Arsenic Transport by the Human Multidrug Resistance Protein 1 (MRP1/ABCC1)

Inorganic arsenic is an established human carcinogen, but its metabolism is incompletely defined. The ATP binding cassette protein, multidrug resistance protein (MRP1/ABCC1), transports conjugated organic anions (e.g. leukotriene C4) and also co-transports certain unmodified xenobiotics (e.g. vincristine) with glutathione (GSH). MRP1 also confers resistance to arsenic in association with GSH; however, the mechanism and the species of arsenic transported are unknown. Using membrane vesicles prepared from the MRP1-overexpressing lung cancer cell line, H69AR, we found that MRP1 transports arsenite (AsIII) only in the presence of GSH but does not transport arsenate (AsV) (with or without GSH). The non-reducing GSH analogs l-γ-glutamyl-l-α-aminobutyryl glycine and S-methyl GSH did not support AsIII transport, indicating that the free thiol group of GSH is required. GSH-dependent transport of AsIII was 2-fold higher at pH 6.5-7 than at a more basic pH, consistent with the formation and transport of the acid-stable arsenic triglutathione (As(GS)3). Immunoblot analysis of H69AR vesicles revealed the unexpected membrane association of GSH S-transferase P1-1 (GSTP1-1). Membrane vesicles from an MRP1-transfected HeLa cell line lacking membrane-associated GSTP1-1 did not transport AsIII even in the presence of GSH but did transport synthetic As(GS)3. The addition of exogenous GSTP1-1 to HeLa-MRP1 vesicles resulted in GSH-dependent AsIII transport. The apparent Km of As(GS)3 for MRP1 was 0.32 μm, suggesting a remarkably high relative affinity. As(GS)3 transport by MRP1 was osmotically sensitive and was inhibited by several conjugated organic anions (MRP1 substrates) as well as the metalloid antimonite (Ki 2.8 μm). As(GS)3 transport experiments using MRP1 mutants with substrate specificities differing from wild-type MRP1 suggested a commonality in the substrate binding pockets of As(GS)3 and leukotriene C4. Finally, human MRP2 also transported As(GS)3. In conclusion, MRP1 transports inorganic arsenic as a tri-GSH conjugate, and GSTP1-1 may have a synergistic role in this process. Inorganic arsenic is an established human carcinogen, but its metabolism is incompletely defined. The ATP binding cassette protein, multidrug resistance protein (MRP1/ABCC1), transports conjugated organic anions (e.g. leukotriene C4) and also co-transports certain unmodified xenobiotics (e.g. vincristine) with glutathione (GSH). MRP1 also confers resistance to arsenic in association with GSH; however, the mechanism and the species of arsenic transported are unknown. Using membrane vesicles prepared from the MRP1-overexpressing lung cancer cell line, H69AR, we found that MRP1 transports arsenite (AsIII) only in the presence of GSH but does not transport arsenate (AsV) (with or without GSH). The non-reducing GSH analogs l-γ-glutamyl-l-α-aminobutyryl glycine and S-methyl GSH did not support AsIII transport, indicating that the free thiol group of GSH is required. GSH-dependent transport of AsIII was 2-fold higher at pH 6.5-7 than at a more basic pH, consistent with the formation and transport of the acid-stable arsenic triglutathione (As(GS)3). Immunoblot analysis of H69AR vesicles revealed the unexpected membrane association of GSH S-transferase P1-1 (GSTP1-1). Membrane vesicles from an MRP1-transfected HeLa cell line lacking membrane-associated GSTP1-1 did not transport AsIII even in the presence of GSH but did transport synthetic As(GS)3. The addition of exogenous GSTP1-1 to HeLa-MRP1 vesicles resulted in GSH-dependent AsIII transport. The apparent Km of As(GS)3 for MRP1 was 0.32 μm, suggesting a remarkably high relative affinity. As(GS)3 