Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P33527 (ABCC1)
 1,164 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MDR1 (P-glycoprotein), multidrug resistance-associated protein (MRP) and lung resistance protein (LRP) are associated with multidrug resistance in various cancer cells. It is known that P-glycoprotein and MRP are also expressed in several normal tissues. However, the exact location of LRP in normal tissues is still unclear. In order to obtain more insight into the physiological role of LRP, its expression in human normal tissues was examined by an immunohistochemical technique, using one monoclonal antibody, LRP-56. Reverse transcriptase-polymerase chain reaction (RT-PCR) was also utilized for several cell lines and fresh-frozen tissues. P-glycoprotein was found to be expressed in the kidney, adrenal, brain vessels, muscle, lung, pancreas, liver, intestine, placenta and testis. MRP was expressed in the kidney, adrenal, lung, pancreas, muscle, intestine, thyroid and prostate, and its distribution mostly overlapped with that of P-glycoprotein. Interestingly, MRP was not expressed in the liver. LRP at 110 kDa was expressed in the kidney, adrenal, heart, lung, muscle, thyroid, prostate, bone marrow and testis. These findings suggest that LRP as well as P-glycoprotein and MRP plays distinct roles in the physiology of various organs.
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PMID:Lung resistance protein (LRP) expression in human normal tissues in comparison with that of MDR1 and MRP. 902 66

The multidrug resistance proteins, discovered as membrane transporters producing chemotherapy-resistance in cancer, are functioning as complex cellular defence systems through recognition and energy-dependent removal of a large variety of toxic agents. The multidrug transporters belong to the ATP-binding cassette (ABC) transporters, present both in prokaryotes and eukaryotes and built from a combination of characteristic membrane-spanning helices and cytoplasmic ATP-binding domains. In mammals the MDR1 (P-glycoprotein) extrudes large hydrophobic compounds and provides the basis of the blood-brain and the blood-testis barrier for such molecules. The multidrug resistance-associated protein (MRP) and its homologues have a major role in the cellular export of large organic anions, including e.g. conjugated bile salts and glutathione-conjugates. The substrate recognition, that is the self and non-self discrimination and the ATP-dependent foreign agent extrusion are directly coupled within the structure of these large plasma membrane proteins. Here we suggest that the multidrug transporters are essential parts of our immune-defence system, working as 'cellular antitoxic' mechanisms.
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PMID:The multidrug transporters--proteins of an ancient immune system. 905 81

Three agents, verapamil, cepharanthine, and 2-[4-(diphenylmethyl)-1-piperazinyl]ethyl-5-(trans-4,6-dimethyl-1, 3,2-dioxaphosphorinan-2-yl)-2,6-dimethyl-4-(3-nitrophenyl)-3-py ridinecarboxylate P-oxide (PAK-104P), that reverse drug resistance in P-glycoprotein (P-Gp)-mediated multidrug-resistant cells were examined for their activity to reverse drug resistance in multidrug resistance-associated protein (MRP)-mediated multidrug-resistant C-A120 cells. Agents other than PAK-104P could not reverse the resistance to doxorubicin in C-A120 cells. PAK-104P moderately reversed the doxorubicin resistance. In contrast, PAK-104P almost completely reversed the resistance to vincristine (VCR) in C-A120 cells as well as in KB-8-5 cells, and other agents moderately reversed the VCR resistance in C-A120 cells. PAK-104P at 10 microM enhanced the accumulation of VCR in C-A120 cells to the level of that in KB-3-1 cells without the agent. PAK-104P competitively inhibited the ATP-dependent [3H]leukotriene C4 uptake in membrane vesicles isolated from C-A120 cells. These findings demonstrate that PAK-104P can completely reverse the resistance to VCR in both P-Gp- and MRP-mediated multidrug-resistant cells and that PAK-104P directly interacts with MRP and inhibits the transporting activity of MRP.
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PMID:Reversal of multidrug resistance-associated protein-mediated drug resistance by the pyridine analog PAK-104P. 905 94

P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) are members of the superfamily of ATP-binding cassette transporter proteins. Because the ATP-dependent export system has been implicated in the release of leukotriene C4 (LTC4), we examined the roles of P-gp and MRP in the release of LTC4 from normal murine mast cells (MC-9). We have previously shown that MC-9 cells express P-gp at the level of protein and mRNA. In the present study, MRP expression in MC-9 cells was examined at the protein level by anti-MRP Ab, using flow cytometry and at the level of mRNA by PCR and Northern blot analyses. MC-9 cells were stimulated with calcium ionophore A23187 for 15 min in the presence or the absence of various concentrations of cyclosporin A (CsA) and its nonimmunosuppressive analogue CsA-1, which are known to inhibit P-gp efflux function, or in the presence or the absence of probenecid, an organic ion transport inhibitor that appears to inhibit MRP-mediated transport function. Culture supernatants were collected, and LTC4 was measured by ELISA assay. CsA and CsA-1 had no effect on LTC4 secretion from MC-9 cells, suggesting that P-gp is not involved in LTC4 release from MC-9 cells. In contrast, probenecid, in a concentration-dependent manner, inhibited LTC4 secretion from MC-9 cells without inhibiting its synthesis. However, MC-9 lacked MRP at both the protein and mRNA levels. These data suggest that LTC4 is secreted by normal mast cells by a probenecid-sensitive mechanism that is independent of MRP.
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PMID:Leukotriene C4 secretion from normal murine mast cells by a probenecid-sensitive and multidrug resistance-associated protein-independent mechanism. 914 9

