REVIEW |
A Family of Drug Transporters: the Multidrug Resistance-Associated Proteins
Piet Borst,
Raymond Evers,
Marcel Kool,
Jan Wijnholds
Affiliation of authors: Division of Molecular Biology and Center of Biomedical Genetics, The Netherlands Cancer Institute, Amsterdam.
Correspondence to: Piet Borst, M.D., Ph.D., Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: pborst{at}nki.nl).
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ABSTRACT
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The human multidrug resistance-associated protein (MRP) family currently has seven members. The ability of several of these membrane proteins to transport a wide range of anticancer drugs out of cells and their presence in many tumors make them prime suspects in unexplained cases of drug resistance, although proof that they contribute to clinical drug resistance is still lacking. Recent studies have begun to clarify the function of the MRP family members. MRPs are organic anion transporters; i.e., they transport anionic drugs, exemplified by methotrexate, and neutral drugs conjugated to acidic ligands, such as glutathione (GSH), glucuronate, or sulfate. However, MRP1, MRP2, and MRP3 can also cause resistance to neutral organic drugs that are not known to be conjugated to acidic ligands by transporting these drugs together with free GSH. MRP1 can even confer resistance to arsenite and MRP2 to cisplatin, again probably by transporting these compounds in complexes with GSH. MRP4 overexpression is associated with high-level resistance to the nucleoside analogues 9-(2-phosphonylmethoxyethyl) adenine and azidothymidine, both of which are used as anti-human immunodeficiency virus drugs. MRPs may, therefore, also have a role in resistance against nucleoside analogues used in cancer chemotherapy. Mice without Mrp1, a high-affinity leukotriene C4 transporter, have an altered response to inflammatory stimuli but are otherwise healthy and fertile. MRP2 is the major transporter responsible for the secretion of bilirubin glucuronides into bile, and humans without MRP2 develop a mild liver disease known as the DubinJohnson syndrome. The physiologic functions of the other MRPs are not known. Whether long-term inhibition of MRPs in humans can be tolerated (assuming that suitable inhibitors will be found) remains to be determined.
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INTRODUCTION
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Drug pumps are an important part of the defense of cells against carcinostatic drugs. This was first realized by the Danish physician Danø (1), who demonstrated in 1973 that multidrug-resistant (MDR) Ehrlich ascites cells were able to lower their intracellular daunorubicin concentration by active drug extrusion. In 1976, Juliano and Ling (2) discovered a large glycoprotein in the plasma membrane of MDR cells, the P-glycoprotein (P-gp), that looked like a good candidate pump. It took a long time, however, before most scientists in the field were convinced that P-gp was a so-called "primary active" drug pump, i.e., a protein able to bind and transport drugs against a drug concentration gradient and at the expense of adenosine triphosphate (ATP) hydrolysis (3,4).
In 1992, Cole et al. (5) discovered a second type of drug pump in MDR cancer cells, the multidrug resistance-associated protein (MRP). While the human genome encodes only two P-gp's (6) [and a distant relative of P-gp, the bile salt transporter (7)], it is shown to contain many more genes related to MRP (8,9).
This MRP family is the subject of this review. We will focus on the ability of MRPs to transport anticancer drugs and the possible contribution of MRPs to drug resistance in patients. Other aspects of MRPs have been summarized in depth in recent reviews and review volumes that deal with multidrug resistance (1012) or with ABC transporters (ATP-binding cassette transporters) in general (13,14).
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OVERVIEW OF THE MEMBERS OF THE MRP FAMILY
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Since several laboratories have contributed to the characterization of the MRP family, individual members may have multiple names (Table 1
). MRP7 is a recent addition to the family and has not yet been characterized. The six MRPs studied thus far fall into one of two groups (Table 2
and Fig. 1
). MRP1, MRP2, MRP3, and MRP6 all have the extra N-terminal domain (indicated as TMD0 in Fig. 1
) that is lacking in P-gp. The percent identity of MRP4 and MRP5 with MRP1 is below 40%; these two MRPs are also smaller than MRP1, and they appear to lack the TMD0 domain. Nevertheless, MRP4 and MRP5 are much more homologous to the other MRPs than to P-gp or other classes of ABC transporters. Moreover, investigators (15) have shown that the TMD0 part of MRP1 is not required for transport activity. The essential L0 part of MRP1 (see Fig. 1
) is, however, conserved in the long N-terminal intracellular parts of MRP4 and MRP5 (15,16).
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Table 1. The human multidrug resistance protein (MRP) family and some of the alternative names used in the literature for individual family members
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Fig. 1. Two-dimensional membrane topology models for P-glycoprotein (Pgp), MRP1, and MRP5. MRP1 is characterized by the presence of an extra N-terminal domain (TMD0), which is absent in P-glycoprotein or MRP5. NBD = nucleotide-binding domain. Note that this figure presents highly schematic models only indicating the trans-membrane segments, adenosine triphosphate-binding sequences, and the location of carbohydrate (CHO) chains. In reality, the trans-membrane segments probably come together in the membrane to form a kind of pore closed off at the exoplasmic phase, as suggested for P-glycoprotein (87,88). L0 = linker domain zero.
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Table 3
summarizes the tissue distribution of MRPs. It also includes what is known about the physiologic functions of these transporters (MRP1 and MRP2 only).
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MRP1: TRANSPORTER OF A REMARKABLE RANGE OF DRUGS
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The substrate specificity of MRP1 initially seemed to be similar to that of P-gp, as shown in Table 4
, which compares the drug resistance profile of transfected cells overexpressing MDR1 P-gp or MRP1. Although MRP1 transports paclitaxel relatively poorly, other differences with P-gp initially seemed minor. Subsequent work showed, however, that the preferred substrates for MRP1 are organic anions (1719), e.g., drugs conjugated to glutathione (GSH), glucuronate, or sulfate (10,11,20), whereas P-gp has a low affinity for such negatively charged compounds. In fact, MRP1 is one of the elusive glutathione-S-conjugate (GS-X) pumps (21), a transporter able to transport drugs conjugated to GSH out of the cell. This explains the ability of MRP1 to transport substrates, such as methotrexate (MTX) or arsenite (H3AsO3). MTX is an organic anion; H3AsO3 can form a complex with three GSH molecules as shown in equation 1
:
 | (1) |
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Table 4. Comparison of drug resistance profiles in cells with elevated levels of human multidrug resistance proteins MRP1 or MDR1 P-glycoprotein*
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Moreover, it is presumably this complex that is transported by MRP1, as indicated by the ability of H3AsO3 to induce increased GSH export from cells with elevated levels of MRP1 (22).
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MRP2: TRANSPORTER OF ANTICANCER DRUGS
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Long before MRP1 was discovered, biochemical and genetic studies (11,23,24) had demonstrated the presence of an organic anion transporter in the canalicular membrane of hepatocytes. This transporter was originally known as the canalicular multispecific organic anion transporter (cMOAT), but it is now called MRP2. Its substrate specificity was defined in detail with the help of a rat strain (TR-/GY) lacking cMOAT. These TR-/GY rats are mainly deficient in bilirubin-glucuronide secretion, and they are now known to contain inactivating mutations in their cMOAT/MRP2 gene (25,26), just like their human counterparts, i.e., patients with the DubinJohnson syndrome (27,28).
Because MRP2 was known to handle a similar range of GSH conjugates as MRP1, it was to be expected that MRP2 would also be able to transport the carcinostatic agents transported by MRP1. This expectation is borne out by recent experiments with transfected cells. Introduction of an antisense construct containing a long segment of DNA complementary to MRP2 RNA into cultured liver HepG2 cells enhanced the sensitivity of these cells to cisplatin, vincristine, doxorubicin, and the camptothecin derivatives CPT11 and SN38 but not to etoposide (29). MRP2 was also shown to mediate vinblastine transport in polarized cells (30). In transfected cells, overexpression of MRP2 resulted in resistance to MTX (31), cisplatin, etoposide, doxorubicin, epirubicin (32), and mitoxantrone (unpublished results from our laboratory). This list is not yet complete because it has been difficult to get transfected cells in which the MRP2 is routed efficiently to the plasma membrane (12,32). The spectrum of drug resistance induced in cells by MRP2 may eventually turn out to be similar to that shown for MRP1 (Table 4
) with one exception: MRP2 induces cisplatin resistance (9,32,33), which has never been seen in cells overexpressing MRP1.
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MRP1 AND MRP2: TRANSPORT OF VINCA ALKALOIDS AND ANTHRACYCLINES
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Vinca alkaloids and anthracyclines are weak organic bases and are not known to be conjugated to acidic ligands in human cells. It is, therefore, puzzling that elevated levels of MRP1 or MRP2 result in resistance to these compounds. GSH is required for resistance, however. Depletion of cellular GSH abolished MRP1-mediated resistance against vinca alkaloids and anthracyclines (22,34); moreover, in vesicular transport experiments, transport of vincristine or daunorubicin occurred only in the presence of reduced GSH (3538). The drugs are probably cotransported with GSH (3638). In polarized kidney cells transfected with an MRP2 construct, the increased transport of vinblastine is associated with a stoichiometrically increased export of GSH (unpublished data from our laboratory). It, therefore, looks as if drug resistance mediated by MRP1 or MRP2 requires a continuing supply of GSH to allow export of unconjugated drug, as indicated in Fig. 2
. Indeed, there is often a simultaneous increase in expression of MRP1 and gamma-glutamylcysteine synthetase in tumor cells (39,40).

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Fig. 2. Model showing interrelation between multidrug resistance-associated protein (MRP) and glutathione (GSH). Some drugs (X) can be conjugated to GSH by glutathione S-transferase (GST) and are then transported by MRP. Other drugs (Y) are cotransported with GSH. In both cases, drug transport is dependent on the continued synthesis of GSH, which can be blocked by DL-buthionine (S, R)-sulfoximine (BSO). Note that some compounds are turned into MRP substrates by conjugation to glucuronate or sulfate, whereas some other substrates are organic anions and do not require conjugation.
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MRP3
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Recent work has shown that MRP3 is also an organic anion transporter (41,42); however, unlike MRP1 and MRP2, it prefers glucuronate conjugates as substrates over GSH conjugates (41). It has been difficult to get transfected, nonpolarized cells with high levels of MRP3; cells with low amounts of MRP3 are resistant to etoposide and teniposide but not to other drugs affected by multidrug resistance. Resistance to short-term exposure to MTX also has been observed in these cells (42), which is in agreement with the observation that MRP3 can transport MTX in vesicular transport experiments (41). In view of the technical problems with transfected cells, the true range of resistance that can be induced by overexpression of MRP3 obviously remains to be sorted out.