transport by MRP1 was osmotically sensitive and was inhibited by several conjugated organic anions (MRP1 substrates) as well as the metalloid antimonite (Ki 2.8 μm). As(GS)3 transport experiments using MRP1 mutants with substrate specificities differing from wild-type MRP1 suggested a commonality in the substrate binding pockets of As(GS)3 and leukotriene C4. Finally, human MRP2 also transported As(GS)3. In conclusion, MRP1 transports inorganic arsenic as a tri-GSH conjugate, and GSTP1-1 may have a synergistic role in this process. The 190-kDa MRP1 1The abbreviations used are: MRP, multidrug resistance protein; AsIII, arsenite; AsV, arsenate; As(GS)3, arsenic triglutathione; As2O3, arsenic trioxide; ABC, ATP binding cassette; CdII, cadmium chloride; E217βG, 17β-estradiol 17-(β-d-glucuronide); GST, glutathione S-transferase; LTC4, leukotriene C4; mAb, monoclonal antibody; SbIII, potassium antimony tartrate; WT, wild type; ArsAB, arsenic resistance onion translocating ATPase. (gene symbol ABCC1) is a member of the ATP binding cassette (ABC) superfamily of transport proteins and was originally isolated on the basis of its elevated expression in the multidrug resistant small cell lung cancer cell line, H69AR (1Cole S.P. 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: 1650-1654Google Scholar). In addition to its ability to confer resistance in tumor cells, MRP1 is expressed constitutively in many non-malignant tissues, with relatively high levels found in testes and lung (1Cole S.P. 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: 1650-1654Google Scholar, 2Flens M.J. Zaman G.J. van der Valk P. Izquierdo M.A. Schroeijers A.B. Scheffer G.L. van der Groep P. de Haas M. Meijer C.J. Scheper R.J. Am. J. Pathol. 1996; 148: 1237-1247Google Scholar). MRP1 is a primary active transporter of GSSG and GSH as well as glucuronate, GSH, and sulfate-conjugated organic anions of physiological and toxicological relevance (3Haimeur A. Conseil G. Deeley R.G. Cole S.P. Curr. Drug Metab. 2004; 5: 21-53Google Scholar). Endogenous substrates of MRP1 include the cysteinyl leukotriene LTC4, an important mediator of inflammatory response, and the conjugated steroids E217βG, estrone 3-sulfate, and dehydroepiandrosterone 3-sulfate (4Loe D.W. Almquist K.C. Cole S.P. Deeley R.G. J. Biol. Chem. 1996; 271: 9683-9689Google Scholar, 5Loe D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Google Scholar, 6Jedlitschky G. Leier I. Buchholz U. Barnouin K. Kurz G. Keppler D. Cancer Res. 1996; 56: 988-994Google Scholar, 7Zelcer N. Reid G. Wielinga P. Kuil A. van der Heijden I. Schuetz J.D. Borst P. Biochem. J. 2003; 371: 361-367Google Scholar, 8Qian Y.M. Song W.C. Cui H. Cole S.P. Deeley R.G. J. Biol. Chem. 2001; 276: 6404-6411Google Scholar). MRP1 and the related MRP2 (gene symbol ABCC2) have also been shown to transport various xenobiotics and are key components of the so-called Phase III elimination pathways of drug metabolism (9Leslie E.M. Deeley R.G. Cole S.P. Toxicology. 2001; 167: 3-23Google Scholar). Several studies show that MRP1 and MRP2 can act synergistically with the phase II conjugating glutathione S-transferases (GST) to confer resistance to the toxicities of some electrophilic drugs and carcinogens (9Leslie E.M. Deeley R.G. Cole S.P. Toxicology. 2001; 167: 3-23Google Scholar, 10Smitherman P.K. Townsend A.J. Kute T.E. Morrow C.S. J. Pharmacol. Exp. Ther. 2004; 308: 260-267Google Scholar, 11Depeille P. Cuq P. Mary S. Passagne I. Evrard A. Cupissol D. Vian L. Mol. Pharmacol. 