., Adler Ilse-Dore, Meier Peter J., Hagenbuch Bruno. Functional characterization of the mouse organic-anion-transporting polypeptide 2. Biochim Biophys Acta. 2002 Aug 19;1564(1):183–188. doi: 10.1016/s0005-2736(02)00445-5. [DOI] [PubMed] [Google Scholar] · DOI

Cited by

Sorted by citations

Metadata

Authors
ZELCER, N., REID, G., WIELINGA, P., KUIL, A., van der HEIJDEN, I., SCHUETZ, J. D., & BORST, P.
Venue
Biochemical Journal
Publisher
Portland Press Ltd.
Published
2003-04-15
Volume
371
Issue
2
Pages
361-367
ISSN
  • 0264-6021
  • 1470-8728
DOI
10.1042/bj20021886
Cited by
281
References
1
Language
en

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review