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.
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April 2003
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Research Article|
April 15 2003
Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4)
Noam ZELCER;
Noam ZELCER
1
∗Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Glen REID;
Glen REID
1
∗Division of Molecular Biology and Center for 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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Peter WIELINGA;
Peter WIELINGA
∗Division of Molecular Biology and Center for 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 Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Ingrid van der HEIJDEN;
Ingrid van der HEIJDEN
∗Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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John D. SCHUETZ;
John D. SCHUETZ
†St. Jude Children's Research Hospital, 501 St. Jude Place, Memphis, TN 38105, U.S.A.
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Piet BORST
Piet BORST
2
∗Division of Molecular Biology and Center for 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:
December 05 2002
Revision Received:
January 08 2003
Accepted:
January 10 2003
Accepted Manuscript online:
January 10 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 371 (2): 361–367.
Article history
Received:
December 05 2002
Revision Received:
January 08 2003
Accepted:
January 10 2003
Accepted Manuscript online:
January 10 2003
Citation
Noam ZELCER, Glen REID, Peter WIELINGA, Annemieke KUIL, Ingrid van der HEIJDEN, John D. SCHUETZ, Piet BORST; Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem J 15 April 2003; 371 (2): 361–367. doi: https://doi.org/10.1042/bj20021886
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