2004; 65: 897-905Google Scholar). However, several substrates of MRP1 and MRP2, including most of the natural product drugs to which they confer resistance, are not conjugated to any significant extent in vivo, but their transport is stimulated by GSH. Current evidence suggests that at least some of these drugs are co-transported with GSH across the membrane J. de M. J. Pharmacol. Scholar, D.W. Deeley R.G. Cole S.P. Cancer Res. Scholar). The metalloid arsenic is an established human and a as a A. P. M. J. A. G. J. and on Scholar). In (e.g. are used in the of several including and P. M. Scholar, J.H. J. G.L. L. J. P. Scholar). the for arsenic transport toxicological and The of inorganic arsenic in the to the of arsenic in species from to Scholar). In and pathways of metalloid resistance have been and been that arsenic is by from or by as thiol S. D. J. Biol. Chem. Scholar, S. M. J. U. S. A. 1996; Scholar, M. J. U. S. A. Scholar). In cell MRP1 been shown to confer resistance to arsenite (AsIII) and arsenate (AsV) in a GSH-dependent S.P. K. D.W. Grant C.E. Deeley R.G. Cancer Res. Scholar, L. N. Toxicology. Scholar, G.J. J. van J. H. Borst P. U. S. A. Scholar, J. H. J.E. Mol. Pharmacol. 2001; Scholar). However, arsenic transport by MRP1 been and the mechanism by which and the of the transported species are of MRP1 to inorganic arsenic been shown to in the of GSH and arsenic the G.J. J. van J. H. Borst P. U. S. A. Scholar). have been isolated and in and this is to their as by M. M. A. J. MRP1 arsenic in association with free GSH. in evidence that MRP2 transports arsenic species G. D.W. J. Biol. Chem. Scholar, A. Biochem. Pharmacol. Scholar). the substrate specificities of MRP1 and MRP2 are not they are MRP1 transport arsenic in a The of arsenic is of arsenic and have been isolated from the of lacking the for an for GSH and GSH G. Chem. Res. 2004; Scholar). is in the of at the G. Chem. Res. 2004; Scholar). In the we have the of arsenic transported by MRP1 using membrane vesicles prepared from the MRP1 H69AR and HeLa cell found that MRP1 transports AsIII but only in the presence of GSH, and this transport is not by GSH analogs that a free thiol we found that the or GSTP1-1 is with the membrane of the H69AR cell evidence that the formation of As(GS)3 is for AsIII by MRP1 and that GSTP1-1 is for this Finally, the transport of As(GS)3 by MRP1 is was from GSH, S-methyl GSH, and from glutathione and from Science. was from and monoclonal and have been Deeley R.G. Cole S.P. Cancer Res. Scholar, E.M. M. Deeley R.G. Cole S.P. J. Biol. Chem. Scholar). The monoclonal was from The was to a to a in the binding of MRP1 which the E.M. M. Deeley R.G. Cole S.P. J. Biol. Chem. Scholar). with The was from and the was from and of the MRP1 and HeLa cell and the human small cell lung cancer cell line and its MRP1-overexpressing H69AR have been (1Cole S.P. 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: 1650-1654Google Scholar, K. Deeley R.G. Cole S.P. J. Biol. Chem. 2001; 276: Scholar). The human cell line was in with and of and was prepared from with as C.J. Biochem. Scholar). of a and was to of and for at The formation of was by on with an M. Biochem. Pharmacol. Scholar). was prepared as by M. J.D. Chem. Biol. with and GSH an in at a pH of and at for of was by as for and was and to for and and consistent with M. Biochem. Pharmacol. Scholar). MRP1 and MRP2 and in and expression of wild-type MRP1 wild-type MRP2 and the MRP1 mutants and in have been K. Deeley R.G. Cole S.P. J. Biol. Chem. 2001; 276: Scholar, A. Deeley R.G. Cole S.P. J. Biol. Chem. Scholar, A. Conseil G. Deeley R.G. Cole S.P. Mol. Pharmacol. 