The physiologic function of MRP3 remains to be established. The massive increase in the expression of MRP3 seen in the liver of cholestatic rats (43,44) and humans, quoted in (11,42), suggests that MRP3, located in the basolateral membrane of the hepatocyte (42,45), may allow efflux of organic anions from the liver into the blood when secretion into bile is blocked. A role for MRP3 in the normal uptake of bile salts from the gut has also been postulated. Why MRP3 expression is high in the adrenal cortex (42) remains to be determined.
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MRP4, A NUCLEOTIDE ANALOGUE PUMP
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Schuetz et al. (46) recently made the interesting discovery that MRP4 can function as a cellular efflux pump for the anti-human immunodeficiency virus drugs 9-(2-phosphonylmethoxyethyl)adenine (PMEA) and azidothymidine monophosphate (AZTMP) in PMEA-resistant cells. High levels of MRP4 severely impaired the antiviral efficacy of several nucleoside analogues. MRP4 can also confer resistance against 9-(2-phosphonylmethoxyethyl)guanine, a compound with some antineoplastic activity. In view of the results obtained with MRP5 (see below), it seems likely that MRP4 may also be able to cause resistance to anticancer base analogues (e.g., 6-mercaptopurine and thioguanine), but this hypothesis has not yet been tested.
PMEA and AZTMP are organic anions; therefore, MRP4 can be considered to be an organic anion transporter, as is expected for an MRP family member. MRP4 might, however, be specific for phosphate conjugates, and it remains to be seen whether MRP4 can also transport GSH, glucuronide, or sulfate conjugates. The physiologic function of MRP4 is not known.
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MRP5
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Our work with transfected cells shows that MRP5 is an organic anion transporter of GSH conjugates and that MRP5 can be inhibited by typical organic anion transport inhibitors like sulfinpyrazone and benzbromarone but not by probenecid (47).
McAleer et al. (48) also found decreased accumulation of anionic fluorochromes in MRP5-transfected cells. It is interesting that we found that MRP5 overexpression results in low-level resistance to thiopurines (e.g., 6-mercaptopurine and thioguanine), as well as PMEA, but no notable resistance to other anticancer drugs tested (e.g., anthracyclines, vinca alkaloids, podophyllotoxins, or MTX). The transfected cells tend to accumulate less 6-mercaptopurine and PMEA and extrude increased amounts of 6-thioinosinemonophosphate and PMEA from the cell. Like MRP4, MRP5, therefore, appears to be a nucleotide analogue pump.
McAleer et al. (48) found that cells transfected with an MRP5 gene construct are resistant to heavy metals (e.g., cadmium chloride and potassium antimonyl tartrate). We did not detect such a resistance in our cells overproducing MRP5. Like MRP2, however, MRP5 does not route efficiently to the plasma membrane in nonpolarized cells, and most of the protein remains in intracellular membranes. More work is, therefore, required to determine the full range of drug resistance that can be caused by MRP5. Since 6-mercaptopurine and thioguanine are used in the treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), it will be interesting to look at MRP5 and MRP4 in 6-mercaptopurine- or thioguanine-resistant ALLs or AMLs in which resistance cannot be attributed to mutations in the hypoxanthine phosphoribosyl transferase gene.
The physiologic function of MRP5 remains to be determined. Mice homozygous for a disrupted Mrp5 gene are viable and healthy at least up to 1 year (47).
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MRP6
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Both the physiologic function and the potential involvement of MRP6 in drug resistance are still unclear. It has been shown recently (49,50) that the 3' end of the MRP6 protein is almost identical to the anthracycline resistance-associated (ARA) protein identified previously in epirubicin-selected leukemia cells (5153). MRP6 is highly expressed in the liver and kidneys and to a low extent in a few other tissues (49). Overexpression and amplification of the complete or partial MRP6 gene in resistant tumor cells were found only in cell lines with high overexpression and amplification of the MRP1 gene. It seems likely that MRP6 does not play a role in the resistance of these cells and that MRP6, or part of it (ARA), is only coamplified with MRP1 because of its location immediately next to it on chromosome 16 (49).1
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INHIBITORS OF MRPS
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The potential involvement of drug pumps in clinical drug resistance has led to a search for compounds that can be used to inhibit these transporters in cancer patients. In the case of MDR1 P-gp, this search has been successful. Examples of effective inhibitors are the nonimmunosuppressive cyclosporin A analogue PSC833 and the carboxamide derivative GG918 [reviewed in (5456)]. Attempts to find inhibitors for MRPs have concentrated mainly on MRP1 and MRP2. Compounds that efficiently block MDR1 P-gp only have a low affinity for MRP1 or MRP2 (57); therefore, it is unlikely that these compounds will be useful for inhibiting MRPs in human cancer. Most high-affinity substrates for MRP1 and MRP2 are organic anions with a substantial hydrophobic moiety and at least one, but preferably two, negative charge(s). Examples of potent competitive inhibitors are high-affinity substrates, such as leukotriene C4, S-decylglutathione, and the leukotriene D4 antagonist MK571 (35,58). Other inhibitors for MRP1 are organic acids that were originally developed to inhibit transport of uric acid, like sulfinpyrazone, benzbromarone, and probenecid [see, for example, Holló] et al. (59)]. Although MRP1 and MRP2 have a similar substrate specificity, inhibitors for MRP1 are not necessarily good inhibitors for MRP2. Sulfinpyrazone, for instance, does not inhibit transport of the model substrate dinitrophenyl S-glutathione by MRP2 (30).
Negatively charged compounds do not readily enter cells. They, therefore, do not provide obvious lead compounds for drug development. Good inhibitors probably have to be made as prodrugs in which the charged moiety is shielded.
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MRPS AND PROTECTION OF NORMAL TISSUES AGAINST ANTICANCER DRUGS
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The contribution of drug transporters to the protection of normal mammalian tissues has been investigated by disrupting the genes for these transporters in mice, resulting in "knockout," null, or (-/-) mice. Experiments on Mdr1a/b (-/-) mice have shown that P-gp plays a major role in normal drug handling (60). The location of P-gp in the gut epithelium helps to prevent entry of drugs into the body (61); its location in renal tubules and in the canalicular membrane of the hepatocytes helps to clear drugs from the body; and its presence in strategic locations in brain (62), testis, and placenta helps to protect these organs and the fetus against drugs (63).
P-gp is invariably located in the apical membrane of epithelial cells, in the appropriate position for its protective role. MRP1, in contrast, is located basolaterally (64) and, therefore, tends to pump drugs into the body. Indeed, no decreased disposal of drugs has been observed in Mrp1 (-/-) mice (6567). Nevertheless, these mice are hypersensitive to etoposide (65), and we have found that MRP1 has nonredundant protective functions against etoposide in the bone marrow, the epithelium of the oropharynx, the testicular tubules, and the urinary-collecting duct cells (68).
Especially interesting is the protection of the testicular tubules. As illustrated in Fig. 3
, the basolateral location of Mrp1 in the Sertoli cells allows this pump to protect the contents of the testicular tubules, the germline cells, against drug damage. A similar situation appears to exist in the choroid plexus, where many substances enter the cerebrospinal fluid from the epithelial cells covering the plexus. The high level of Mrp1 in these cells (69,70) plays a crucial role in preventing the entry of a drug, such as etoposide, into the cerebrospinal fluid (71).

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Fig. 3. Bloodtestis barrier: schematic representation of the localization of multidrug resistance protein 1 (MRP1) and multidrug resistance 1 (MDR1) P-glycoprotein in a testicular tubule and blood capillary, respectively. The physical barrier between the luminal (apical) and basal plasma membrane is formed by tight junctions, indicated by .
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Hardly anything is known about the possible protective role of MRPs other than MRP1. An Mrp5 (-/-) mouse exists (47), but it has not yet been analyzed in detail.
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MRPS AND CLINICAL MULTIDRUG RESISTANCE
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P-gp was discovered in 1976 (2). Today, 24 years later, there is still no consensus on its contribution to drug resistance in cancer patients. The first MRP, MRP1, was discovered only 8 years ago (5); therefore, it is not surprising that we still do not know much about its clinical significance. Because MRP1 is ubiquitous in human tissues (Table 3
), it is potentially present in most tumors and could, therefore, play a role in resistance. Indeed, MRP1 has been detected in almost every tumor type examined, but no strong association has emerged between MRP1 levels and clinical resistance [reviewed in (10)]. In the absence of effective and specific MRP inhibitors, it is impossible to analyze the possible contribution of MRP1 to resistance by use of intervention studies in which anticancer drugs transported by MRP1 are combined with an inhibitor of MRP1.
No association between the expression of MRP2 and multidrug resistance was ever found in cell lines selected for multidrug resistance. However, MRP2 was found in 95% of renal clear-cell carcinomas, and MRP2 was also detected in lung, gastric, colorectal, and hepatocellular carcinomas [reviewed in (11)]. Initial studies on MRP3 (9) did not find any association between MRP3 and drug resistance in cell lines, but a more recent survey of lung cancer cell lines (72) showed a strong association between MRP3 and doxorubicin resistance and a weaker association between MRP3 and resistance to vincristine, etoposide, and cisplatin. The potential contribution of MRP47 to multidrug resistance remains to be studied.
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MRPS AND CLINICAL MTX RESISTANCE
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Biochemical experiments have identified several different GS-X pumps that are able to extrude MTX from erythrocytes and leukemic cells (31,73,74), and several lines of evidence support the idea that these pumps might be identical to MRPs. For example, MTX excretion into bile is diminished in TR- rats lacking MRP2 (75), and vesicular transport of MTX is increased in membrane vesicles from cells with increased MRP1 levels (31) and decreased in erythrocytes from Mrpl (-/-) mice (unpublished results from our laboratory). Nevertheless, no MTX resistance was found in cells overexpressing any MRP during continuous MTX exposure.
