Glutathione Stimulates Sulfated Estrogen Transport by Multidrug Resistance Protein 1

Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette (ABC) transporter that transports a range of hydrophobic xenobiotics, as well as relatively hydrophilic organic anion conjugates. The protein is present at high levels in testicular Leydig and Sertoli cells. Studies with knockout mice suggest that MRP1 may protect germ cells from exposure to some cytotoxic xenobiotics, but potential endobiotic substrates in this organ have not been identified. Previously, we have shown certain D-ring, but not A-ring, estrogen glucuronides can act as competitive inhibitors of MRP1 mediated transport, suggesting that they are potential substrates for the protein. In the case of 17μ-estradiol-17μ-d-glucuronide, this has been confirmed by direct transport studies. The Leydig cell is the major site of estrogen conjugation in the testis. However, the principal products of conjugation are A-ring estrogen sulfates, which are then effluxed from the cell by an unknown transporter. To determine whether MRP1/mrp1 could fulfill this function, we used membrane vesicles from MRP1-transfected HeLa cells to assess this possibility. We found that estradiol and estrone 3-sulfate alone were poor competitors of MRP1-mediated transport of the cysteinyl leukotriene, leukotriene C4. However, in the presence of reduced glutathione (GSH), their inhibitory potency was markedly increased. Direct transport studies using [3H]estrone 3-sulfate confirmed that the conjugated estrogen could be efficiently transported (Km = 0.73 μm,Vmax = 440 pmol mg−1protein min−1), but only in the presence of either GSH or the nonreducing alkyl derivative, S-methyl GSH. In contrast to previous studies using vincristine as a substrate, we detected no reciprocal increase in MRP1-mediated GSH transport. These results provide the first example of GSH-stimulated, MRP1-mediated transport of a potential endogenous substrate and expand the range of MRP1 substrates whose transport is stimulated by GSH to include certain hydrophilic conjugated endobiotics, in addition to previously identified hydrophobic xenobiotics. Multidrug resistance protein 1 (MRP1) is an ATP-binding cassette (ABC) transporter that transports a range of hydrophobic xenobiotics, as well as relatively hydrophilic organic anion conjugates. The protein is present at high levels in testicular Leydig and Sertoli cells. Studies with knockout mice suggest that MRP1 may protect germ cells from exposure to some cytotoxic xenobiotics, but potential endobiotic substrates in this organ have not been identified. Previously, we have shown certain D-ring, but not A-ring, estrogen glucuronides can act as competitive inhibitors of MRP1 mediated transport, suggesting that they are potential substrates for the protein. In the case of 17μ-estradiol-17μ-d-glucuronide, this has been confirmed by direct transport studies. The Leydig cell is the major site of estrogen conjugation in the testis. However, the principal products of conjugation are A-ring estrogen sulfates, which are then effluxed from the cell by an unknown transporter. To determine whether MRP1/mrp1 could fulfill this function, we used membrane vesicles from MRP1-transfected HeLa cells to assess this possibility. We found that estradiol and estrone 3-sulfate alone were poor competitors of MRP1-mediated transport of the cysteinyl leukotriene, leukotriene C4. However, in the presence of reduced glutathione (GSH), their inhibitory potency was markedly increased. Direct transport studies using [3H]estrone 3-sulfate confirmed that the conjugated estrogen could be efficiently transported (Km = 0.73 μm,Vmax = 440 pmol mg−1protein min−1), but only in the presence of either GSH or the nonreducing alkyl derivative, S-methyl GSH. In contrast to previous studies using vincristine as a substrate, we detected no reciprocal increase in MRP1-mediated GSH transport. These results provide the first example of GSH-stimulated, MRP1-mediated transport of a potential endogenous substrate and expand the range of MRP1 substrates whose transport is stimulated by GSH to include certain hydrophilic conjugated endobiotics, in addition to previously identified hydrophobic xenobiotics. multidrug resistance protein ATP-binding cassette leukotriene C4 17μ-estradiol-17μ-d-glucuronide 17μ-estradiol-3μ-d-glucuronide 16α,17μ-estriol 16μ-d-glucuronide reduced glutathione glutathione disulfide dithiothreitol monoclonal antibody estrogen sulfotransferase Dulbecco's modified Eagle's medium Human multidrug resistance protein (MRP)1 1 is a member of the ATP-binding cassette superfamily of transmembrane transporters, which was originally discovered by virtue of its association with drug resistance in tumor cells (1Cole S.P.C. Bhardwaj G. Gerlach J.H. Mackie J.E. Grant C.E. Almquist K.C. Stewart A.J. Kurz E.U. Duncan A.M. Deeley R.G. Science. 