2004; 65: Scholar, K. C.J. Deeley R.G. Cole S.P. J. Biol. Chem. 2001; 276: Scholar). Membrane and membrane vesicles from H69AR, HeLa and prepared as with D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Google Scholar). in pH and by at and to and was to The was at at for and the was of a pH at at for the was and in a pH and at at for The with pH and by with a by a and of membrane vesicles at levels of MRP1 protein in membrane vesicles of by analysis as with the human Deeley R.G. Cole S.P. Cancer Res. Scholar). levels of GSTP1-1 protein in membrane vesicles of by analysis as for with a for human GSTP1-1 at a of of MRP1 and MRP2 protein expression levels was using the at a of as E.M. M. Deeley R.G. Cole S.P. J. Biol. Chem. Scholar). relative levels of MRP1 and MRP2 expression by analysis using a of protein was by of the and transport by a as D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Google Scholar). Membrane vesicles of protein at at a of or the transport used was pH and ATP or glutathione with and without GSH and or for of resulted in the presence of GSH in transport the of transport was and in of pH and and was by in the presence of was from transport in the presence of ATP and as or transport. The of of or transport and or S-methyl GSH or pH or GSSG or or potassium antimony or at a of The of exogenous GSTP1-1 or on in the presence of GSH by HeLa-MRP1 vesicles was as the GSTP1-1 was to and arsenic using a to the by the of at substrate at a of The of As(GS)3 transport by was by in the presence and of of this experiments for MRP1 a membrane and GSTP1-1 using the H69AR and HeLa-MRP1 cell H69AR and HeLa-MRP1 at and in a on with the with for and in in for in in and with the in and the with and with and in the for with with in for with and on with with a was used to the The and the and for and the and for The was that the was experiments with in the of primary also experiments in the presence of and primary also to of AsIII and Membrane AsIII was a substrate for membrane vesicles prepared from the human small cell lung cancer cell line and its MRP1-overexpressing H69AR, was of AsIII by the and H69AR membrane vesicles is shown in of AsIII by the H69AR vesicles was and to with or with the However, in the presence of GSH of AsIII by the H69AR but not the vesicles was was at at which a of experiments with also and transport was in the presence or of GSH not of AsIII with GSH resulted in the formation of As(GS)3 as by GSH of As(GS)3 by the and H69AR membrane vesicles was also of As(GS)3 by H69AR membrane vesicles was for at which a of and to The for As(GS)3 was 2-fold than the with AsIII GSH). for the vesicles to that of the AsIII of by the have been shown to transport of conjugated and MRP1 substrates including LTC4, E217βG, and (4Loe D.W. Almquist K.C. Cole S.P. Deeley R.G. J. Biol. Chem. 1996; 271: 9683-9689Google Scholar, 5Loe D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Google Scholar, D.W. Deeley R.G. Cole S.P. Cancer Res. Scholar, E.M. M. Deeley R.G. Cole S.P. J. Biol. Chem. Scholar, E.M. K. P. Deeley R.G. Cole S.P. J. Biol. Chem. 2001; 276: Scholar). the a was for its ability to of As(GS)3 by H69AR membrane was at a of which a in of the of MRP1 and does not transport of MRP1 substrates Almquist K.C. Deeley R.G. Cole S.P. Cancer Res. 1996; 56: on As(GS)3 transport. the MRP1 of transport of As(GS)3. and GSH AsIII been shown that and S-methyl GSH can for GSH and support the transport of several GSH-dependent MRP1 substrates Y.M. Song W.C. Cui H. Cole S.P. Deeley R.G. J. Biol. Chem. 2001; 276: 6404-6411Google Scholar, D.W. Deeley R.G. Cole S.P. Cancer Res. Scholar, E.M. K. P. Deeley R.G. Cole S.P. J. Biol. Chem. 2001; 276: Scholar, E.M. R.J. Deeley R.G. Cole S.P. J. Pharmacol. Exp. Ther. 2003; Scholar). that the thiol group of GSH is not for transport of these substrates and the that formation of a GSH is for transport to In with MRP1 S-methyl GSH the of AsIII H69AR membrane that the free thiol group of GSH is for AsIII transport by GSH-dependent