This paradox was resolved when Jansen and co-workers (31,42) found that MRP1, MRP2, and MRP3 do protect cells against a 4-hour exposure to high MTX concentrations but not to a 96-hour continuous exposure to low-dose MTX. Apparently, there is a competition in the cell between export of MTX via MRPs and polyglutamylation, as indicated in Fig. 4
. MTX polyglutamates are not detectably transported by MRP1, and the gradual accumulation of these polyglutamates in chronically exposed cells may explain the loss of resistance during long-term drug exposure. It is possible that polyglutamylation of folates also prevents depletion of cellular folate pools by MRP, but this hypothesis has not yet been analyzed.

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Fig. 4. Multidrug resistance proteins (MRPs) and folylpoly- -glutamate synthetase (FPGS) compete for methotrexate (MTX). MTX is taken up by the cells via the reduced folate carrier (RFC), and overexpression of MRP results in transport of unmodified MTX. Polyglutamylated MTX (MTX-Glu26) formed in a relatively slow reaction by FPGS, which results in the efficient inhibition of dehydrofolate reductase (DHFR).
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The results now available suggest that at least some of the MTX-transporting GS-X pumps, identified in cultured cells by Henderson and co-workers (73,74), are actually MRP1, MRP2, and MRP3. Whether raised levels of MRPs could contribute to MTX resistance in vivo has not yet been studied.
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MRPS AND CLINICAL CISPLATIN OR ARSENITE RESISTANCE
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Ishikawa et al. (76) first pointed out that cisplatin can form complexes with GSH (equation 2
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Moreover, they (76) showed that these complexes are themselves toxic and that they might be removed from the cells by a GS-X pump. All attempts to demonstrate transport of cisPt-(SG)2 complexes by MRP1 have failed, but there is now good evidence that MRP2 could mediate cisplatin resistance, as discussed above. Whether there is any association between clinical cisplatin resistance and raised MRP2 levels in tumors remains to be studied.
Clinical interest in arsenite comes from observations showing that arsenite treatment can induce remissions in promyelocytic leukemia, probably by promoting apoptosis [see (77,78)]. Clinical resistance against arsenite arises rapidly during treatment, and it seems possible that overexpression of MRPs could be involved in some forms of resistance. Although vesicular transport experiments demonstrating As(SG)3 (see equation 1
) transport by MRPs are lacking (and technically difficult), there is good indirect evidence for transport. Some cell lines overexpressing MRP1 are somewhat resistant to arsenite (79), embryonic stem cells with disrupted Mrp1 genes are arsenite hypersensitive (80), and arsenite increases the GSH efflux from cells overexpressing MRP1 (22), MRP2, or MRP3 (unpublished results from our laboratory). It will, therefore, be of interest to test whether increased expression of one of these MRPs can help cells escape death from arsenite.
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WHY SO MANY PUMPS?
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Many toxins found in nature and used by oncologists as natural-product drugs enter cells by passive diffusion. These amphipathic drugs are hydrophobic enough to diffuse through a lipid bilayer, but they are hydrophilic enough to be water soluble and to reach their target. Because of the hydrophilic parts in these drugs, they enter cells slowly. The rate of entry of doxorubicin, for instance, is measured in minutes rather than in milliseconds (81). Because doxorubicin does not require a protein to enter the cell, organisms cannot defend themselves against this drug by altering an import protein. This is an effective strategy to keep out water-soluble drugs, such as MTX, which is dependent on the reduced folate carrier for rapid cellular uptake.
Once inside, these amphipathic drugs can be inactivated by oxidation and/or conjugation. However, as Ishikawa (21) pointed out, conjugation by itself is not enough to get rid of the drug. The conjugated drug is now more hydrophilic because of the GSH attached to it and cannot leave the cell by passive diffusion. As drug continues to enter the cell, the GSH conjugate will accumulate to excessive concentrations (that will be toxic in themselves) unless exported by a dedicated export pump, a GS-X pump.
Genes for drug pumps and drug-conjugate pumps are prominent in all of the genomes of simple organisms sequenced. Three classes of drug (-conjugate) pumps have been found in the human genome [i.e., the P-gp's, the MRPs, and the breast cancer resistance proteins (8285)], with a total of 12 members identified so far. It will be a formidable task to sort out which of these pumps contributes to resistance, to which anticancer drugs, and in which tumors.
The potential benefit of this knowledge to cancer treatment is, however, large. As the rapid analysis of the expression levels of thousands of genes in tumor samples is entering the phase of clinical application, it will become possible to reconstruct a resistance profile for the predominant cell types in each tumor and to adjust the chemotherapy accordingly. This should at least make it possible to spare some patients an aggressive therapy that does not work.
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OUTLOOK
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What makes the MRP family so remarkable is the range of anticancer drugs handled by its members. Whereas P-gp's have become deservedly famous for transporting a wide range of neutral or slightly basic organic compounds, the current members of the MRP family are even more versatile. In addition to the P-gp-transported neutral organic compounds, MRP1, MRP2, and MRP3 also transport drugs conjugated to GSH, glucuronate, or sulfate and other organic anions, such as MTX. Because of the ability of these transporters to handle compounds associated with GSH, they can even cause resistance to small molecules that can form GSH complexes, such as cisplatin (MRP2) or arsenite. The newer family members, MRP4 and MRP5, are able to cause resistance to nucleotide analogues, such as PMEA and purine base analogues, such as 6-mercaptopurine and thioguanine. Transport by MRPs, therefore, affects a stunning range of anticancer drugs and provides a link between transporters and the GSH system previously associated with resistance to carcinostatics.
The potential importance of MRPs in drug resistance is, therefore, high. What remains to be done is to sort out which fraction of this awesome potential is actually used in cancer patients and how we could make use of this knowledge to treat patients more effectively.
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NOTES
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1 Mutations in the MRP6 gene were very recently shown to cause a skin and eye disease known as pseudoxanthoma elasticum (9193). 
Present address: R. Evers, Georg Speyer-Haus, Institute for Biomedical Research, Frankfurt, Germany.
Present address: M. Kool, Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands.
Present address: J. Wijnholds, Department of Ophthalmogenetics, The Netherlands Ophthalmic Research Institute, Amsterdam.
Our experimental work on multidrug resistance-associated proteins is supported by grants from the Dutch Cancer Society to P. Borst.
We thank Dr. Fiona Stewart (The Netherlands Cancer Institute, Amsterdam) for many helpful comments.
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REFERENCES
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1
Dano K. Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochim Biophys Acta 1973;323:46683.[Medline]
2
Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim Biophys Acta 1976;455:15262.[Medline]
3
Germann UA. P-glycoproteina mediator of multidrug resistance in tumour cells. Eur J Cancer 1996;32A:92744.
4
Borst P, Schinkel AH. Genetic dissection of the function of mammalian P-glycoproteins. Trends Genet 1997;13:21722.[Medline]
5
Cole SP, Bhardwaj G, Gerlach JH, Mackie JE, Grant CE, Almquist KC, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 1992;258:16504.[Medline]
6
Lincke CR, Smit JJ, van der Velde-Koerts T, Borst P. Structure of the human MDR3 gene and physical mapping of the human MDR locus. J Biol Chem 1991;266:530310.[Abstract/Free Full Text]
7
Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, et al. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 1998;273:1004650.[Abstract/Free Full Text]
8
Allikmets R, Gerrard B, Hutchinson A, Dean M. Characterization of the human ABC superfamily: isolation and mapping of 21 new genes using the expressed sequence tags database. Hum Mol Genet 1996;5:164955.[Abstract/Free Full Text]
9
Kool M, de Haas M, Scheffer GL, Scheper RJ, van Eijk MJ, Juijn JA, et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res 1997;57:353747.[Abstract]
10
Hipfner DR, Deeley RG, Cole SP. Structural, mechanistic and clinical aspects of MRP1. Biochim Biophys Acta 1999;1461:35976.[Medline]
11
Konig J, Nies AT, Cui Y, Leier I, Keppler D. Conjugate export pumps of the multidrug resistance protein (MRP) family: localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta 1999;1461:37794.[Medline]
12
Borst P, Evers R, Kool M, Wijnholds J. The multidrug resistance protein family. Biochim Biophys Acta 1999;1461:34757.[Medline]
13
Borst P. Multidrug resistant proteins. Semin Cancer Biol 1997;8:1314.[Medline]
14
Kuchler K, Sarkadi B, Szakacs G, editors. Structure and function of ABC transporters. Biochim Biophys Acta 1999;1461:special issue.
