Identification of an Amino Acid Residue in Multidrug Resistance Protein 1 Critical for Conferring Resistance to Anthracyclines

Murine multidrug resistance protein 1 (mrp1), unlike human MRP1, does not confer resistance to anthracyclines. Previously, we have shown that a human/murine hybrid protein containing amino acids 959–1187 of MRP1 can confer resistance to these drugs. We have now examined the functional characteristics of mutant proteins in which we have converted individual amino acids in the comparable region of mrp1 to those present at the respective locations in MRP1. These mutations had no effect on the drug resistance profile conferred by mrp1 with the exception of converting glutamine 1086 to glutamate, as it is in the corresponding position (1089) in MRP1. This mutation created a protein that conferred resistance to doxorubicin without affecting vincristine resistance, or the ability of mrp1 to transport leukotriene C4 (LTC4) and 17β-estradiol 17-(β-d-glucuronide) (E217βG). Furthermore, mutation Q1086D conferred the same phenotype as mutation Q1086E while the mutation Q1086N did not detectably alter the drug resistance profile of mrp1, suggesting that an anionic side chain was required for anthracycline resistance. To confirm the importance of MRP1 E1089 for conferring resistance to anthracyclines, we mutated this residue to Gln, Asp, Ala, Leu, and Lys in the human protein. The mutation E1089D showed the same phenotype as MRP1, while the E1089Q substitution markedly decreased resistance to anthracyclines without affecting LTC4 and E217βG transport. Conversion of Glu-1089 to Asn, Ala, or Leu had a similar effect on resistance to anthracyclines, while conversion to a positive amino acid, Lys, completely eliminated resistance to anthracyclines and vincristine without affecting transport of LTC4, E217βG, and the GSH-dependent substrate, estrone-3-sulfate. These results demonstrate that an acidic amino acid residue at position 1089 in predicted TM14 of MRP1 is critical for the ability of the protein to confer drug resistance particularly to the anthracyclines, but is not essential for its ability to transport conjugated organic anions such as LTC4 and E217βG. Murine multidrug resistance protein 1 (mrp1), unlike human MRP1, does not confer resistance to anthracyclines. Previously, we have shown that a human/murine hybrid protein containing amino acids 959–1187 of MRP1 can confer resistance to these drugs. We have now examined the functional characteristics of mutant proteins in which we have converted individual amino acids in the comparable region of mrp1 to those present at the respective locations in MRP1. These mutations had no effect on the drug resistance profile conferred by mrp1 with the exception of converting glutamine 1086 to glutamate, as it is in the corresponding position (1089) in MRP1. This mutation created a protein that conferred resistance to doxorubicin without affecting vincristine resistance, or the ability of mrp1 to transport leukotriene C4 (LTC4) and 17β-estradiol 17-(β-d-glucuronide) (E217βG). Furthermore, mutation Q1086D conferred the same phenotype as mutation Q1086E while the mutation Q1086N did not detectably alter the drug resistance profile of mrp1, suggesting that an anionic side chain was required for anthracycline resistance. To confirm the importance of MRP1 E1089 for conferring resistance to anthracyclines, we mutated this residue to Gln, Asp, Ala, Leu, and Lys in the human protein. The mutation E1089D showed the same phenotype as MRP1, while the E1089Q substitution markedly decreased resistance to anthracyclines without affecting LTC4 and E217βG transport. Conversion of Glu-1089 to Asn, Ala, or Leu had a similar effect on resistance to anthracyclines, while conversion to a positive amino acid, Lys, completely eliminated resistance to anthracyclines and vincristine without affecting transport of LTC4, E217βG, and the GSH-dependent substrate, estrone-3-sulfate. These results demonstrate that an acidic amino acid residue at position 1089 in predicted TM14 of MRP1 is critical for the ability of the protein to confer drug resistance particularly to the anthracyclines, but is not essential for its ability to transport conjugated organic anions such as LTC4 and E217βG. Human multidrug resistance protein 1 (MRP1) 1The abbreviations used are:MRPmultidrug resistance