AsIII and formation of As(GS)3 are to at pH M. M. A. J. Scholar, M. J.D. Chem. Biol. MRP1 transport of been shown to relatively to in transport was pH and and pH E.M. Deeley R.G. Cole S.P. Scholar). transport of AsIII is by pH, transport was a pH of of AsIII was at and pH by vesicles at more basic pH and was by The AsIII transport at and pH is consistent with the formation and of As(GS)3 at pH and the that this GSH is transport. GSTP1-1 with the Membrane of and H69AR of AsIII analysis that the transport As(GS)3 was from free AsIII and GSH. However, that formation did not in the of membrane vesicles not suggested that the membrane vesicles a that the formation of As(GS)3. Immunoblot analysis revealed the presence of GSTP1-1 found in the and in the membrane vesicles prepared from the and H69AR cell In GSTP1-1 was found in the of HeLa cell with or MRP1 The of GSTP1-1 was by analysis of H69AR and HeLa-MRP1 significant of GSTP1-1 was to a the membrane of H69AR, was in the HeLa cell line The H69AR and HeLa-MRP1 cell with the to the membrane of MRP1 and GSTP1-1 for cell line are shown and for the AsIII in the of ability of the H69AR, and HeLa-MRP1 to transport AsIII and As(GS)3 was membrane vesicles prepared from the cell and which not did not transport free AsIII or As(GS)3. with the in the H69AR membrane vesicles transported AsIII and As(GS)3, with an 2-fold in As(GS)3 transport with AsIII In with the H69AR of AsIII was for the HeLa-MRP1 However, the transport of the by HeLa-MRP1 vesicles was an the with the AsIII GSH). of As(GS)3 by HeLa-MRP1 was that of the of transport by H69AR is most a of the higher of MRP1 in the H69AR vesicles that the in GSTP1-1 expression levels of for AsIII exogenous GSTP1-1 was to HeLa-MRP1 vesicles transport analysis The addition of GSTP1-1 resulted in a in transport of AsIII with an of to the transport of the As(GS)3 by HeLa-MRP1 of that the As(GS)3 by the H69AR membrane vesicles transport the than or the of in on was As(GS)3 was as the of in the transport indicating that As(GS)3 by the vesicles is osmotically as for a transport of of As(GS)3 was by the of several of As(GS)3 to analysis the apparent Km for As(GS)3 was 0.32 μm, and the was of of by of MRP1 including the conjugated organic anions LTC4, E217βG, and GSSG have been shown to of MRP1 transport (4Loe D.W. Almquist K.C. Cole S.P. Deeley R.G. J. Biol. Chem. 1996; 271: 9683-9689Google Scholar, 5Loe D.W. Almquist K.C. Deeley R.G. Cole S.P. J. Biol. Chem. 1996; 271: 9675-9682Google Scholar, I. G. Buchholz U. M. Cole S.P. Deeley R.G. Keppler D. Biochem. J. 1996; Scholar). As(GS)3 transport was also inhibited by and GSSG by and used at shown in studies to their Km to of binding of and on using cell have shown that MRP1 confers resistance to the AsIII, AsV, and but does not confer resistance to the S.P. K. D.W. Grant C.E. Deeley R.G. Cancer Res. Scholar). was of to these any on the transport of As(GS)3. As(GS)3 transport was not in the presence of and or and However, inhibited transport of As(GS)3 to that of The of As(GS)3 transport was by the of on As(GS)3 that as a of As(GS)3 transport with an apparent of 2.8 and the evidence from studies that MRP1 confers resistance to that this metalloid is also a high substrate of MRP1 S.P. K. D.W. Grant C.E. Deeley R.G. Cancer Res. Scholar, L. A. N. L. A. Scholar). for the of As(GS)3 in the presence of GSH in transport the formation of is and this may well the As(GS)3 MRP1 and been that of several in or to the of the of MRP1 resulted in in MRP1 substrate A. Deeley R.G. Cole S.P. J. Biol. Chem. Scholar, A. Conseil G. Deeley R.G. Cole S.P. Mol. Pharmacol. 