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