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

被引:251
作者
Zelcer, N
Reid, G
Wielinga, P
Kuil, A
Van Der Heijden, I
Schuetz, JD
Borst, P
机构
[1] Netherlands Canc Inst, Div Mol Biol, NL-1066 CX Amsterdam, Netherlands
[2] Netherlands Canc Inst, Ctr Biomed Genet, NL-1066 CX Amsterdam, Netherlands
[3] St Jude Childrens Res Hosp, Memphis, TN 38105 USA
关键词
adrenal gland; bile acid; cholestasis; dehydroepiandrosterone 3-sulphate (DHEAS); multidrug-resistance protein (MRP); steroid;
D O I
10.1042/BJ20021886
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 trans-port of DHEAS by MRP4 showed saturable kinetics with K-m and V-max values of 2 muM and 45 pmol/mg per min, respectively (at 27 degreesC). 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 muM and 73 pmol/mg per min, respectively (at 27 degreesC). 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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收藏
页码:361 / 367
页数:7
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