2004; 65: Scholar). and of the at in the of of MRP1 resulted in a but in the ability of MRP1 to transport and GSH, MRP1 transport of estrone 3-sulfate and In of the at of MRP1 and resulted in a of transport In of at and with resulted in a of GSH transport but on MRP1 transport of LTC4, estrone 3-sulfate, and these are for transport of As(GS)3, transport using membrane vesicles prepared from with and The MRP1 and proteins expressed at levels that of in as by analysis of the membrane vesicles with the of and GSH transport by and the of transport by these mutants also did not transport As(GS)3 the that and have a ability to transport GSH, these mutants transported As(GS)3 at levels to these that As(GS)3 with MRP1 in a as of studies of arsenic by wild-type and revealed that is for transport of G. D.W. J. Biol. Chem. Scholar). the transport of As(GS)3 by MRP1 and MRP2 and that human MRP2 also transports As(GS)3, membrane vesicles prepared from with and Immunoblot analysis of membrane vesicles prepared from revealed that MRP2 was expressed at higher levels than MRP1 of As(GS)3 transport by MRP2 for relative and transport by MRP1 vesicles the was at Inorganic arsenic is a and in in formation of of the and A. P. M. J. A. G. J. and on Scholar). The pathways for metabolism and transport of inorganic arsenic are and a role in this to inorganic arsenic in which inorganic arsenic and In this we have the ability of MRP1 to transport arsenic in its and triglutathione using membrane primary evidence that MRP1 transports AsIII in an and GSH-dependent (with or without is not a substrate or of MRP1 transport MRP1 been shown to confer resistance to AsIII and expressed in S.P. K. D.W. Grant C.E. Deeley R.G. Cancer Res. Scholar, L. N. Toxicology. and the that is to AsIII from the was not an unexpected as the in arsenic metabolism in and is the of to AsIII, which is by Scholar). The of to AsIII in was to in the presence of GSH. The of a arsenate suggests A. H. Chem. Res. Scholar, however, the in relevance of this is not established I. 2003; Scholar). been that the of AsIII to a M.J. A. Pharmacol. 2003; however, from more AsIII is more that and S-methyl GSH not support the transport of AsIII that the free of GSH is and suggests that an is M. M. A. J. an analysis of As(GS)3 formation using and in with a of AsIII and in the human small cell lung cancer cell line and its MRP1-overexpressing The found that in As(GS)3 was at physiological pH, of arsenic and GSH from MRP1-overexpressing was relatively the that MRP1 arsenic a mechanism with GSH. However, the that the formation of As(GS)3 by an as GSTP1-1 was not that GSTP1-1 was for transport of AsIII evidence that this is to the of GSTP1-1 been in several cell to AsIII, and been suggested that this the of arsenic J. H. J.E. Mol. Pharmacol. 2001; Scholar, Biochem. J. 1992; Scholar, Biochem. Res. Scholar). However, the of GSTP1-1 in the of arsenic from been to many of the used to GSTP1-1 also MRP1 (e.g. J. H. J.E. Mol. Pharmacol. 2001; Scholar, Biochem. J. 1992; Scholar, Biochem. Res. Scholar, G.J. van Borst P. 1996; Scholar, S. J. H. J. Pharmacol. Exp. Ther. Scholar). In the role of GSTP1-1 in arsenic resistance is more in addition to its conjugating GSTP1-1 the protein binding and of M. L. M. C.J. R.J. J. Scholar). expression of GSTP1-1 also the of and confer resistance to arsenic in this and analysis that GSTP1-1 levels are at or the membrane of the and H69AR cell GSTP1-1 is a or protein, and its association with the membrane was The HeLa-MRP1 cell line, which GSTP1-1 in the and is also resistant to indicating that the association of GSTP1-1 with the membrane is to for resistance in the cell S.P. K. D.W. Grant C.E. Deeley R.G. Cancer Res. Scholar). However, the of conjugating in the membrane important for the and of been that are in with proteins