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

Noam Zelcer, Glen Reid, Pieter Wielinga, Annemieke Kuil, Ingrid van der Heijden, John D Schuetz, Piet Borst

Research output: Contribution to journalJournal articleResearchpeer-review


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-beta-D-glucuronide (E(2)17betaG), 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 E(2)17betaG. 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 K (m) and V (max) values of 2 microM and 45 pmol/mg per min, respectively (at 27 degrees 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 K (m) and V (max) values of 5 microM and 73 pmol/mg per min, respectively (at 27 degrees 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.
Original languageEnglish
JournalBiochemical Journal
Issue numberPt 2
Pages (from-to)361-367
Publication statusPublished - 2003
Externally publishedYes


  • Bile Acids and Salts
  • Dehydroepiandrosterone Sulfate
  • Drug Resistance, Multiple
  • Estradiol
  • Humans
  • Kinetics
  • Multidrug Resistance-Associated Proteins
  • Recombinant Proteins
  • Steroids
  • Substrate Specificity
  • Transfection
  • ABCC4 protein, human
  • 4TI98Z838E Estradiol
  • 57B09Q7FJR Dehydroepiandrosterone Sulfate

Fingerprint Dive into the research topics of 'Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4).'. Together they form a unique fingerprint.

Cite this