1992; 258: 1650-1654Crossref PubMed Scopus (3022) Google Scholar). It is now also known to be a primary active transporter of many conjugated organic anions (2Hipfner D.R. Deeley R.G. Cole S.P.C. Biochim. Biophys. Acta. 1999; 1461: 359-376Crossref PubMed Scopus (380) Google Scholar). The first substrate shown to be actively transported by MRP1 using inside-out membrane vesicles was the glutathione-conjugated leukotriene, LTC4 (3Leier I. Jedlitschky G. Buchholz U. Cole S.P.C. Deeley R.G. Keppler D. J. Biol. Chem. 1994; 269: 27807-27810Abstract Full Text PDF PubMed Google Scholar, 4Muller M. Meijer C. Zaman G.J. Borst P. Scheper R.J. Mulder N.H. de Vries E.G. Jansen P.L. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 13033-13037Crossref PubMed Scopus (640) Google Scholar). Since then, the spectrum of molecules transported by MRP1 has been extended to include many other GSH conjugates, as well as several glucuronate and sulfate conjugates (5Loe D.W. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. 1996; 271: 9683-9689Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar,6Jedlitschky G. Leier I. Buchholz U. Barnouin K. Kurz G. Keppler D. Cancer Res. 1996; 56: 988-994PubMed Google Scholar). A number of unconjugated amphiphilic anions have also been demonstrated to be substrates for MRP1 (7Keppler D. Cui Y. Konig J. Leier I. Nies A. Adv. Enzyme Regul. 1999; 39: 237-246Crossref PubMed Scopus (93) Google Scholar). However, using an in vitro membrane vesicle system unmodified forms of the natural product drugs to which MRP1 confers resistance are not directly transported by this protein, although primary active transport of some of them has been observed in the presence of reduced glutathione (GSH) (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, 9Renes J. de Vries E.G. Nienhuis E.F. Jansen P.L. Muller M. Br. J. Pharmacol. 1999; 126: 681-688Crossref PubMed Scopus (245) Google Scholar, 10Loe D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google Scholar, 11Ding G.Y. Shen T. Center M.S. Anticancer Res. 1999; 19: 3243-3248PubMed Google Scholar). Potential endogenous substrates of MRP1 that show a similar dependence on the presence of GSH have not been identified, although it has been observed that the intracellular levels of GSH are reduced in some drug selected and transfected cells overexpressing MRP1 in the absence of an exogenous substrate (12Cole S.P.C. Downes H.F. Mirski S.E. Clements D.J. Pharmacol. Google Scholar, D. Y. Deeley R.G. Cole S.P.C. Pharmacol. 1996; PubMed Scopus Google Scholar, G.J. J. J. Borst P. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). In GSH levels are in some mice G. A. Cancer Res. Google Scholar). this is to the of GSH in association with transport of endogenous has not been MRP1/mrp1 is in the Leydig cells of the and Zaman G.J. G. P. de M. Meijer Scheper R.J. J. 1996; Google Scholar, J. M. P. J.H. Scheper R.J. Borst P. J. 1998; PubMed Scopus Google as well as in Sertoli cells of the J. M. P. J.H. Scheper R.J. Borst P. J. 1998; PubMed Scopus Google Scholar). of cell have high levels of J. Google Scholar, 1994; PubMed Scopus Google and are to to in the by the of conjugates, which may be substrates for MRP1 or Studies of mice have that testicular the J. M. P. J.H. Scheper R.J. Borst P. J. 1998; PubMed Scopus Google Scholar). the of mice with the with no of and an number of germ cells. In the of the mice only a and In addition to a with to the relatively high levels of MRP1 in Leydig cells may also to protect the from the potential of estrogen conjugates. is in the and is for testicular function, as by studies of mice in which the estrogen or have been 1996; PubMed Scopus Google Scholar, D. J. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. 1998; PubMed Scopus Google Scholar). MRP1 has been shown to transport certain estrogen glucuronides but the major in Leydig cells is estrogen sulfate by estrogen sulfotransferase (5Loe D.W. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. 