Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance-associated protein (MRP) and P-glycoprotein are drug efflux pumps conferring multidrug resistance to tumor cells and sharing numerous substrates. In order to determine a flow cytometric assay allowing to analyse MRP activity in cancerous cells in a sensitive and specific manner, cellular accumulation and efflux of the anionic fluorescent dye carboxy-2',7'-dichlorofluorescein (CDF) were studied by flow cytometry using mainly MRP-overexpressing lung GLC4/Sb30 cells and parental GLC4 cells. GLC4/Sb30 cells were found to display reduced accumulation and enhanced efflux of the dye when compared to their parental counterparts. Probenecid, a well known blocker of MRP, strongly enhanced CDF accumulation in GLC4/Sb30 cells through inhibiting efflux of the dye; it also increased CDF levels in GLC4 cells, although to a lesser extent, which may likely be linked to the low, but detectable, expression of MRP in these cells. Comparison of CDF retention with that of calcein demonstrated that the former dye was the most efficiently effluxed by GLC4/Sb30 cells. In contrast to MRP overexpression, that of P-glycoprotein was not found to alter cellular CDF labelling whereas it strongly impaired calcein staining. These results indicate that CDF is a substrate for MRP, but not for P-gp, which may likely be useful for sensitive and specific flow cytometric determination of MRP activity in clinical samples.
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PMID:Use of the anionic dye carboxy-2',7'-dichlorofluorescein for sensitive flow cytometric detection of multidrug resistance-associated protein activity. 1042 42

The clinical benefit of Cyclosporine A (CsA) in IBD is controversial. Drugs including CsA are substrates of the P-glycoprotein-170 (Pgp-170) cell surface pump. Although the mechanism of action of CsA is complex, we determined that Pgp-170 might be expressed differentially between these two diseases. Intra-epithelial, lamina propria and peripheral blood lymphocytes were stained with the antibody MRK-16, which recognizes the surface antigen Pgp-170. Functional activity was assayed using a Rhodamine dye efflux assay (Rh123). RT-PCR was used to detect Pgp-170 mRNA. Overall, less P-gp-170 surface expression was found on UC CD3+ intestinal lymphocytes compared to controls and Crohn's disease. A decrease in Pgp-170 activity was also measured using the Rh123 functional assay. Fewer CD8+ intraepithelial lymphocytes (IEL) (which intrinsically have more Pgp-170 function) were also found in UC. Furthermore, UC IEL P-gp expression was under the limit of detection by RT-PCR. Overall, greater and differential expression, function and mRNA for Pgp-170 was found in Crohn's disease compared to the UC and normal tissues analyzed.
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PMID:Differences in P-glycoprotein-170 expression and activity between Crohn's disease and ulcerative colitis. 1043 13

Methadone is used as a treatment for opiate detoxification in methadone maintenance programs. Intra- and inter-patient variations in methadone bioavailability have been observed after oral methadone treatment and this makes it difficult to predict a dosing regimen. Intestinal absorption and metabolism could explain these variations. The in vitro gut sac model was used to study the intestinal absorption of methadone, and it confirmed that methadone is a substrate for P-glycoprotein. The transport of methadone was increased in presence of P-gp inhibitors verapamil and quinidine. The appearance of a major metabolite of methadone, 2-ethylidene-1, 5-dimethyl-3, 3-diphenyl pyrrolidine (EDDP) in the gut sac contents also demonstrated the existence of intestinal metabolism of methadone.
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PMID:The roles of P-glycoprotein and intracellular metabolism in the intestinal absorption of methadone: in vitro studies using the rat everted intestinal sac. 1045 92

The expression of P-glycoprotein in 159 non-small cell lung cancers was immunohistochemically examined using a monoclonal antibody (MoAb C219). A total of 93 (60%) cancers were found to be positive for P-glycoprotein. The 5-year survival rates of patients with P-glycoprotein (P-gp+) and those without P-glycoprotein (P-gp-) were 47.6% and 73.6%, respectively (P < 0.05). According to a univariate analysis, P-gp+ was associated with a poor prognosis for males, those with stage I cancer, those who underwent complete resection, and those with adenocarcinoma or squamous cell carcinoma. A multivariate study using the Cox regression analysis indicated that the expression of P-glycoprotein is useful for predicting the prognosis. Among 24 patients who underwent complete resection and postoperative adjuvant chemotherapy, 18 were P-gp+ and the remaining 6 were P-gp-. Of the 18 with P-gp+ cancer, 11 relapsed and 9 died from tumor-related causes, while the other 7 remain free from tumor recurrence; however, all with P-gp- cancer are alive without recurrence. These observations suggest a bias toward a shorter survival for patients with P-gp+ cancer because P-glycoprotein may be associated with chemoresistance. Thus, detection of the expression of P-glycoprotein will aid in planning appropriate adjuvant chemotherapy for patients with non-small cell lung cancer.
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PMID:Immunohistochemical evidence that P-glycoprotein in non-small cell lung cancers is associated with shorter survival. 1055 31