Scholar). Membrane association of important for of in the membrane S. Drug Metab. Scholar). is that an in the GSH of is also with the membrane S.P. A.J. S. P. J. Biol. Chem. Scholar). In from the and the have been shown to with in addition to a role in these proteins as J. Scholar). have also that GSTP1-1 is with membrane vesicles prepared from cells, M. and M. P. and this association is not only to the and H69AR lung tumor studies are to the of the membrane the and cell the presence of GSTP1-1 and in membrane have for of transport The of As(GS)3 transport 0.32 μm, that MRP1 is a high transporter of this metalloid of As(GS)3 by human MRP1 is of remarkably higher than transport of AsIII by the or As(GS)3 by the membrane transport protein S. D. J. Biol. Chem. Scholar, S. M. J. U. S. A. 1996; Scholar). However, the transport was in the of for ArsAB, and the L. the cadmium protein and the L. are of with and and are well of As(GS)3 and have higher for this substrate than and the membrane however, of As(GS)3 transport by these proteins have not been The in Km human MRP1 and the may related to the that the cell in high of MRP1 in to analysis of AsIII in human and S. M. Pharmacol. 1996; Scholar, S. M. Pharmacol. 1996; Scholar, M. J. Pharmacol. the Km for MRP1 is of high physiological with levels in the of the of the which AsIII in its proteins in the transport of arsenic have been to transport the As(GS)3 S. D. J. Biol. Chem. Scholar, S. M. J. U. S. A. 1996; Scholar, M. J. U. S. A. Scholar, D. D. A. M. J. Biol. Chem. 2001; 276: Scholar). of transport in and transport of AsIII in the presence of GSH without of however, the was apparent for of formation S. M. J. U. S. A. 1996; Scholar, M. J. U. S. A. Scholar). The high levels of AsIII and the more pH used in these studies have resulted in formation of As(GS)3. a for As(GS)3 formation have been in the and membrane been that a thiol is a for arsenite resistance K. A. M. J. Scholar). the in that MRP1 is important for from arsenic some in evidence is not consistent with this A. A. G. Biochem. Res. Scholar, A. G. D. Cancer Res. that have to high In of arsenic of AsIII was in from and The suggested that the of to the as the A. A. G. Biochem. Res. Scholar, A. G. D. Cancer Res. Scholar). of from the revealed that of AsIII in of AsIII and suggesting that is not to of arsenic G. Chem. Res. 2004; Scholar). In to the and relatively high of arsenic used in these studies G. Chem. Res. 2004; Scholar, A. A. G. Biochem. Res. Scholar, A. G. D. Cancer Res. human tumor formation is with to of arsenic A. P. M. J. A. G. J. and on Scholar). The high transport of As(GS)3 by MRP1 suggests that MRP1 to from levels of arsenic and at higher may and are required. in of arsenic used in studies may this transport MRP1 important for from the of arsenic in studies are to In addition to MRP1 and MRP2, and several of which are to transport conjugated organic anions and in the of from the of arsenic (3Haimeur A. Conseil G. Deeley R.G. Cole S.P. Curr. Drug Metab. 2004; 5: 21-53Google Scholar, G. Chem. Res. 2004; Scholar). The of to inorganic arsenic is of several in the metabolism of this inorganic have been including in arsenic and M.J. Chem. Res. 2003; Scholar). of GSTP1-1 and many of MRP1 and MRP2 have been (3Haimeur A. Conseil G. Deeley R.G. Cole S.P. Curr. Drug Metab. 2004; 5: 21-53Google Scholar, G. J. J. Biol. Chem. Scholar, E.M. Deeley R.G. Cole S.P. 2003; Scholar, S. K. E.M. Deeley R.G. D. Cole S.P. Scholar). The of these on arsenic metabolism and is and studies are of Cole for the of the MRP1 and and the cell used in this are also to Cole for and is for the membrane is for and for for and are for of the

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