1996; 271: 9683-9689Abstract Full Text Full Text PDF PubMed Scopus (277) Google M. PubMed Scopus Google Scholar). as a sulfate this at the of the the hydrophilic estrogen The of estrogen 3-sulfate its the it has been that an is in its from the of estrogen sulfotransferase is in Leydig cells and is by of levels M. PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar). the of mice Leydig cell as well as and for The of MRP1 and estrogen sulfotransferase in the to whether estrogen were also substrates of We found that estrogen alone were poor substrates and for transport and of the high MRP1 substrate However, in the presence of their inhibitory potency was and direct transport of [3H]estrone sulfate could be These results provide the first of potential endogenous MRP1 substrates that on the presence of GSH for transport and the first of conjugated that this of sulfate and were from and were from glutathione disulfide and were from were with to at and with transport The monoclonal and have been previously D.R. Deeley R.G. Cole S.P.C. Cancer Res. 1994; Google Scholar, D.R. M. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The HeLa cells transfected with the the MRP1 and the HeLa cells transfected with have been previously C.E. G. D.R. Almquist K.C. Cole S.P.C. Deeley R.G. Cancer Res. 1994; Google Scholar). and were in medium with and in cells were in Dulbecco's modified Eagle's medium with membrane vesicles were as (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). cell were with and inhibitors and at The cells were then and by at was to 1 at for to cell To increase the of membrane the was with of transport and and The were in and at for 1 The was in and and by at for The membrane in transport and a for vesicle The membrane vesicles were then and at transport of the inside-out membrane vesicles was by a (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). In transport of membrane vesicles were used in a and at in the presence of and or in transport GSH was to 1 was by in transport and by that been at in transport of the been for the of to the in the absence of the membrane which was of the of LTC4 transport in the presence of estrogen LTC4 was at from to 1 and was as of [3H]estrone 3-sulfate was by as that the was and substrate was was or at the by in and the was were to and with membrane vesicles on for 1 were by of [3H]estrone 3-sulfate to the which was of the of estrone 3-sulfate transport in the absence or presence of estrone 3-sulfate was at from to and [3H]estrone 3-sulfate was as of GSH the membrane vesicles was also by as In a of membrane vesicle protein were at for in the presence of or and or in transport 3-sulfate or estradiol 3-sulfate was to several from to was used a for of transport D.W. Deeley R.G. Cole S.P.C. J. Pharmacol. Google and was to were by the of that to the in the presence of which was of the vesicles of protein in were with in the absence or presence of of estrone 3-sulfate or estradiol 3-sulfate at for and in were for at in a by in for a of vesicles were in and on a by The was in for and then in for at the was in with at for (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). The and MRP1 were previously C. J. Pharmacol. 1998; Google Scholar, S.P.C. K. D.W. Grant C.E. Deeley R.G. Cancer Res. 1994; Google and was with cells were and transfected on the with a of of and of or with of the cells were of the cells were then used for and the other for an sulfate was by addition of to a of to a of or transfected cells cells in of at and at by 1 of The cells were with in of and with of The was for and was as cells. The for of and were the as previously C. J. Pharmacol. 1998; Google Scholar, M. PubMed Scopus Google Scholar). To determine whether estrogen were potential substrates for we the of estrone and estradiol 3-sulfate to for transport of the high MRP1 substrate, estrogen sulfate alone was a of by vesicles from MRP1-transfected HeLa cells A and of the conjugated a increase in the of LTC4 transport was observed with of transport observed of the estrogen Previously, GSH has been shown to increase the inhibitory potency of some hydrophobic xenobiotics, which are poor competitive inhibitors of (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). However, no on the transport of conjugated has been We found that addition of 1 GSH markedly the inhibitory potency of the in a in from and to and for estrone sulfate