15
Bakos E, Evers R, Szakacs G, Tusnady GE, Welker E, Szabo K, et al. Functional multidrug resistance protein (MRP) lacking the N-terminal transmembrane domain. J Biol Chem 1998;273:3216775.[Abstract/Free Full Text]
16
Gao M, Loe DW, Grant CE, Cole SP, Deeley RG. Reconstitution of ATP-dependent leukotriene C4 transport by co-expression of both half-molecules of human multidrug resistance protein in insect cells . J Biol Chem 1996;271:277827.[Abstract/Free Full Text]
17
Jedlitschky G, Leier I, Buchholz U, Center M, Keppler D. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res 1994;54:48336.[Abstract]
18
Leier I, Jedlitschky G, Buchholz U, Cole SP, Deeley RG, Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem 1994;269:2780710.[Abstract/Free Full Text]
19
Muller M, Meijer C, Zaman GJ, Borst P, Scheper RJ, Mulder NH, et al. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci U S A 1994;91:130337.[Abstract/Free Full Text]
20
Jedlitschky G, Leier I, Buchholz U, Barnouin K, Kurz G, Keppler D. Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump. Cancer Res 1996;56:98894.[Abstract]
21
Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci 1992;17:4638.[Medline]
22
Zaman GJ, Lankelma J, van Tellingen O, Beijnen J, Dekker H, Paulusma C, et al. Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proc Natl Acad Sci U S A 1995;92:76904.[Abstract]
23
Oude Elferink RP, Meijer DK, Kuipers F, Jansen PL, Groen AK, Groothuis GM. Hepatobiliary secretion of organic compounds; molecular mechanisms of membrane transport. Biochim Biophys Acta 1995;1241:215 68.[Medline]
24
Roelofsen H, Muller M, Jansen PL. Regulation of organic anion transport in the liver. Yale J Biol Med 1997;70:43545.[Medline]
25
Paulusma CC, Bosma PJ, Zaman GJ, Bakker CT, Otter M, Scheffer GL, et al. Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science 1996;271:11268.[Abstract]
26
Buchler M, Konig J, Brom M, Kartenbeck J, Spring H, Horie T, et al. cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. J Biol Chem 1996;271:150918.[Abstract/Free Full Text]
27
Kartenbeck J, Leuschner U, Mayer R, Keppler D. Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in DubinJohnson syndrome. Hepatology 1996;23:10616.[Medline]
28
Paulusma CC, Kool M, Bosma PJ, Scheffer GL, Ter Borg F, Scheper RJ, et al. A mutation in the human canalicular multispecific organic anion transporter gene causes the DubinJohnson syndrome. Hepatology 1997;25:153942.[Medline]
29
Koike K, Kawabe T, Tanaka T, Toh S, Uchiumi T, Wada M, et al. A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res 1997;57:54759.[Abstract]
30
Evers R, Kool M, van Deemter L, Jansen H, Calafat J, Oomen LC, et al. Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. J Clin Invest 1998;101:13109.[Abstract/Free Full Text]
31
Hooijberg JH, Broxterman HJ, Kool M, Assaraf YG, Peters GJ, Noordhuis P, et al. Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 1999;59:25325.[Abstract/Free Full Text]
32
Cui Y, Konig J, Buchholz JK, Spring H, Leier I, Keppler D. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 1999;55:92937.[Abstract/Free Full Text]
33
Ohga T, Koike K, Ono M, Makino Y, Itagaki Y, Tanimoto M, et al. Role of the human Y box-binding protein YB-1 in cellular sensitivity to the DNA-damaging agents cisplatin, mitomycin C, and ultraviolet light. Cancer Res 1996;56:42248.[Abstract]
34
Versantvoort CH, Broxterman HJ, Bagrij T, Scheper RJ, Twentyman PR. Regulation by glutathione of drug transport in multidrug-resistant human lung tumour cell lines overexpressing multidrug resistance-associated protein. Br J Cancer 1995;72:829.[Medline]
35
Loe DW, Almquist KC, Deeley RG, Cole SP. Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. J Biol Chem 1996;271:967582.[Abstract/Free Full Text]
36
Loe DW, Deeley RG, Cole SP. Characterization of vincristine transport by the Mr 190,000 multidrug resistance protein (MRP): evidence for cotransport with reduced glutathione. Cancer Res 1998;58:51306.[Abstract]
37
Renes J, de Vries EG, Nienhuis EF, Jansen PL, Muller M. ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. Br J Pharmacol 1999;126:6818.[Abstract/Free Full Text]
38
Rappa G, Lorico A, Flavell RA, Sartorelli AC. Evidence that the multidrug resistance protein (MRP) functions as a co-transporter of glutathione and natural product toxins. Cancer Res 1997;57:52327.[Abstract]
39
Ishikawa T, Bao JJ, Yamane Y, Akimaru K, Frindrich K, Wright CD, et al. Coordinated induction of MRP/GS-X pump and gamma-glutamylcysteine synthetase by heavy metals in human leukemia cells. J Biol Chem 1996;271:149818.[Abstract/Free Full Text]
40
Kuo MT, Bao J, Furuichi M, Yamane Y, Gomi A, Savaraj N, et al. Frequent coexpression of MRP/GS-X pump and gamma-glutamylcysteine synthetase mRNA in drug-resistant cells, untreated tumor cells, and normal mouse tissues. Biochem Pharmacol 1998;55:60515.[Medline]
41
Hirohashi T, Suzuki H, Sugiyama Y. Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). J Biol Chem 1999;274:151815.[Abstract/Free Full Text]
42
Kool M, van der Linden M, de Haas M, Scheffer GL, de Vree JM, Smith AJ, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci U S A 1999;96:69149.[Abstract/Free Full Text]
43
Hirohashi T, Suzuki H, Ito K, Ogawa K, Kume K, Shimizu T, et al. Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats. Mol Pharmacol 1998;53:1068 75.[Abstract/Free Full Text]
44
Ortiz DF, Li S, Iyer R, Zhang X, Novikoff P, Arias IM. MRP3, a new ATP-binding cassette protein localized to the canalicular domain of the hepatocyte. Am J Physiol 1999;276:G1493500.[Abstract/Free Full Text]
45
Konig J, Rost D, Cui Y, Keppler D. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology 1999;29:115663.[Medline]
46
Schuetz JD, Connelly MC, Sun D, Paibir SG, Flynn PM, Srinivas RV, et al. MRP4: a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med 1999;5:104851.[Medline]
47
Wijnholds J, Mol CA, van Deemter L, de Haas M, Scheffer GL, Baas F, et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci U S A 2000;97:747681.[Abstract/Free Full Text]
48
McAleer MA, Breen MA, White NL, Matthews N. pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem 1999;274:235418.[Abstract/Free Full Text]
49
Kool M, van der Linden M, de Haas M, Baas F, Borst P. Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Res 1999;59:17582.[Abstract/Free Full Text]
50
Belinsky MG, Kruh GD. MOAT-E (ARA) is a full-length MRP/cMOAT subfamily transporter expressed in kidney and liver. Br J Cancer 1999;80:13429.[Medline]
51
Longhurst TJ, O'Neill GM, Harvie RM, Davey RA. The anthracycline resistance-associated (ara) gene, a novel gene associated with multidrug resistance in a human leukaemia cell line. Br J Cancer 1996;74:13315.[Medline]
52
O'Neill GM, Peters GB, Harvie RM, MacKenzie HB, Henness S, Davey RA. Amplification and expression of the ABC transporters ARA and MRP in a series of multidrug-resistant leukaemia cell sublines. Br J Cancer 1998;77:207680.[Medline]
53
Kuss BJ, O'Neill GM, Eyre H, Doggett NA, Callen DF, Davey RA. ARA, a novel ABC transporter, is located at 16p13.1, is deleted in inv(16) leukemias, and is shown to be expressed in primitive hematopoietic precursors. Genomics 1998;51:4558.[Medline]
54
Ford JM, Yang J, Hait WN. P-glycoprotein-mediated multidrug resistance: experimental and clinical strategies for its reversal. In: Hait WN, editor. Drug resistance. Boston (MA): Kluwer Academic Publishers; 1996. p. 339.
55
Sikic BI. Pharmacologic approaches to reversing multidrug resistance. Semin Hematol 1997;34(4 Suppl 5):407.[Medline]
56
Sandor V, Fojo T, Bates SE. Future perspectives for the development of P-glycoprotein modulators. Drug Resist Updates 1998;1:190200.
57
Wallstab A, Koester M, Bohme M, Keppler D. Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918. Br J Cancer 1999;79:105360.[Medline]
58
Keppler D, Leier I, Jedlitschky G, Konig J. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance protein MRP1 and its apical isoform MRP2. Chem Biol Interact 1998;111112:15361.
59
Hollo Z, Homolya L, Hegedus T, Sarkadi B. Transport properties of the multidrug resistance-associated protein (MRP) in human tumour cells. FEBS Lett 1996;383:99104.[Medline]
60
Schinkel AH, Mayer U, Wagenaar E, Mol CA, van Deemter L, Smit JJ, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci U S A 1997;94:402833.[Abstract/Free Full Text]
61
Sparreboom A, van Asperen J, Mayer U, Schinkel AH, Smit JW, Meijer DK, et al. Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proc Natl Acad Sci U S A 1997;94:20315.[Abstract/Free Full Text]
62
Schinkel AH, Smit JJ, van Tellingen O, Beijnen JH, Wagenaar E, van Deemter L, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994;77:491502.[Medline]
63
Lankas GR, Wise LD, Cartwright ME, Pippert T, Umbenhauer DR. Placental P-glycoprotein deficiency enhances susceptibility of chemically induced birth defects in mice. Reprod Toxicol 1998;12:45763.[Medline]
64
Evers R, Zaman GJ, van Deemter L, Jansen H, Calafat J, Oomen LC, et al. Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells. J Clin Invest 1996;97:12118.[Abstract/Free Full Text]
65
Wijnholds J, Evers R, van Leusden MR, Mol CA, Zaman GJ, Mayer U, et al. Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Nat Med 1997;3:12759.[Medline]
66
Lorico A, Rappa G, Finch RA, Yang D, Flavell RA, Sartorelli AC. Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res 1997;57:523842.[Abstract]
67
Rappa G, Finch RA, Sartorelli AC, Lorico A. New insights into the biology and pharmacology of the multidrug resistance protein (MRP) from gene knockout models. Biochem Pharmacol 1999;58:55762.[Medline]
68
Wijnholds J, Scheffer GL, van der Valk M, van der Valk P, Beijnen JH, Scheper RJ, et al. Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage. J Exp Med 1998;188:797808.[Abstract/Free Full Text]
69
Rao VV, Dahlheimer JL, Bardgett ME, Snyder AZ, Finch RA, Sartorelli AC, et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci U S A 1999;96:39005.[Abstract/Free Full Text]
70
Nishino J, Suzuki H, Sugiyama D, Kitazawa T, Ito K, Hanano M, et al. Transepithelial transport of organic anions across the choroid plexus: possible involvement of organic anion transporter and multidrug resistance-associated protein. J Pharmacol Exp Ther 1999;290:28994.[Abstract/Free Full Text]
71
Wijnholds J, deLange EC, Scheffer GL, van den Berg DJ, Mol CA, van der Valk M, et al. Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. J Clin Invest 2000;105;27985.[Abstract/Free Full Text]
72
Young LC, Campling BG, Voskoglou-Nomikos T, Cole SP, Deeley RG, Gerlach JH. Expression of multidrug resistance protein-related genes in lung cancer: correlation with drug response. Clin Cancer Res 1999;5:67380.[Abstract/Free Full Text]
73
Henderson GB, Hughes TR, Saxena M. Functional implications from the effects of 1-chloro-2,4-dinitrobenzene and ethacrynic acid on efflux routes for methotrexate and cholate in L1210 cells. J Biol Chem 1994;269:133829.[Abstract/Free Full Text]
74
Saxena M, Henderson GB. MOAT4, a novel multispecific organic-anion transporter for glucuronides and mercapturates in mouse L1210 cells and human erythrocytes. Biochem J 1996;320:27381.[Medline]
75
Masuda M, I'izuka Y, Yamazaki M, Nishigaki R, Kato Y, Ni'inuma K, et al. Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Res 1997;57:350610.[Abstract]
76
Ishikawa T, Wright CD, Ishizuka H. GS-X pump is functionally overexpressed in cis-diamminedichloroplatinum (II)-resistant human leukemia HL-60 cells and down-regulated by cell differentiation. J Biol Chem 1994;269:2908593.[Abstract/Free Full Text]
77
Zhu XH, Shen YL, Jing YK, Cai X, Jia PM, Huang Y, et al. Apoptosis and growth inhibition in malignant lymphocytes after treatment with arsenic trioxide at clinically achievable concentrations. J Natl Cancer Inst 1999;91:7728.[Abstract/Free Full Text]
78
Dai J, Weinberg RS, Waxman S, Jing Y. Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system. Blood 1999;93:26877.[Abstract/Free Full Text]
79
Cole SP, Sparks KE, Fraser K, Loe DW, Grant CE, Wilson GM, et al. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res 1994;54:590210.[Abstract]
80
Lorico A, Rappa G, Flavell RA, Sartorelli AC. Double knockout of the MRP gene leads to increased drug sensitivity in vivo. Cancer Res 1996;56:53515.[Abstract]
81
Regev R, Eytan GD. Flip-flop of doxorubicin across erythrocyte and lipid membranes. Biochem Pharmacol 1997;54:11518.[Medline]
82
Doyle LA, Yang W, Abruzzo LV, Krogmann T, Gao Y, Rishi AK, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci U S A 1998;95:1566570.[Abstract/Free Full Text]
83
Allikmets R, Schriml LM, Hutchinson A, Romano-Spica V, Dean M. A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Res 1998;58:53379.[Abstract]
84
Miyake K, Mickley L, Litman T, Zhan Z, Robey R, Cristensen B, et al. Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: demonstration of homology to ABC transport genes. Cancer Res 1999;59:813.[Abstract/Free Full Text]
85
Allen JD, Brinkhuis RF, Wijnholds J, Schinkel AH. The mouse Bcrp1/Mxr/Abcp gene: amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res 1999;59:423741.[Abstract/Free Full Text]
86
Cole SP. Re: Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins [letter]. J Natl Cancer Inst 1999;91:8889.[Free Full Text]
87
Rosenberg MF, Callaghan R, Ford RC, Higgins CF. Structure of the multidrug resistance P-glycoprotein to 2.5 nm resolution determined by electron microscopy and image analysis. J Biol Chem 1997;272:1068594.[Abstract/Free Full Text]
88
Higgins CF, Callaghan R, Linton KJ, Rosenberg MF, Ford RC. Structure of the multidrug resistance P-glycoprotein. Semin Cancer Biol 1997;8:13542.[Medline]
89
Grant CE, Valdimarsson G, Hipfner DR, Almquist KC, Cole SP, Deeley RG. Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. Cancer Res 1994;54:35761.[Abstract]
90
Zaman GJ, Borst P. MRP, mode of action and role in MDR. In: Gupta S, Tsuruo T, editors. Multidrug resistance in cancer cells. Sussex (U.K.): John Wiley & Sons Ltd.; 1996. p. 95107.