proteinP-gpP-glycoproteinTMtransmembranemAbmonoclonal antibodyE217βG17β-estradiol 17-(β-d-glucuronide)LTC4leukotriene C4MTT3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideHEKhuman embryonic kidneyCLcytoplasmic loop is a member of the ATP-binding cassette transporter superfamily that confers resistance to a wide range of natural product drugs, including anthracyclines,Vinca alkaloids, and epipodophyllotoxins, as well as methotrexate and certain heavy metal oxyanions (1Deeley R.G. Cole S.P.C. Semin. Cancer Biol. 1997; 8: 193-204Crossref PubMed Scopus (165) Google Scholar, 2Hipfner D.R. Deeley R.G. Cole S.P.C. Biochim. Biophys. Acta. 1999; 1461: 359-376Crossref PubMed Scopus (379) Google Scholar, 3Cole 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 (3010) Google Scholar, 4Cole S.P.C. Sparks K.E. Fraser K. Loe D.W. Grant C.E. Wilson G.M. Deeley R.G. Cancer Res. 1994; 54: 5902-5910PubMed Google Scholar). The predicted structures of MRP1 and several of its related proteins differ from that of a typical eukaryotic ATP-binding cassette transporter such as P-glycoprotein (P-gp). MRPs 1, 2, 3, and 6 contain an additional NH2-terminal membrane-spanning domain with an extracellular NH2 terminus (5Higgins C.F. Callaghan R. Linton K.J. Rosenberg M.F. Ford R.C. Semin. Cancer Biol. 1997; 8: 135-142Crossref PubMed Scopus (117) Google Scholar, 6Hipfner D.R. Almquist K.C. Leslie E.M. Gerlach J.H. Grant C.E. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1997; 272: 23623-23630Crossref PubMed Scopus (200) Google Scholar, 7Borst P. Evers R. Kool M. Wijnholds J. Biochim. Biophys. Acta. 1999; 1461: 347-357Crossref PubMed Scopus (583) Google Scholar, 8Tusnady G.E. Bakos E. Varadi A. Sarkadi B. FEBS Lett. 1997; 402: 1-3Crossref PubMed Scopus (216) Google Scholar, 9Kool M. van der, Linden M. de Haas M. Baas F. Borst P. Cancer Res. 1999; 59: 175-182PubMed Google Scholar). Thus, MRP1 is predicted to contain three membrane-spanning domains with 5+6+6 transmembrane (TM) helices (6Hipfner D.R. Almquist K.C. Leslie E.M. Gerlach J.H. Grant C.E. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1997; 272: 23623-23630Crossref PubMed Scopus (200) Google Scholar, 7Borst P. Evers R. Kool M. Wijnholds J. Biochim. Biophys. Acta. 1999; 1461: 347-357Crossref PubMed Scopus (583) Google Scholar) (Fig. 1). Based on comparisons of amino acid sequence and the intron/exon organization of their respective genes, the MRPs and the cystic fibrosis transmembrane conductance regulator appear to have evolved from a common four-domain ancestor, the progenitor of the C branch of the ATP-binding cassette superfamily (1Deeley R.G. Cole S.P.C. Semin. Cancer Biol. 1997; 8: 193-204Crossref PubMed Scopus (165) Google Scholar, 10Bakos E. Hegedus T. Hollo Z. Welker E. Tusnady G.E. Zaman G.J. Flens M.J. Varadi A. Sarkadi B. J. Biol. Chem. 1996; 271: 12322-12326Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar). multidrug resistance protein P-glycoprotein transmembrane monoclonal antibody 17β-estradiol 17-(β-d-glucuronide) leukotriene C4 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide human embryonic kidney cytoplasmic loop MRP1 and P-gp confer resistance to many of the same commonly used, structurally diverse natural product chemotherapeutic agents (2Hipfner D.R. Deeley R.G. Cole S.P.C. Biochim. Biophys. Acta. 1999; 1461: 359-376Crossref PubMed Scopus (379) Google Scholar, 4Cole S.P.C. Sparks K.E. Fraser K. Loe D.W. Grant C.E. Wilson G.M. Deeley R.G. Cancer Res. 1994; 54: 5902-5910PubMed Google Scholar,11Schinkel A.H. Semin. Cancer Biol. 1997; 8: 161-170Crossref PubMed Scopus (442) Google Scholar, 12Grant C.E. Bhardwaj G. Cole S.P.C. Deeley R.G. Methods Enzymol. 1998; PubMed Scopus Google Scholar, C.E. G. D.R. Almquist K.C. Cole S.P.C. Deeley R.G. Cancer Res. 1994; 54: Google Scholar). unlike MRP1 is of a wide range of organic and A. F. J. PubMed Scopus Google Scholar, D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, J. A. 1999; PubMed Scopus Google Scholar). that MRP1, in to for the transport of of its such as and and that in with these D.W. Stewart Deeley R.G. Cole S.P.C. 1997; PubMed Scopus Google Scholar, T. Res. 1999; Google Scholar, D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; Google Scholar, J. de M. J. 1999; PubMed Scopus Google Scholar, D.W. Deeley R.G. Cole S.P.C. J. Google Scholar). is of the of MRP1 