Multidrug resistance (MDR) is a major hindrance to the successful treatment of neoplastic disease. The development of resistance to multiple chemotherapeutic drugs is a complex phenomenon which has been described in both tumor cell lines and human cancers. To date, two mechanisms associated with overexpression of membrane glycoproteins that function as energy-dependent efflux pumps to reduce intracellular drug levels have been identified for MDR. The first described was the product of the MDR1 gene, P-glycoprotein. The second mechanism is mediated by overexpression of the multidrug resistance-associated protein (MRP). While these proteins both belong to the ATP-binding cassette superfamily of transporters, they are only distantly related. Despite this low homology, they mediate resistance to a similar range of chemotherapeutic drugs. While P-glycoprotein has been well described in the literature, much less is known about the recently identified MRP. This review gives an overview of the characteristics of MRP at both the phenotypic and genotypic levels, and discusses its possible relevance in drug-refractory cancer.
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PMID:The role of multidrug resistance-associated protein (MRP) expression in multidrug resistance. 914 6

Previous work investigating the role of MDR-1 overexpression in relapsed and refractory lymphoma led us to investigate a possible role for multidrug resistance-associated protein (MRP) as a cause of resistance in patients who did not overexpress MDR-1. A quantitative polymerase chain reaction (PCR) method for measuring MRP expression was validated. Immunoblot analysis suggested that no major discrepancy was present between mRNA expression and protein levels. MRP levels were found to be independent of sample tumor content by immunophenotyping, suggesting that the presence of normal cells had no significant impact on measurements of MRP expression. We evaluated MRP in 55 biopsy samples from 40 patients with refractory lymphoma enrolled on a trial of infusional chemotherapy (EPOCH). Pre- and post-EPOCH samples were available from 15 patients. MRP levels were also evaluated in 16 newly diagnosed, untreated lymphoma patient samples. No significant difference in MRP mRNA expression was noted between pre- and post-EPOCH groups. Also, MRP levels in the newly diagnosed patient samples were not significantly different from either pre- or post-EPOCH groups. Two of 15 paired pre- and post-EPOCH patient samples exhibited overexpression of MRP after EPOCH chemotherapy, with measured increases of 10-fold and 18-fold. We conclude that MRP overexpression is not responsible for non-P-glycoprotein (Pgp)-mediated drug resistance in the majority of these patients, although it may be important in a subset of patients. Defining this subset prospectively could aid in the development of clinical trials of MRP modulation in drug-resistant lymphoma.
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PMID:Expression of the multidrug resistance-associated protein gene in refractory lymphoma: quantitation by a validated polymerase chain reaction assay. 916 Jun 86

An attempt was made to isolate resistant sublines of acute myelogenous leukemia (OCI/ AML-2) cells by chronic exposure to gradually increasing concentrations of daunorubicin in order to determine the mechanism of its resistance to this drug. Four daunorubicin-resistant sublines, AML-2/D100, /D250, /D500, and /D1,000 were isolated. The values of relative resistance of each daunorubicin-resistant AML subline were about 3, 6, 18, and 23-fold, respectively, as compared to the AML-2 line with an IC50 of 5 nM. The daunorubicin-resistant AML-2 sublines also showed cross resistance to various anticancer drugs including another anthracycline doxorubicin, a Vinca alkaloid vincristine, and an epipodophyllotoxin etoposide. A functional assay using flow cytometry showed decreased accumulation of daunorubicin in these sublines as compared to that of AML-2, which was reversed by cyclosporin A or cyanide. The development of the ATP-dependent multidrug resistant phenotype was due to low to high levels of expression of P-glycoprotein (PGP). The major mechanisms of increased PGP appears to be associated with gene amplification. In addition, other mechanisms such as increased stability of protein or mRNA might be involved depending on the concentration of daunorubicin used for selection. However, a multidrug resistance-associated protein (MRP) was not involved in these resistant sublines. These daunorubicin-resistant AML-2 sublines could provide a useful model for the study of multidrug resistance mediated by PGP.
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PMID:Isolation and characterization of daunorubicin-resistant AML-2 sublines. 916 28