91
Bergen AA, Plomp AS, Schuurman EJ, Terry S, Breuning M, Dauwerse H, et al. Mutations in ABCC6 cause pseudoxanthoma elasticum. Nat Genet 2000;25:22831.[Medline]
92
Le Saux O, Urban Z, Tschuch C, Csiszar K, Bacchelli B, Quaglino D, et al. Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum. Nat Genet 2000;25:2237.[Medline]
93
Ringpfeil F, Lebwohl MG, Christiano Am, Uitto J. Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter. Proc Natl Acad Sci U S A 2000;97:60016.[Abstract/Free Full Text]
Manuscript received November 11, 1999;
revised February 29, 2000;
accepted June 23, 2000.
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-
Situ, D., Haimeur, A., Conseil, G., Sparks, K. E., Zhang, D., Deeley, R. G., Cole, S. P. C.
(2004). Mutational Analysis of Ionizable Residues Proximal to the Cytoplasmic Interface of Membrane Spanning Domain 3 of the Multidrug Resistance Protein, MRP1 (ABCC1): GLUTAMATE 1204 IS IMPORTANT FOR BOTH THE EXPRESSION AND CATALYTIC ACTIVITY OF THE TRANSPORTER. J. Biol. Chem.
279: 38871-38880
[Abstract]
[Full Text]
-
Iohom, G., Fitzgerald, D., Cunningham, A. J.
(2004). Principles of pharmacogenetics--implications for the anaesthetist. Br J Anaesth
93: 440-450
[Full Text]
-
Morioka, N., Kumagai, K., Morita, K., Kitayama, S., Dohi, T.
(2004). Nonsteroidal Anti-Inflammatory Drugs Potentiate 1-Methyl-4-phenylpyridinium (MPP+)-Induced Cell Death by Promoting the Intracellular Accumulation of MPP+ in PC12 Cells. J. Pharmacol. Exp. Ther.
310: 800-807
[Abstract]
[Full Text]
-
Wright, S. H., Dantzler, W. H.
(2004). Molecular and Cellular Physiology of Renal Organic Cation and Anion Transport. Physiol. Rev
84: 987-1049
[Abstract]
[Full Text]
-
Michot, J.-M., Van Bambeke, F., Mingeot-Leclercq, M.-P., Tulkens, P. M.
(2004). Active Efflux of Ciprofloxacin from J774 Macrophages through an MRP-Like Transporter. Antimicrob. Agents Chemother.
48: 2673-2682
[Abstract]
[Full Text]
-
Ito, K., Koresawa, T., Nakano, K., Horie, T.
(2004). Mrp2 is involved in benzylpenicillin-induced choleresis. Am. J. Physiol.
287: G42-G49
[Abstract]
[Full Text]
-
Haimeur, A., Conseil, G., Deeley, R. G., Cole, S. P.C.
(2004). Mutations of Charged Amino Acids in or near the Transmembrane Helices of the Second Membrane Spanning Domain Differentially Affect the Substrate Specificity and Transport Activity of the Multidrug Resistance Protein MRP1 (ABCC1). Mol Pharmacol
65: 1375-1385
[Abstract]
[Full Text]
-
Ozvaran, M. K., Cao, X. X., Miller, S. D., Monia, B. A., Hong, W. K., Smythe, W. R.
(2004). Antisense oligonucleotides directed at the bcl-xl gene product augment chemotherapy response in mesothelioma. Mol Cancer Ther
3: 545-550
[Abstract]
[Full Text]
-
Chu, X.-Y., Huskey, S.-E. W., Braun, M. P., Sarkadi, B., Evans, D. C., Evers, R.
(2004). Transport of Ethinylestradiol Glucuronide and Ethinylestradiol Sulfate by the Multidrug Resistance Proteins MRP1, MRP2, and MRP3. J. Pharmacol. Exp. Ther.
309: 156-164
[Abstract]
[Full Text]
-
Koike, K., Conseil, G., Leslie, E. M., Deeley, R. G., Cole, S. P. C.
(2004). Identification of Proline Residues in the Core Cytoplasmic and Transmembrane Regions of Multidrug Resistance Protein 1 (MRP1/ABCC1) Important for Transport Function, Substrate Specificity, and Nucleotide Interactions. J. Biol. Chem.
279: 12325-12336
[Abstract]
[Full Text]
-
Qiu, R., Kalhorn, T. F., Slattery, J. T.
(2004). ABCC2-Mediated Biliary Transport of 4-Glutathionylcyclophosphamide and Its Contribution to Elimination of 4-Hydroxycyclophosphamide in Rat. J. Pharmacol. Exp. Ther.
308: 1204-1212
[Abstract]
[Full Text]
-
Kharasch, E. D., Hoffer, C., Altuntas, T. G., Whittington, D.
(2004). Quinidine as a Probe for the Role of P-Glycoprotein in the Intestinal Absorption and Clinical Effects of Fentanyl. J Clin Pharmacol
44: 224-233
[Abstract]
[Full Text]
-
van der Heijden, J, de Jong, M C, Dijkmans, B A C, Lems, W F, Oerlemans, R, Kathmann, I, Schalkwijk, C G, Scheffer, G L, Scheper, R J, Jansen, G
(2004). Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNF{alpha}. Ann Rheum Dis
63: 138-143
[Abstract]
[Full Text]
-
van der Heijden, J, de Jong, M C, Dijkmans, B A C, Lems, W F, Oerlemans, R, Kathmann, I, Scheffer, G L, Scheper, R J, Assaraf, Y G, Jansen, G
(2004). Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs. Ann Rheum Dis
63: 131-137
[Abstract]
[Full Text]
-
Smitherman, P. K., Townsend, A. J., Kute, T. E., Morrow, C. S.
(2004). Role of Multidrug Resistance Protein 2 (MRP2, ABCC2) in Alkylating Agent Detoxification: MRP2 Potentiates Glutathione S-Transferase A1-1-Mediated Resistance to Chlorambucil Cytotoxicity. J. Pharmacol. Exp. Ther.
308: 260-267
[Abstract]
[Full Text]
-
Taniguchi, S., Mochida, Y., Uchiumi, T., Tahira, T., Hayashi, K., Takagi, K., Shimada, M., Maehara, Y., Kuwano, H., Kono, S., Nakano, H., Kuwano, M., Wada, M.
(2003). Genetic polymorphism at the 5' regulatory region of multidrug resistance 1 (MDR1) and its association with interindividual variation of expression level in the colon. Mol Cancer Ther
2: 1351-1359
[Abstract]
[Full Text]
-
Steinbach, D., Wittig, S., Cario, G., Viehmann, S., Mueller, A., Gruhn, B., Haefer, R., Zintl, F., Sauerbrey, A.
(2003). The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype. Blood
102: 4493-4498
[Abstract]
[Full Text]
-
Litman, T., Skovsgaard, T., Stein, W. D.
(2003). Pumping of Drugs by P-Glycoprotein: A Two-Step Process?. J. Pharmacol. Exp. Ther.
307: 846-853
[Abstract]
[Full Text]
-
Brooks, T., Minderman, H., O'Loughlin, K. L., Pera, P., Ojima, I., Baer, M. R., Bernacki, R. J.
(2003). Taxane-based reversal agents modulate drug resistance mediated by P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Mol Cancer Ther
2: 1195-1205
[Abstract]
[Full Text]
-
Yang, H. H., Ma, M. H., Vescio, R. A., Berenson, J. R.