that for and transport. in P-gp have that amino acids in helices 1, and as well as amino acids in cytoplasmic of the protein K. M. Semin. Cancer Biol. 1997; 8: PubMed Scopus Google Scholar, 1994; PubMed Scopus Google Scholar, J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar, J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, K. M. T. K. 1997; PubMed Scopus Google Scholar, P. R. J. F. A. PubMed Scopus Google Scholar, J. Biol. Chem. 1997; 272: PubMed Scopus Google Scholar). an to of amino acid for the transport of and the organic that MRP1 we have of well functional the human and of the protein G. Gerlach J.H. Wilson G.M. Cole S.P.C. Deeley R.G. 1996; Google Scholar, Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar, Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The mrp1, and MRP1 and proteins confer resistance and with similar mrp1 to confer resistance to anthracycline that including and mrp1 17β-estradiol 17-(β-d-glucuronide) MRP1, the that proteins transport leukotriene with similar G. Gerlach J.H. Wilson G.M. Cole S.P.C. Deeley R.G. 1996; Google Scholar, Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). Previously, we have hybrid human/murine proteins that the of MRP1 of the ability to confer anthracycline resistance and to transport E217βG. These the region from amino acid to of MRP1 as particularly for anthracycline resistance Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the present we have used this to the of mutations in mrp1 in which amino acids in the region and have with the corresponding amino acid from MRP1 and These mutant human and proteins in human embryonic kidney and the with to their drug resistance and their ability to transport LTC4, E217βG, in the of the human estrone-3-sulfate. The results of these 1089 in MRP1 as critical for the ability to confer resistance to anthracyclines. mutations at this had no effect on the ability to transport E217βG and no effect on the transport of estrone-3-sulfate. and from was from and and from and vincristine from and from mutations the by of human MRP1 or mrp1 was to the a that a in the to an at the to mutated by as mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation mutation The and by this The mutation used the with the containing mutation as a the mutation used the with containing mutation as a The mutation used the with the containing mutation as a mutations by and to the containing the mutations or the mutations the respective the of the mutated and was by of with the containing the MRP1 or mrp1 Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). of the mutated MRP1 or mrp1 as in with and with containing mutant MRP1 or mrp1 to the the with containing B. the by and the for of the mutant as D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). of protein by of protein by and to by proteins the monoclonal which with and human protein D.R. M. G. Deeley R.G. Cole S.P.C. J. 1998; PubMed Scopus Google Scholar). was with by in well of a on with the had to in for and with in for in for with a of in for and by in containing and an antibody MRP1. used a of which amino acids in the cytoplasmic region of MRP1, or a of which with an to the terminus of MRP1 acids D.R. M. G. Deeley R.G. Cole S.P.C. J. 1998; PubMed Scopus Google Scholar, D.R. Leslie E.M. M. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). with for with for 1 with for and in in for on the with of of MRP1 in the was a for and for resistance was the bromide as S.P.C. Sparks K.E. Fraser K. Loe D.W. Grant C.E. Wilson G.M. Deeley R.G. Cancer Res. 1994; 54: 5902-5910PubMed Google Scholar, C.E. G. D.R. Almquist K.C. Cole S.P.C. Deeley R.G. Cancer Res. 1994; 54: Google Scholar, Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). at in of in The of drug in to for an additional of was from well and the was the was by with was the of from the of the to a resistance is as the of the of with MRP1 and mrp1 with with was in three or as and transport of the was by a D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). of at in of transport containing and 1 and to 1 of transport by with of transport and the was by for the of that to the in the of protein of the was to the protein of the and by at of LTC4, by of was as for that of protein was used and the was at for for and with of for 1 to of was as for that the was at for 1 in the or of 1 with