Contemporary therapies for acute myeloid leukemia (AML) commonly fail to cure patients because of the emergence of drug resistance. Drug resistance in AML is multifactorial but can be associated with the overexpression of transmembrane transporter molecules, including P-glycoprotein (Pgp) or the multidrug resistance-associated protein (MRP), or associated with inactivation of the p53 tumor suppressor gene, as well as overexpression of the anti-apoptotic protein bcl-2. We are investigating if novel recombinant biotherapeutics can circumvent these resistance mechanisms to effectively treat refractory AML. To target the lethal action of diphtheria toxin (DT) to high affinity granulocyte-macrophage colony-stimulating factor (GMCSF) receptors on AML blasts, we have produced a recombinant chimeric fusion toxin, DTctGMCSF. Since DTctGMCSF enters and kills its target cells by unique mechanisms (GMCSF-receptor binding and protein synthesis inhibition) and is not similar in structure to Pgp or MRP substrates, we postulated that it would be an active agent against therapy-resistant AML. DTctGMCSF was selectively cytotoxic (IC50 1-10ng/ml) to GMCSF-receptor positive AML cells expressing the Pgp- or MRP-associated multi-drug resistant phenotypes, despite high level resistance to conventional chemotherapeutic agents. DTctGMCSF also efficiently killed AML cells deficient in p53 expression, as well as radiation-resistant AML cells and mixed lineage leukemia cells expressing high levels of bcl-2. In addition, DTctGMCSF killed > 99% of primary leukemic progenitor cells from therapy-refractory AML patients under conditions that we have previously found to not adversely affect the proliferative capacity or differentiation of pluripotent normal hematopoietic progenitor cells. DTctGMCSF may prove useful in treating myeloid leukemias that are otherwise resistant to a wide range of conventional therapies.
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PMID:Granulocyte-macrophage colony-stimulating factor receptor-targeted therapy of chemotherapy- and radiation-resistant human myeloid leukemias. 916 35

1. Multidrug resistance (MDR) is a phenomenon originally seen in cultured tumor cells that, following selection for resistance to a single anticancer agent, become resistant to a range of chemically diverse anticancer agents. These MDR cells show a decrease in intracellular drug accumulation due to active efflux by transporter proteins. The transporter best characterized is P-glycoprotein (Pgp). This protein has been identified in many cancers and has been the target for agents able to inhibit its action, thereby reversing resistance. 2. More recently, another transporter, multidrug resistance-associated protein (MRP) has been identified in a number of MDR human tumor cell lines that do not apparently express Pgp. The presence of MRP at the cell surface of these cells is associated with alterations in drug accumulation and distribution. 3. The gene-encoding MRP has been cloned and sequenced and shown by transfection studies to be able to confer resistance and changes in drug accumulation in sensitive tumor cells. The profile of anticancer drugs expelled in the presence of MRP is similar, but not identical, to that of Pgp. 4. MRP has been identified in a number of different types of cancers, but it is not yet clear to what extent it is involved with clinical resistance. Furthermore, resistance modulators useful against Pgp are less effective in reversing MRP-mediated resistance. 5. It is not fully understood how MRP brings about drug efflux, but it is clear that the underlying mechanisms are different from those responsible for Pgp-mediated drug efflux. In particular, glutathione (GSH) is required for the effective expulsion of the anticancer agents. 6. Unlike Pgp, MRP is able to transport metallic oxyanions and glutathione and other conjugates, including peptidyl leukotrienes. Agents that inhibit organic anion transport, such as probenecid, can block MRP activity. 7. Like Pgp, MRP is expressed not only in resistant tumor cells, but also in normal human tissues. These include the epithelial cells lining the airways and the gastrointestinal tract. In cells in normal tissues, MRP appears to be located within the cytoplasm, which may mean that it functions here in a manner slightly different to that in malignant cells. It is now also recognized in cells and tissues from other species, such as the rat and mouse.
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PMID:Multidrug resistance-associated protein: a protein distinct from P-glycoprotein involved in cytotoxic drug expulsion. 918 95

In summary, the data suggest that E217G is transported by both MOAT and P-glycoprotein into bile, but that P-glycoprotein serves as the target site for cholestasis. We postulate that this target site may be accessed from either the intracellular compartment or the canaliculus, and that MOAT serves as the major delivery route for E217G to the canaliculus. At low, physiologic concentrations of E217G, MOAT-mediated excretion into bile is a detoxification mechanism, serving to prevent intracellular accumulation of a toxic metabolite. However, following administration of high, cholestatic doses, MOAT-mediated excretion into bile results in very high concentrations in bile, on the other of 2-3 mM (see Fig. 4). It is likely that the hydrophobic nature of E217G allows it to partition from bile into the canalicular membrane, from which it can access P-glycoprotein and thus induce cholestasis. Much work is still needed to validate this model of E217G cholestasis. Definitive evidence of P-glycoprotein-mediated transport of E217G must be obtained in cell lines transfected with P-glycoprotein where MRP is absent. More importantly, the mechanism by which interaction of E217G with P-glycoprotein influences bile flow is unknown. Higgins and colleagues have provided evidence that P-glycoprotein regulates a Cl- channel in a manner analogous to that of CFTR, the cystic fibrosis transmembrane conductance regulator. While Cl- channels have been shown to be important in the regulation of the volume of the hepatocyte in the presence of altered osmotic conditions, a role for this channel in bile flow has not been demonstrated. Nevertheless, these studies implicate a role of P-glycoprotein in the regulation of bile secretion by the liver.
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PMID:Cholestatic properties and hepatic transport of steroid glucuronides. 918 18


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