(2003). Overcoming Drug Resistance in Multiple Myeloma: The Emergence of Therapeutic Approaches to Induce Apoptosis. J Clin Oncol
21: 4239-4247
[Abstract]
[Full Text]
-
de Jong, M. C., Scheffer, G. L., Broxterman, H. J., Hooijberg, J. H., Slootstra, J. W., Meloen, R. H., Kreitman, R. J., Husain, S. R., Joshi, B. H., Puri, R. K., Scheper, R. J.
(2003). Multidrug-Resistant Tumor Cells Remain Sensitive to a Recombinant Interleukin-4-Pseudomonas Exotoxin, Except When Overexpressing the Multidrug Resistance Protein MRP1. Clin Cancer Res
9: 5009-5017
[Abstract]
[Full Text]
-
HURBAIN, I., SERMET-GAUDELUS, I., VALLEE, B., FEUILLET, M.-N., LENOIR, G., BERNAUDIN, J.-F., EDELMAN, A., FAJAC, A.
(2003). Evaluation of MRP1-5 Gene Expression in Cystic Fibrosis Patients Homozygous for the {Delta}F508 Mutation. Pediatr Res
54: 627-634
[Abstract]
[Full Text]
-
Vaidyanathan, J. B., Walle, T.
(2003). Cellular Uptake and Efflux of the Tea Flavonoid (-)Epicatechin-3-gallate in the Human Intestinal Cell Line Caco-2. J. Pharmacol. Exp. Ther.
307: 745-752
[Abstract]
[Full Text]
-
Leonard, G. D., Fojo, T., Bates, S. E.
(2003). The Role of ABC Transporters in Clinical Practice. Oncologist
8: 411-424
[Abstract]
[Full Text]
-
Dazert, P., Meissner, K., Vogelgesang, S., Heydrich, B., Eckel, L., Bohm, M., Warzok, R., Kerb, R., Brinkmann, U., Schaeffeler, E., Schwab, M., Cascorbi, I., Jedlitschky, G., Kroemer, H. K.
(2003). Expression and Localization of the Multidrug Resistance Protein 5 (MRP5/ABCC5), a Cellular Export Pump for Cyclic Nucleotides, in Human Heart. Am J Pathol
163: 1567-1577
[Abstract]
[Full Text]
-
Gallo, J. M., Li, S., Guo, P., Reed, K., Ma, J.
(2003). The Effect of P-glycoprotein on Paclitaxel Brain and Brain Tumor Distribution in Mice. Cancer Res
63: 5114-5117
[Abstract]
[Full Text]
-
Slitt, A. L., Cherrington, N. J., Maher, J. M., Klaassen, C. D.
(2003). INDUCTION OF MULTIDRUG RESISTANCE PROTEIN 3 IN RAT LIVER IS ASSOCIATED WITH ALTERED VECTORIAL EXCRETION OF ACETAMINOPHEN METABOLITES. Drug Metab. Dispos.
31: 1176-1186
[Abstract]
[Full Text]
-
Li, T., Ito, K., Horie, T.
(2003). Transport of fluorescein methotrexate by multidrug resistance-associated protein 3 in IEC-6 cells. Am. J. Physiol.
285: G602-610
[Abstract]
[Full Text]
-
Warner, T. D., Mitchell, J. A.
(2003). Nonsteroidal antiinflammatory drugs inhibiting prostanoid efflux: As easy as ABC?. Proc. Natl. Acad. Sci. U. S. A.
100: 9108-9110
[Full Text]
-
Solary, E., Drenou, B., Campos, L., de Cremoux, P., Mugneret, F., Moreau, P., Lioure, B., Falkenrodt, A., Witz, B., Bernard, M., Hunault-Berger, M., Delain, M., Fernandes, J., Mounier, C., Guilhot, F., Garnache, F., Berthou, C., Kara-Slimane, F., Harousseau, J.-L.
(2003). Quinine as a multidrug resistance inhibitor: a phase 3 multicentric randomized study in adult de novo acute myelogenous leukemia. Blood
102: 1202-1210
[Abstract]
[Full Text]
-
Lockhart, A. C., Tirona, R. G., Kim, R. B.
(2003). Pharmacogenetics of ATP-binding Cassette Transporters in Cancer and Chemotherapy. Mol Cancer Ther
2: 685-698
[Abstract]
[Full Text]
-
Seward, D. J., Koh, A. S., Boyer, J. L., Ballatori, N.
(2003). Functional Complementation between a Novel Mammalian Polygenic Transport Complex and an Evolutionarily Ancient Organic Solute Transporter, OST{alpha}-OST{beta}. J. Biol. Chem.
278: 27473-27482
[Abstract]
[Full Text]
-
David-Cordonnier, M.-H., Laine, W., Joubert, A., Tardy, C., Goossens, J.-F., Kouach, M., Briand, G., Thi Mai, H. D., Michel, S., Tillequin, F., Koch, M., Leonce, S., Pierre, A., Bailly, C.
(2003). Covalent binding to glutathione of the DNA-alkylating antitumor agent, S23906-1. FEBS J
270: 2848-2859
[Abstract]
[Full Text]
-
Zelcer, N., Huisman, M. T., Reid, G., Wielinga, P., Breedveld, P., Kuil, A., Knipscheer, P., Schellens, J. H. M., Schinkel, A. H., Borst, P.
(2003). Evidence for Two Interacting Ligand Binding Sites in Human Multidrug Resistance Protein 2 (ATP Binding Cassette C2). J. Biol. Chem.
278: 23538-23544
[Abstract]
[Full Text]
-
Nzila, A., Mberu, E., Bray, P., Kokwaro, G., Winstanley, P., Marsh, K., Ward, S.
(2003). Chemosensitization of Plasmodium falciparum by Probenecid In Vitro. Antimicrob. Agents Chemother.
47: 2108-2112
[Abstract]
[Full Text]
-
Schroeder, U., Bernt, K. M., Lange, B., Wenkel, J., Jikai, J., Shabat, D., Amir, R., Huebener, N., Niethammer, A. G., Hagemeier, C., Wiebusch, L., Gaedicke, G., Wrasidlo, W., Reisfeld, R. A., Lode, H. N.
(2003). Hydrolytically activated etoposide prodrugs inhibit MDR-1 function and eradicate established MDR-1 multidrug-resistant T-cell leukemia. Blood
102: 246-253
[Abstract]
[Full Text]
-
Schroppel, B., Murphy, B.
(2003). Gene Variants Affecting Bioavailability of Drugs: Towards Individualized Immunosuppressive Therapy?. J Am Soc Nephrol
14: 1955-1957
[Full Text]
-
Suzuki, M., Suzuki, H., Sugimoto, Y., Sugiyama, Y.
(2003). ABCG2 Transports Sulfated Conjugates of Steroids and Xenobiotics. J. Biol. Chem.
278: 22644-22649
[Abstract]
[Full Text]
-
Mayer, F., Honecker, F., Looijenga, L. H. J., Bokemeyer, C.
(2003). Towards an understanding of the biological basis of response to cisplatin-based chemotherapy in germ-cell tumors. Ann Oncol
14: 825-832
[Abstract]
[Full Text]
-
Wang, S., Hartley, D. P., Ciccotto, S. L., Vincent, S. H., Franklin, R. B., Kim, M.-S.
(2003). INDUCTION OF HEPATIC PHASE II DRUG-METABOLIZING ENZYMES BY 1,7-PHENANTHROLINE IN RATS IS ACCOMPANIED BY INDUCTION OF MRP3. Drug Metab. Dispos.
31: 773-775
[Abstract]
[Full Text]
-
Hider, S L, Morgan, C, Bell, E, Bruce, I N, Ranganathan, P, McLeod, H L
(2003). Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with RA?. Ann Rheum Dis
62: 591-591
[Full Text]
-
Pedley, T. A., Hirano, M.
(2003). Is Refractory Epilepsy Due to Genetically Determined Resistance to Antiepileptic Drugs?. NEJM
348: 1480-1482
[Full Text]
-
Evans, W E
(2003). Pharmacogenomics: marshalling the human genome to individualise drug therapy. Gut
52: ii10-18
[Abstract]
[Full Text]
-
Allen, J. D., van Dort, S. C., Buitelaar, M., van Tellingen, O., Schinkel, A. H.
(2003). Mouse Breast Cancer Resistance Protein (Bcrp1/Abcg2) Mediates Etoposide Resistance and Transport, but Etoposide Oral Availability Is Limited Primarily by P-glycoprotein. Cancer Res
63: 1339-1344
[Abstract]
[Full Text]
-
Steinbach, D., Lengemann, J., Voigt, A., Hermann, J., Zintl, F., Sauerbrey, A.
(2003). Response to Chemotherapy and Expression of the Genes Encoding the Multidrug Resistance-associated Proteins MRP2, MRP3, MRP4, MRP5, and SMRP in Childhood Acute Myeloid Leukemia. Clin Cancer Res
9: 1083-1086
[Abstract]
[Full Text]
-
Mayer, F., Stoop, H., Scheffer, G. L., Scheper, R., Oosterhuis, J. W., Looijenga, L. H. J., Bokemeyer, C.
(2003). Molecular Determinants of Treatment Response in Human Germ Cell Tumors. Clin Cancer Res
9: 767-773
[Abstract]
[Full Text]
-
Burger, H., Foekens, J. A., Look, M. P., Meijer-van Gelder, M. E., Klijn, J. G. M., Wiemer, E. A. C., Stoter, G., Nooter, K.
(2003). RNA Expression of Breast Cancer Resistance Protein, Lung Resistance-related Protein, Multidrug Resistance-associated Proteins 1 and 2, and Multidrug Resistance Gene 1 in Breast Cancer: Correlation with Chemotherapeutic Response. Clin Cancer Res
9: 827-836
[Abstract]
[Full Text]
-
Evans, W. E., McLeod, H. L.
(2003). Pharmacogenomics -- Drug Disposition, Drug Targets, and Side Effects. NEJM
348: 538-549
[Full Text]
-
Leslie, E. M., Bowers, R. J., Deeley, R. G., Cole, S. P. C.
(2003). Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1). J. Pharmacol. Exp. Ther.
304: 643-653
[Abstract]
[Full Text]
-
Hitzl, M., Klein, K., Zanger, U. M., Fritz, P., Nussler, A. K., Neuhaus, P., Fromm, M. F.