hybrid human and proteins that sequence mrp1 and MRP1 in the region amino acids and of the protein to its to confer resistance to anthracyclines Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). This region predicted helices and cytoplasmic loop the predicted amino acid the human and proteins of of the amino acids in mrp1 was with the corresponding residue from MRP1. additional sequence present in predicted cytoplasmic in this the and of these was with the corresponding amino acid from the human protein. to the and mutations as in drug resistance of with and mutant resistance resistance of with and mutant mrp1 to that of with was a as The resistance was by the for by the for The shown the of from three to in a The resistance of with and mutant mrp1 to that of with was a as The resistance was by the for by the for The shown the of from three to The containing mutated of mrp1 and MRP1 was used to the of we by on of mutant protein to the of mrp1 and MRP1 in The This mutant protein that those in the The of mrp1 and MRP1 mutant proteins used in to the respective by with which with and human by MRP1 in with the was the used not The resistance of of the mrp1 mutant proteins was by to of vincristine and The results as and as resistance of the mutations the of resistance conferred to The mutation that doxorubicin resistance was the conversion of glutamine 1086 to as it is at the corresponding in MRP1. The of in a resistance to doxorubicin of as did mutation of this residue to a mutation to had no effect for mrp1 and the mutant proteins and Q1086N shown in These results the importance of the residue at this position in and that a side chain an for conferring resistance to Based on the with mrp1 Q1086E and Q1086D we critical 1089 was for the ability of the human MRP1 to confer resistance to anthracyclines, and or not mutations of this residue resistance and Thus, 1089 was mutated to and and had a resistance profile from the protein conversion of 1089 to as it is in the eliminated the ability of MRP1 to confer resistance to and as did mutations and mutation of 1089 to and decreased the resistance to vincristine by while mutation to eliminated resistance to this The three mutations that amino acids with side had effect on resistance, the resistance to this drug by The resistance to with a resistance of with for protein. for MRP1 and the mutant proteins and shown in These confirm the essential by 1089 in MRP1 with to the ability of the protein to confer resistance to anthracyclines and that of a side chain at this the with which the protein confers resistance to of natural product drug resistance of with and mutant resistance resistance of with and mutant MRP1 to that of with was as in The resistance was by the for by the for The shown the of resistance from three to in a The resistance of with and mutant MRP1 to that of with was as in The resistance was by the for by the for The shown the of resistance from three to To the of mutations in TM14 on drug resistance in to in of MRP1, we examined the of and as well as MRP1 by and MRP1 was of the and which in the region and the terminus of the D.R. Leslie E.M. M. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). shown in the mutant proteins showed a of comparable with that of MRP1, that the of mutant proteins was to in the drug resistance conferred by mrp1 and MRP1, we have shown that the proteins differ with to their ability to transport mrp1 and MRP1 transport LTC4 with similar but mrp1 is a transporter of E217βG with the human protein Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). in the of resistance to anthracyclines, with hybrid proteins sequence in the of MRP1 and mrp1 as for in the with which the proteins transport this Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). To of the mutations of mrp1 that the ability to confer resistance to anthracyclines the with which the protein LTC4 or E217βG, we examined of these by from and the effect of the and mutations on doxorubicin resistance, of the mutations to transport of LTC4 or E217βG (Fig. and of the effect of mutations of 1089 in the human protein on resistance to vincristine and in to the anthracyclines, we examined LTC4 and E217βG transport by and mutant human MRP1, including MRP1, and of these mutations had on transport including the mutation that decreased resistance to (Fig. and transport