and estradiol and To determine whether of LTC4 transport by the estrogen was of LTC4 transport in the absence or presence of estrogen sulfate were this estrone sulfate alone transport by estradiol sulfate stimulated transport by A However, in the presence of 1 estrone and estradiol sulfate as competitive inhibitors of transport, with of and and To determine whether of LTC4 transport was the of direct for we the of the conjugated to of MRP1 in membrane vesicles in the absence or presence of GSH. GSH alone with by at a of 1 of estrone or estradiol sulfate alone in but in of MRP1 either or The of MRP1 observed with of alone was not in the presence of 1 GSH and was in the presence of 1 GSH and estrone sulfate or estradiol sulfate the of GSH could be by a nonreducing GSH derivative, S-methyl GSH that of of MRP1 was not by a in the of the protein. To determine whether it was to MRP1-mediated transport of the estrogen sulfates, we the of [3H]estrone 3-sulfate using membrane The of of estrone 3-sulfate was pmol protein However, an increase in the of transport was observed 1 was present transport was for to at a of pmol protein with an of estrone In the presence of and 1 estrone 3-sulfate by the vesicles was pmol protein and estrone 3-sulfate transport was not detected with membrane vesicles from HeLa cells To that estrone sulfate was of transport the vesicle or we the of for transport, the of [3H]estrone sulfate with of to at To that transport was we used previously which have been shown to MRP1-mediated transport of LTC4 and other MRP1 substrates (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, 9Renes J. de Vries E.G. Nienhuis E.F. Jansen P.L. Muller M. Br. J. Pharmacol. 1999; 126: 681-688Crossref PubMed Scopus (245) Google Scholar, 10Loe D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google Scholar, D.R. M. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. Deeley R.G. Cole S.P.C. J. Pharmacol. Google Scholar, D.W. Stewart Deeley R.G. Cole S.P.C. Pharmacol. PubMed Scopus Google Scholar). observed for other MRP1 that in the first and and of MRP1 D.R. M. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and estrone sulfate transport by vesicles In which a in the of no inhibitory To determine the of estrone sulfate transport and the of of in the presence and absence of 1 GSH were at several of estrone 3-sulfate to to A of the an of 0.73 for estrone 3-sulfate and a of 440 pmol protein in the presence of and an of for estrone 3-sulfate and a of pmol protein in its The an of the the nonreducing S-methyl GSH was used in of 1 S-methyl GSH stimulated estrone 3-sulfate by membrane the of GSH In the and and glutathione no on estrone 3-sulfate transport. Since S-methyl GSH to be a of estrone sulfate transport of transport were as a of GSH or S-methyl GSH a similar dependence with of observed at a of However, the of estrone sulfate transport GSH was with GSH Since we found that estrogen MRP1-mediated transport in the presence of we whether the was also the of LTC4 to [3H]estrone 3-sulfate transport by MRP1 was in estrone 3-sulfate was by LTC4 in a of estrone 3-sulfate in the presence of that the was with an of studies of the GSH stimulated transport of the unconjugated vincristine a reciprocal of GSH transport by the suggesting a D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google Scholar). In was shown to markedly GSH transport by but in this case no transport of could be detected D.W. Deeley R.G. Cole S.P.C. J. Pharmacol. Google Scholar). we the of the estrogen to GSH transport using as a at GSH transport by In the first of of was used in and no of GSH transport was observed with either estrogen sulfate at and A was observed at but only with estrone sulfate In a of the of was to to a of the transport The of GSH transport by estrone sulfate was also detected at the of However, addition of estradiol sulfate the of transport, which was pmol at an of is to the of [3H]estrone sulfate in the presence of GSH. To determine whether the of GSH transport observed with vesicles from MRP1 transfected cells was we also the of GSH transport by vesicles from HeLa cells transfected with an and the of the MRP1 to transport. The of transport by vesicles was pmol and GSH transport by vesicles was by at To determine whether the MRP1-mediated estrogen sulfate transport observed in vitro with membrane vesicles could also be detected in cells. cells were transfected with alone and with The and of sulfate in the cells was then and with and with cells and estrogen and the of the products have been confirmed previously by high to be estrogen M. PubMed Scopus Google Scholar). an of in the cells with the of which estradiol not the were also from and transfected cells and directly for as previously C. J. Pharmacol. 