(2003). Influence of Omeprazole on Multidrug Resistance Protein 3 Expression in Human Liver. J. Pharmacol. Exp. Ther.
304: 524-530
[Abstract]
[Full Text]
-
Chen, Z.-S., Hopper-Borge, E., Belinsky, M. G., Shchaveleva, I., Kotova, E., Kruh, G. D.
(2003). Characterization of the Transport Properties of Human Multidrug Resistance Protein 7 (MRP7, ABCC10). Mol Pharmacol
63: 351-358
[Abstract]
[Full Text]
-
Oleschuk, C. J., Deeley, R. G., Cole, S. P. C.
(2003). Substitution of Trp1242 of TM17 alters substrate specificity of human multidrug resistance protein 3. Am. J. Physiol.
284: G280-289
[Abstract]
[Full Text]
-
Manzini, I., Schild, D.
(2003). Multidrug resistance transporters in the olfactory receptor neurons of Xenopus laevis tadpoles. J Physiol
546: 375-385
[Abstract]
[Full Text]
-
Hong, J., Lu, H., Meng, X., Ryu, J.-H., Hara, Y., Yang, C. S.
(2002). Stability, Cellular Uptake, Biotransformation, and Efflux of Tea Polyphenol (-)-Epigallocatechin-3-Gallate in HT-29 Human Colon Adenocarcinoma Cells. Cancer Res
62: 7241-7246
[Abstract]
[Full Text]
-
Lamba, J. K., Adachi, M., Sun, D., Tammur, J., Schuetz, E. G., Allikmets, R., Schuetz, J. D.
(2003). Nonsense mediated decay downregulates conserved alternatively spliced ABCC4 transcripts bearing nonsense codons. Hum Mol Genet
12: 99-109
[Abstract]
[Full Text]
-
Kruijtzer, C.M.F., Beijnen, J.H., Schellens, J.H.M.
(2002). Improvement of Oral Drug Treatment by Temporary Inhibition of Drug Transporters and/or Cytochrome P450 in the Gastrointestinal Tract and Liver: An Overview. Oncologist
7: 516-530
[Abstract]
[Full Text]
-
Koike, K., Oleschuk, C. J., Haimeur, A., Olsen, S. L., Deeley, R. G., Cole, S. P. C.
(2002). Multiple Membrane-associated Tryptophan Residues Contribute to the Transport Activity and Substrate Specificity of the Human Multidrug Resistance Protein, MRP1. J. Biol. Chem.
277: 49495-49503
[Abstract]
[Full Text]
-
Mason, D. L., Michaelis, S.
(2002). Requirement of the N-Terminal Extension for Vacuolar Trafficking and Transport Activity of Yeast Ycf1p, an ATP-binding Cassette Transporter. Mol. Biol. Cell
13: 4443-4455
[Abstract]
[Full Text]
-
Ozvegy, C., Varadi, A., Sarkadi, B.
(2002). Characterization of Drug Transport, ATP Hydrolysis, and Nucleotide Trapping by the Human ABCG2 Multidrug Transporter. MODULATION OF SUBSTRATE SPECIFICITY BY A POINT MUTATION. J. Biol. Chem.
277: 47980-47990
[Abstract]
[Full Text]
-
Wielinga, P. R., Reid, G., Challa, E. E., van der Heijden, I., van Deemter, L., de Haas, M., Mol, C., Kuil, A. J., Groeneveld, E., Schuetz, J. D., Brouwer, C., De Abreu, R. A., Wijnholds, J., Beijnen, J. H., Borst, P.
(2002). Thiopurine Metabolism and Identification of the Thiopurine Metabolites Transported by MRP4 and MRP5 Overexpressed in Human Embryonic Kidney Cells. Mol Pharmacol
62: 1321-1331
[Abstract]
[Full Text]
-
Haimeur, A., Deeley, R. G., Cole, S. P. C.
(2002). Charged Amino Acids in the Sixth Transmembrane Helix of Multidrug Resistance Protein 1 (MRP1/ABCC1) Are Critical Determinants of Transport Activity. J. Biol. Chem.
277: 41326-41333
[Abstract]
[Full Text]
-
Burg, D., Wielinga, P., Zelcer, N., Saeki, T., Mulder, G. J., Borst, P.
(2002). Inhibition of the Multidrug Resistance Protein 1 (MRP1) by Peptidomimetic Glutathione-Conjugate Analogs. Mol Pharmacol
62: 1160-1166
[Abstract]
[Full Text]
-
Witt, K. A., Huber, J. D., Egleton, R. D., Davis, T. P.
(2002). Pluronic P85 Block Copolymer Enhances Opioid Peptide Analgesia. J. Pharmacol. Exp. Ther.
303: 760-767
[Abstract]
[Full Text]
-
Alcorn, J., Lu, X., Moscow, J. A., McNamara, P. J.
(2002). Transporter Gene Expression in Lactating and Nonlactating Human Mammary Epithelial Cells Using Real-Time Reverse Transcription-Polymerase Chain Reaction. J. Pharmacol. Exp. Ther.
303: 487-496
[Abstract]
[Full Text]
-
Lin, Z. P., Johnson, D. R., Finch, R. A., Belinsky, M. G., Kruh, G. D., Sartorelli, A. C.
(2002). Comparative Study of the Importance of Multidrug Resistance-associated Protein 1 and P-Glycoprotein to Drug Sensitivity in Immortalized Mouse Embryonic Fibroblasts. Mol Cancer Ther
1: 1105-1114
[Abstract]
[Full Text]
-
Adachi, M., Sampath, J., Lan, L.-b., Sun, D., Hargrove, P., Flatley, R., Tatum, A., Edwards, M. Z., Wezeman, M., Matherly, L., Drake, R., Schuetz, J.
(2002). Expression of MRP4 Confers Resistance to Ganciclovir and Compromises Bystander Cell Killing. J. Biol. Chem.
277: 38998-39004
[Abstract]
[Full Text]
-
Cox, D. S., Scott, K. R., Gao, H., Eddington, N. D.
(2002). Effect of P-Glycoprotein on the Pharmacokinetics and Tissue Distribution of Enaminone Anticonvulsants: Analysis by Population and Physiological Approaches. J. Pharmacol. Exp. Ther.
302: 1096-1104
[Abstract]
[Full Text]
-
Cao, J., Stieger, B., Meier, P. J., Vore, M.
(2002). Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy. Am. J. Physiol.
283: G757-766
[Abstract]
[Full Text]
-
Stein, U., Jurchott, K., Schlafke, M., Hohenberger, P.
(2002). Expression of Multidrug Resistance Genes MVP, MDR1, and MRP1 Determined Sequentially Before, During, and After Hyperthermic Isolated Limb Perfusion of Soft Tissue Sarcoma and Melanoma Patients. J Clin Oncol
20: 3282-3292
[Abstract]
[Full Text]
-
Cool, R. H., Veenstra, M. K., van Klompenburg, W., Heyne, R. I. R., Muller, M., de Vries, E. G. E., van Veen, H. W., Konings, W. N.
(2002). S-Decyl-glutathione nonspecifically stimulates the ATPase activity of the nucleotide-binding domains of the human multidrug resistance-associated protein, MRP1 (ABCC1). FEBS J
269: 3470-3478
[Abstract]
[Full Text]
-
Kimchi-Sarfaty, C., Gribar, J. J., Gottesman, M. M.
(2002). Functional Characterization of Coding Polymorphisms in the Human MDR1 Gene Using a Vaccinia Virus Expression System. Mol Pharmacol
62: 1-6
[Abstract]
[Full Text]
-
Smith, V., Rowlands, M. G., Barrie, E., Workman, P., Kelland, L. R.
(2002). Establishment and Characterization of Acquired Resistance to the Farnesyl Protein Transferase Inhibitor R115777 in a Human Colon Cancer Cell Line. Clin Cancer Res
8: 2002-2009
[Abstract]
[Full Text]
-
Zhang, D.-W., Cole, S. P. C., Deeley, R. G.
(2002). Determinants of the Substrate Specificity of Multidrug Resistance Protein 1. ROLE OF AMINO ACID RESIDUES WITH HYDROGEN BONDING POTENTIAL IN PREDICTED TRANSMEMBRANE HELIX 17. J. Biol. Chem.
277: 20934-20941
[Abstract]
[Full Text]
-
Sharma, K. G., Mason, D. L., Liu, G., Rea, P. A., Bachhawat, A. K., Michaelis, S.
(2002). Localization, Regulation, and Substrate Transport Properties of Bpt1p, a Saccharomyces cerevisiae MRP-Type ABC Transporter. Eukaryotic Cell
1: 391-400
[Abstract]
[Full Text]
-
Khokhar, N. Z., Lam, A. F. Y., Rusch, V. W., Sirotnak, F. M.
(2002). Despite some expression of folate receptor {alpha} in human mesothelioma cells, internalization of methotrexate is predominantly carrier mediated. J Thorac Cardiovasc Surg
123: 862-868
[Abstract]
[Full Text]
-
Bera, T. K., Iavarone, C., Kumar, V., Lee, S., Lee, B., Pastan, I.
(2002). MRP9, an unusual truncated member of the ABC transporter superfamily, is highly expressed in breast cancer. Proc. Natl. Acad. Sci. U. S. A.
99: 6997-7002
[Abstract]
[Full Text]
-
Scheffer, G L, Pijnenborg, A C L M, Smit, E F, Muller, M, Postma, D S, Timens, W, van der Valk, P, de Vries, E G E, Scheper, R J
(2002). Multidrug resistance related molecules in human and murine lung. J Clin Pathol
55: 332-339
[Abstract]
[Full Text]
-
Ilias, A., Urban, Z., Seidl, T. L., Le Saux, O., Sinko, E., Boyd, C. D., Sarkadi, B., Varadi, A.
(2002). Loss of ATP-dependent Transport Activity in Pseudoxanthoma Elasticum-associated Mutants of Human ABCC6 (MRP6). J. Biol. Chem.
277: 16860-16867
[Abstract]
[Full Text]
-
Allen, J. D., Schinkel, A. H.
(2002). Multidrug Resistance and Pharmacological Protection Mediated by the Breast Cancer Resistance Protein (BCRP/ABCG2). Mol Cancer Ther
1: 427-434
[Full Text]
-
Allen, J. D., van Loevezijn, A., Lakhai, J. M., van der Valk, M., van Tellingen, O., Reid, G., Schellens, J. H. M., Koomen, G.-J., Schinkel, A. H.