no effect of mutations of glutamine 1086 in mrp1 or 1089 in human MRP1 on transport of LTC4 or E217βG. to these mutations have the of mrp1 or MRP1 for these we and for the and mutant proteins for LTC4 and E217βG. The of by was at a of and a of the was used to a for protein mrp1 and mutant which at comparable the for LTC4 transport and (Fig. The for E217βG similar for and mutant protein and Thus, in mrp1, converting glutamine 1086 to had no effect on the ability of the protein to transport LTC4 or E217βG. The of LTC4 and E217βG transport examined for the and mutant human proteins (Fig. C and these the of MRP1 by and as as that of the mutant (Fig. The for LTC4 transport with containing MRP1 or mutant and The for the protein and for mutant which to the of protein a of E217βG for and mutant MRP1 and The for MRP1 or and and for in the for the and mutant proteins and Thus, as with mrp1, mutation of 1089 in the human protein did not transport of LTC4 and E217βG. of 1089 in human MRP1 with glutamine decreased the ability of the protein to confer anthracycline resistance and resistance to vincristine by mutation of 1089 to completely eliminated resistance to anthracyclines and vincristine transport of such as LTC4 and E217βG, and such as vincristine and is a for which with the drug T. Res. 1999; Google Scholar, D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; Google Scholar, J. de M. J. 1999; PubMed Scopus Google Scholar). we have shown that can the transport of anionic such as Cole S.P.C. Deeley R.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). transport of these is to such as vincristine and the anthracyclines, we used to the mutation had the transport of the used, and that the of mutant protein that of MRP1. The of transport for from with the and mutant MRP1 in the and of (Fig. and the of a of was for MRP1, which was to that for mutant or and The for MRP1, and similar in the of and The for transport by from MRP1 or mutations and and in the of and and in its for in the for MRP1 or mutations and similar and in the of and in the of These in the or of mutations and in a similar to that of the protein. Human MRP1 and mrp1 confer resistance to and with the same the that the the human protein confers resistance to anthracyclines G. Gerlach J.H. Wilson G.M. Cole S.P.C. Deeley R.G. 1996; Google Scholar, Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). mrp1 and MRP1 transport LTC4 with similar differ markedly in their ability to transport E217βG Grant C.E. Loe D.W. D.R. Cole S.P.C. Deeley R.G. 1997; PubMed Scopus Google Scholar). Previously, we have of these to of the human protein that to its ability to transport E217βG mrp1 and to confer resistance to anthracyclines. of the drug resistance conferred by hybrid proteins and their in transport characteristics for anthracycline resistance and transport of E217βG to the of MRP1. that amino acids 959–1187 and to the ability of the human protein to transport E217βG Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the hybrid containing was as as the hybrid containing the region at conferring anthracycline resistance Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). We have now examined the of converting in mrp1 in the region amino acids and to the corresponding amino acid present in human MRP1 to of in conferring resistance to anthracyclines and to the same the transport of E217βG. of the have amino acid at locations in the protein that but similar the is to A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the in P-gp in predicted 1, and in and have shown to K. M. Semin. Cancer Biol. 1997; 8: PubMed Scopus Google Scholar). The region of we have helices which of the additional helices to helices of as well as predicted of corresponding to of to in the of P-gp in is a cytoplasmic region mutation of to shown to resistance to and doxorubicin J. Biol. Chem. 1994; Full Text PDF PubMed Google Scholar). MRP1 and mrp1 present in in to the results from of of of the in mrp1 with those present in MRP1 had no effect on its drug resistance Furthermore, mutations in helices of the protein that converted mrp1 and MRP1 to the human sequence had no with the exception of glutamine Conversion of this residue to glutamate, as it is in MRP1, the ability of mrp1 to confer resistance to anthracyclines to a to that conferred by the hybrid containing amino acids 959–1187 of the human protein. This with the of effect of amino acids this 1089 is critical for the ability of the hybrid protein to confer anthracycline resistance. with results the mutation was with to anthracycline resistance and had no effect on the ability of mrp1 to confer resistance to vincristine and or to transport LTC4 and E217βG. The results with mrp1 1089 of the human protein in the ability to confer anthracycline resistance. the of resistance conferred by the 959–1187 hybrid and the mutant protein that of the protein Cole S.P.C. Deeley R.G. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). The that the hybrid and mutant mrp1 the human protein the that 1089 but not essential resistance to this of drugs. the results with MRP1 that 1089 was essential for anthracycline resistance. that mutation of this in to the comparable mrp1 resistance to drugs. of 1089 to glutamine eliminated anthracycline resistance, the of this unlike the mutation in the which had no effect on resistance to of drugs, the mutation decreased resistance to vincristine and to a the anthracyclines. This was to a similar with of the mutations that eliminated a in the amino acid side The in the effect of the and mutations the that the of 1089 in MRP1 have a critical in of the ability to confer resistance to anthracyclines, and that the protein evolved that this residue now a in drug transport. or not this is the as the drug resistance and of MRP1 in of P-gp of in predicted that the of the side chain of the residue was that substitution by an amino acid with a side chain resistance to while of a side chain resistance to including and doxorubicin K. M. T. K. 1997; PubMed Scopus Google Scholar). We no the mutant in which amino acids had for suggesting that a in the side chain was the the drug resistance profile of the protein. This was by the results by substitution of 1089 with which in no in resistance and by conversion to which eliminated resistance to anthracyclines and and decreased resistance to Thus, the drug resistance profile of MRP1 on the or of the residue at position The effect that the of a positive at this on resistance to anthracyclines and vincristine to the that the and the is at while is The effect of the mutation on the ability of the protein to confer resistance to of the that the transport of the protein was or that the mutation have of the protein in This mutation results not in a of positive in predicted but in the of (Fig. the that to an in the of this region of the protein. no of a that of of the protein. the protein with to the transport of LTC4 and E217βG, that the effect of the mutation was for the chemotherapeutic and did not alter the transport of these conjugated organic The for this is not MRP1 transport of LTC4 and E217βG, and such as vincristine and is a for which with the drug T. Res. 1999; Google Scholar, D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; Google Scholar, J. de M. J. 1999; PubMed Scopus Google Scholar). We have shown that can markedly the with which conjugated organic anions such as this substrate, it to demonstrate that the and for transport of the conjugated Cole S.P.C. Deeley R.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). This the to mutations that drug resistance the of the transport of the of transport by the the which eliminated anthracycline resistance and vincristine resistance, and the which eliminated resistance to anthracyclines and no from the protein. Thus, the of the mutations at position 1089 in human MRP1 appear to to the of the have such as vincristine and doxorubicin as of LTC4 suggesting that to common or on the protein. the of shown to markedly the of these D.W. Almquist K.C. Deeley R.G. Cole S.P.C. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. Almquist K.C. Cole S.P.C. Deeley R.G. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, D.W. Deeley R.G. Cole S.P.C. Cancer Res. 1998; Google Scholar). The results of with that at of the these that critical for the of differ from those required for and transport of such as LTC4 and E217βG. we have a amino acid, mutation of which the ability of MRP1 to confer drug resistance and to transport E217βG but transport R. and P. J. Biol. in of these in the of MRP1 agents that at of the of the protein while its ability to confer drug resistance.

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