1998; Google Scholar, M. PubMed Scopus Google Scholar). The of with from cells transfected with either the alone or with the MRP1 were in cells. with the MRP1 no on the levels of not shown in a cells transfected with the cells and with the MRP1 this to a that was only the was with an MRP1-mediated of estrogen from the cells. from studies with membrane vesicles and cells that estrone and estradiol are potential endogenous substrates for The in in which transport of [3H]estrone sulfate was directly using membrane vesicles from MRP1-transfected confirmed that the conjugated estrogen is an MRP1 substrate and also that a of GSH is for its transport. Direct of MRP1-mediated estrogen sulfate from cells was by the that the hydrophilic conjugates cells it was to the estradiol 3-sulfate by conjugation of was by using to in cells in the presence and absence of The results demonstrated that the presence of MRP1 of the estrogen by The for MRP1-mediated and estrone sulfate transport is with that for organic anion transporter or organic anion transporter transport of estrone sulfate T. M. Y. Y. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, T. Y. Y. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). However, have a MRP1/mrp1 and are in the of organic The relatively high of MRP1/mrp1 with in Leydig cells that MRP1 is to be in estrogen sulfate from the testis. Since estrone sulfate can be estrone by estrogen of estrone sulfate by an is to be for of estrogen levels in as the testis. Studies of mice with suggest that may also protect the from exposure to cytotoxic J. M. P. J.H. Scheper R.J. Borst P. J. 1998; PubMed Scopus Google Scholar). In the that is to sulfate as and the that MRP1 or could a in the of the conjugates of M. Y. Biophys. Res. PubMed Scopus Google Scholar). The of GSH for transport of the estrogen the first example of transport of a conjugated endogenous substrate by studies have shown that GSH is for the transport of some unmodified as vincristine (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar, 9Renes J. de Vries E.G. Nienhuis E.F. Jansen P.L. Muller M. Br. J. Pharmacol. 1999; 126: 681-688Crossref PubMed Scopus (245) Google Scholar, 10Loe D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google J. de Vries E.G. Nienhuis E.F. Jansen P.L. Muller M. Br. J. Pharmacol. 1999; 126: 681-688Crossref PubMed Scopus (245) Google G.Y. Shen T. Center M.S. Anticancer Res. 1999; 19: 3243-3248PubMed Google and D.W. Stewart Deeley R.G. Cole S.P.C. Pharmacol. PubMed Scopus Google and transport of conjugated with glucuronate K. T. Cancer 1999; PubMed Scopus Google Scholar). GSH has been to transport of in but the transporter has not been However, it to be a member of the superfamily M. G. G. J. PubMed Google Scholar). We have previously that MRP1 a site to which the hydrophobic and of its conjugated substrates (8Loe D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: 9675-9682Abstract Full Text Full Text PDF PubMed Scopus (545) Google Scholar). Studies of the transport of and the of GSH on the of vincristine to for LTC4 transport by that GSH not only the for the drug but also the with which it with the protein, as by an increase in its inhibitory These studies also that vincristine the of MRP1 for GSH D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google Scholar). The suggest that of either GSH or drug by MRP1 a in the protein that high of the substrate can In this the from the by Borst P. M. J. Biochim. Biophys. Acta. 1999; 1461: PubMed Scopus Google in which the protein is to have that has a relatively high for drug and for GSH and with high for GSH and for drug P. M. J. Biochim. Biophys. Acta. 1999; 1461: PubMed Scopus Google Scholar). this may the of drug and GSH to it is to GSH markedly the of drug to transport of high conjugated substrates as with the of a site for GSH with that GSH and S-methyl GSH of MRP1 in a in the suggesting that the for LTC4 a site to which GSH can studies of drug and transport by the multidrug resistance protein, suggest and high substrate A. Muller M. J. 19: PubMed Scopus Google Scholar). A which the by Cancer Biol. PubMed Scopus Google has been in which the transport of drug from a high intracellular site to a site on the of the is by the of at or the other the with to exposure of high or A. Muller M. J. 19: PubMed Scopus Google Scholar). The for is in on the that substrates that for transport at high transport of other at the and as the of the are relatively to that they are also not and may not M. Cui D.W. Grant C.E. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is no of primary the and of However, we have observed that of the estrogen in the absence of GSH LTC4 transport and as by they at the are also with the of present on However, the estrogen and LTC4 are relatively hydrophilic and the of transport is the observed that the are from the of the In the of in the absence of that in with substrate, they not the of In some the results we have in the present with estrone sulfate are similar to previous on the of GSH on of transport and of unmodified hydrophobic substrates as the that the is However, in the case of and it has not been to determine of transport in the absence of GSH. that GSH the for estrone sulfate from to 0.73 and from to 440 pmol In GSH also markedly the of estrone sulfate to of MRP1 with In the inhibitory potency of estrone sulfate was in the absence of that in for the conjugated estrogen a for either or studies with conjugated that could for LTC4 and transport by MRP1 conjugated with at the of the A-ring are poor inhibitors (5Loe D.W. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. 1996; 271: 9683-9689Abstract Full Text Full Text PDF PubMed Scopus (277) Google Scholar). These studies also that a in site of from the to on the markedly the for the protein, as by the the for and as inhibitors of transport. the that with to the site of of the be to with MRP1 as a substrate or competitive at the of the A-ring of or no on its to for transport, that the presence of the sulfate with the protein. In the conjugated 3-sulfate was an of transport with that were not conjugated at this of the is with the that of the A-ring, in the absence of with A of transport of estrone sulfate could be detected in the absence of suggesting that in the of a relatively substrate in which the sulfate not GSH from with the protein, either it to a site or it only with the GSH be with the of MRP1-mediated GSH transport by HeLa vesicles observed at high of estradiol However, the GSH has no on the inhibitory potency of other A-ring conjugates, as or on the transport of or estradiol not with to of transport by it to which conjugated or be by the presence of GSH. It has been observed that GSH levels are in some knockout mice G. A. Cancer Res. Google and in or transfected cells that MRP1 (12Cole S.P.C. Downes H.F. Mirski S.E. Clements D.J. Pharmacol. Google Scholar, D. Y. Deeley R.G. Cole S.P.C. Pharmacol. 1996; PubMed Scopus Google suggesting that MRP1 GSH either alone or with endogenous The of estrogen sulfate transport by GSH that be for vesicle transport studies have for of GSH with some G. A. Cancer Res. Google Scholar, 10Loe D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google Scholar). However, in other it has not been to a of GSH transport D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; 58: 5130-5136PubMed Google Scholar, 11Ding G.Y. Shen T. Center M.S. Anticancer Res. 1999; 19: 3243-3248PubMed Google Scholar). In we have shown that some as can markedly MRP1-mediated GSH transport with no transport of the D.W. Deeley R.G. Cole S.P.C. J. Pharmacol. Google Scholar). the GSH of estrone sulfate transport, we have not been to reciprocal of GSH transport by the conjugated increase in GSH by membrane vesicles could be detected in the presence of either estradiol or estrone sulfate a range of conjugated estrogen However, of the of used in studies is and at this the of estrone sulfate transport is pmol with a used in previous we were to a but of MRP1-mediated GSH transport in the absence of a of GSH transport was to the of estrone sulfate transport the the that the of GSH transport by the protein is the to of some However, this that the of substrates as the estrogen sulfates, in contrast to not the and transport of GSH. These studies expand the range of potential MRP1 substrates that GSH for transport to include certain hydrophilic as well as previously identified unconjugated We and for membrane vesicles for

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