(2002). Potent and Specific Inhibition of the Breast Cancer Resistance Protein Multidrug Transporter in Vitro and in Mouse Intestine by a Novel Analogue of Fumitremorgin C. Mol Cancer Ther
1: 417-425
[Abstract]
[Full Text]
-
Audus, K. L., Soares, M. J., Hunt, J. S.
(2002). Characteristics of the Fetal/Maternal Interface with Potential Usefulness in the Development of Future Immunological and Pharmacological Strategies. J. Pharmacol. Exp. Ther.
301: 402-409
[Abstract]
[Full Text]
-
Crivellato, E., Candussio, L., Rosati, A. M., Bartoli-Klugmann, F., Mallardi, F., Decorti, G.
(2002). The Fluorescent Probe Bodipy-FL-Verapamil Is a Substrate for Both P-glycoprotein and Multidrug Resistance-related Protein (MRP)-1. J. Histochem. Cytochem.
50: 731-734
[Abstract]
[Full Text]
-
Loscher, W., Potschka, H.
(2002). Role of Multidrug Transporters in Pharmacoresistance to Antiepileptic Drugs. J. Pharmacol. Exp. Ther.
301: 7-14
[Abstract]
[Full Text]
-
van Aubel, R. A. M. H., Smeets, P. H. E., Peters, J. G. P., Bindels, R. J. M., Russel, F. G. M.
(2002). The MRP4/ABCC4 Gene Encodes a Novel Apical Organic Anion Transporter in Human Kidney Proximal Tubules: Putative Efflux Pump for Urinary cAMP and cGMP. J Am Soc Nephrol
13: 595-603
[Abstract]
[Full Text]
-
Zinchuk, V. S., Okada, T., Akimaru, K., Seguchi, H.
(2002). Asynchronous expression and colocalization of Bsep and Mrp2 during development of rat liver. Am. J. Physiol.
282: G540-548
[Abstract]
[Full Text]
-
Maggio-Price, L., Shows, D., Waggie, K., Burich, A., Zeng, W., Escobar, S., Morrissey, P., Viney, J. L.
(2002). Helicobacter bilis Infection Accelerates and H. hepaticus Infection Delays the Development of Colitis in Multiple Drug Resistance-Deficient (mdr1a-/-) Mice. Am J Pathol
160: 739-751
[Abstract]
[Full Text]
-
Zembutsu, H., Ohnishi, Y., Tsunoda, T., Furukawa, Y., Katagiri, T., Ueyama, Y., Tamaoki, N., Nomura, T., Kitahara, O., Yanagawa, R., Hirata, K., Nakamura, Y.
(2002). Genome-wide cDNA Microarray Screening to Correlate Gene Expression Profiles with Sensitivity of 85 Human Cancer Xenografts to Anticancer Drugs. Cancer Res
62: 518-527
[Abstract]
[Full Text]
-
Goldman, I. D.
(2002). Membrane Transport of Chemotherapeutics and Drug Resistance: Beyond the ABC Family of Exporters to the Role of Carrier-mediated Processes. Clin Cancer Res
8: 4-6
[Full Text]
-
Mathijssen, R. H.J., Verweij, J., de Jonge, M. J.A., Nooter, K., Stoter, G., Sparreboom, A.
(2002). Impact of Body-Size Measures on Irinotecan Clearance: Alternative Dosing Recommendations. J Clin Oncol
20: 81-87
[Abstract]
[Full Text]
-
Sisodiya, S. M., Lin, W.-R., Harding, B. N., Squier, M. V., Thom, M.
(2002). Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy. Brain
125: 22-31
[Abstract]
[Full Text]
-
Lee, G., Dallas, S., Hong, M., Bendayan, R.
(2001). Drug Transporters in the Central Nervous System: Brain Barriers and Brain Parenchyma Considerations. Pharmacological Reviews
53: 569-596
[Abstract]
[Full Text]
-
Zelcer, N., Saeki, T., Reid, G., Beijnen, J. H., Borst, P.
(2001). Characterization of Drug Transport by the Human Multidrug Resistance Protein 3 (ABCC3). J. Biol. Chem.
276: 46400-46407
[Abstract]
[Full Text]
-
Cui, Y., Konig, J., Keppler, D.
(2001). Vectorial Transport by Double-Transfected Cells Expressing the Human Uptake Transporter SLC21A8 and the Apical Export Pump ABCC2. Mol Pharmacol
60: 934-943
[Abstract]
[Full Text]
-
Smith, V., Raynaud, F., Workman, P., Kelland, L. R.
(2001). Characterization of a Human Colorectal Carcinoma Cell Line with Acquired Resistance to Flavopiridol. Mol Pharmacol
60: 885-893
[Abstract]
[Full Text]
-
Sampath, J., Sun, D., Kidd, V. J., Grenet, J., Gandhi, A., Shapiro, L. H., Wang, Q., Zambetti, G. P., Schuetz, J. D.
(2001). Mutant p53 Cooperates with ETS and Selectively Up-regulates Human MDR1 Not MRP1. J. Biol. Chem.
276: 39359-39367
[Abstract]
[Full Text]
-
Ito, K.-i., Oleschuk, C. J., Westlake, C., Vasa, M. Z., Deeley, R. G., Cole, S. P. C.
(2001). Mutation of Trp1254 in the Multispecific Organic Anion Transporter, Multidrug Resistance Protein 2 (MRP2) (ABCC2), Alters Substrate Specificity and Results in Loss of Methotrexate Transport Activity. J. Biol. Chem.
276: 38108-38114
[Abstract]
[Full Text]
-
Duesberg, P., Stindl, R., Hehlmann, R.
(2001). Origin of multidrug resistance in cells with and without multidrug resistance genes: Chromosome reassortments catalyzed by aneuploidy. Proc. Natl. Acad. Sci. U. S. A.
98: 11283-11288
[Abstract]
[Full Text]
-
Taipalensuu, J., Tornblom, H., Lindberg, G., Einarsson, C., Sjoqvist, F., Melhus, H., Garberg, P., Sjostrom, B., Lundgren, B., Artursson, P.
(2001). Correlation of Gene Expression of Ten Drug Efflux Proteins of the ATP-Binding Cassette Transporter Family in Normal Human Jejunum and in Human Intestinal Epithelial Caco-2 Cell Monolayers. J. Pharmacol. Exp. Ther.
299: 164-170
[Abstract]
[Full Text]
-
DeCory, H. H., Piech-Dumas, K. M., Sheu, S.-S., Federoff, H. J., Anders, M. W.
(2001). Efflux of Glutathione Conjugate of Monochlorobimane from Striatal and Cortical Neurons. Drug Metab. Dispos.
29: 1256-1262
[Abstract]
[Full Text]
-
Yamada, A., Kawano, K., Koga, M., Matsumoto, T., Itoh, K.
(2001). Multidrug Resistance-associated Protein 3 Is a Tumor Rejection Antigen Recognized by HLA-A2402-restricted Cytotoxic T Lymphocytes. Cancer Res
61: 6459-6466
[Abstract]
[Full Text]
-
Kihara, C., Tsunoda, T., Tanaka, T., Yamana, H., Furukawa, Y., Ono, K., Kitahara, O., Zembutsu, H., Yanagawa, R., Hirata, K., Takagi, T., Nakamura, Y.
(2001). Prediction of Sensitivity of Esophageal Tumors to Adjuvant Chemotherapy by cDNA Microarray Analysis of Gene-Expression Profiles. Cancer Res
61: 6474-6479
[Abstract]
[Full Text]
-
Ohno, N., Tani, A., Uozumi, K., Hanada, S., Furukawa, T., Akiba, S., Sumizawa, T., Utsunomiya, A., Arima, T., Akiyama, S.-i.
(2001). Expression of functional lung resistance-related protein predicts poor outcome in adult T-cell leukemia. Blood
98: 1160-1165
[Abstract]
[Full Text]
-
Wang, W., Seward, D. J., Li, L., Boyer, J. L., Ballatori, N.
(2001). Expression cloning of two genes that together mediate organic solute and steroid transport in the liver of a marine vertebrate. Proc. Natl. Acad. Sci. U. S. A.
98: 9431-9436
[Abstract]
[Full Text]
-
Legare, D., Richard, D., Mukhopadhyay, R., Stierhof, Y.-D., Rosen, B. P., Haimeur, A., Papadopoulou, B., Ouellette, M.
(2001). The Leishmania ATP-binding Cassette Protein PGPA Is an Intracellular Metal-Thiol Transporter ATPase. J. Biol. Chem.
276: 26301-26307
[Abstract]
[Full Text]
-
Dean, M., Rzhetsky, A., Allikmets, R.
(2001). The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Genome Res.
11: 1156-1166
[Abstract]
[Full Text]
-
Dean, M., Hamon, Y., Chimini, G.
(2001). The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid Res.
42: 1007-1017
[Abstract]
[Full Text]
-
Harris, M. J., Kuwano, M., Webb, M., Board, P. G.
(2001). Identification of the Apical Membrane-targeting Signal of the Multidrug Resistance-associated Protein 2 (MRP2/cMOAT). J. Biol. Chem.
276: 20876-20881
[Abstract]
[Full Text]
-
Advani, R., Fisher, G. A., Lum, B. L., Hausdorff, J., Halsey, J., Litchman, M., Sikic, B. I.
(2001). A Phase I Trial of Doxorubicin, Paclitaxel, and Valspodar (PSC 833), a Modulator of Multidrug Resistance. Clin Cancer Res
7: 1221-1229
[Abstract]
[Full Text]
-
Vulevic,, B., Chen, Z., Boyd, J. T., Davis, W. Jr., Walsh, E. S., Belinsky, M. G., Tew, K. D.
(2001). Cloning and Characterization of Human Adenosine 5'-triphosphate-binding Cassette, Sub-family A, Transporter 2 (ABCA2). Cancer Res
61: 3339-3347
[Abstract]
[Full Text]
-
Allen, J. D., Brinkhuis, R. F., Deemter, L. v., Wijnholds, J., Schinkel, A. H.
(2000). Extensive Contribution of the Multidrug Transporters P-Glycoprotein and Mrp1 to Basal Drug Resistance. Cancer Res
60: 5761-5766
[Abstract]
[Full Text]
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