Elucidating the molecular function of hu MDR 1 protein (also called P-glycoprotein or P-gp 1) and the precise role this protein plays in clinically relevant tumor drug resistance remains a perplexing problem. Hundreds of reports over the past decades summarize a dizzying array of observations relevant to hu MDR 1 protein function. A dominant model in the MDR literature that is used to explain many observations is the well known "drug pump" model first suggested by Keld Dano in 1973 [1]. Although this model has proved useful in conceptualizing additional experiments, it violates fundamental laws of biology and chemistry and in well over a decade of intense effort, active outward drug pumping via hu MDR 1 protein has still never been unequivocally measured. Also, in recent years it has become clear that the drug pump model cannot explain several important phenomena that are highly relevant to the cancer clinic. Thus, other models have also proved increasingly popular. One is the altered partitioning model, which does not violate fundamental laws, is consistent with the vast majority of available data, and has important predictive ability. This newer model has several novel facets that are relevant for cancer pharmacology, and that help explain phenomena not explained by the drug pump model. The basic principle of this model is that MDR proteins do not directly transport drugs, but that their altered expression leads to altered regulation of ion transport or signal transduction that is critical for setting key biophysical parameters of the cell (e.g. compartmental pH and membrane potentials) that dictate relative passive diffusion of drugs as well as important signal transduction linked to the cytotoxic actions of these drugs. Along with debate over the molecular details of hu MDR 1 function, additional controversy surrounds the precise role of hu MDR 1 in the clinic. Many investigators now debate the significance of its function (regardless of precise mechanism) with regard to "real" drug resistance phenotypes exhibited in the clinic. I believe that thorough debate on the pros and cons of various molecular models for hu MDR 1 function will help to address confusion over the clinical relevance of hu MDR1. In the current atmosphere of disappointment over the relative success of clinical trials based in large part on the logic of the drug pump model, it is important that we not lose sight of critical points. Namely, hu MDR 1 protein remains an extremely important window in on the complex pathways that lead to induced chemotherapeutic drug resistance. Exploring the rationale behind newer models for hu MDR 1 function leads to key predictions that can be tested.
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PMID:What is the precise role of human MDR 1 protein in chemotherapeutic drug resistance? 1063 78

Mobilized peripheral blood progenitor cells (PBPC) are a potential target for the retrovirus-mediated transfer of cytostatic drug-resistance genes. We analyzed nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse-repopulating CD34+ PBPC from patients with cancer after retroviral transduction in various cytokine combinations with the hybrid vector SF-MDR, which is based on the Friend mink cell focus-forming/murine embryonic stem-cell virus and carries the human multidrug resistance 1 (MDR1) gene. Five to 13 weeks after transplantation of CD34+ PBPC into NOD/SCID mice (n = 84), a cell dose-dependent multilineage engraftment of human leukocytes up to an average of 33% was observed. The SF-MDR provirus was detected in the bone marrow (BM) and in its granulocyte fractions in 96% and 72%, respectively, of chimeric NOD/SCID mice. SF-MDR provirus integration assessed by quantitative real-time polymerase chain reaction (PCR) was optimal in the presence of Flt-3 ligand/thrombopoietin/stem-cell factor, resulting in a 6-fold (24% +/- 5% [mean +/- SE]) higher average proportion of gene-marked human cells in NOD/SCID mice than that achieved with IL-3 alone (P <.01). A population of clearly rhodamine-123(dull) human myeloid progeny cells could be isolated from BM samples from chimeric NOD/SCID mice. On the basis of PCR and rhodamine-123 efflux data, up to 18% +/- 4% of transduced cells were calculated to express the transgene. Our data suggest that the NOD/SCID model provides a valid assay for estimating the gene-transfer efficiency to repopulating human PBPC that may be achievable in clinical autologous transplantation. P-glycoprotein expression sufficient to prevent marrow aplasia in vivo may be obtained with this SF-MDR vector and an optimized transduction protocol. (Blood. 2000;95:1237-1248)
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PMID:Quantitative assessment of retroviral transfer of the human multidrug resistance 1 gene to human mobilized peripheral blood progenitor cells engrafted in nonobese diabetic/severe combined immunodeficient mice. 1066 96

The MDR1 multidrug transporter P-gp (P-glycoprotein) is an efflux pump that extrudes diverse hydrophobic drugs and peptides from cells. Since the entry of HIV-1 into cells involves an initial interaction of the viral gp41 hydrophobic peptide with the plasma membrane, a potential effect of P-gp on HIV-1 infectivity was explored. Virus production was greatly decreased when P-gp was overexpressed at the surface of a continuous CD4(+) human T-leukemic cell line (12D7) infected with HIV-1(NL4-3), a T-tropic molecular clone of HIV-1. P-gp overexpression did not significantly alter the surface expression or distribution of either the HIV-1 receptor CD4 or the coreceptor CXCR4. Reduction of HIV-1 infectivity in P-gp-expressing cells occurred both during the fusion of viral and plasma membranes and at subsequent step(s) in the HIV-1 life cycle.
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PMID:Effect of ABC transporters on HIV-1 infection: inhibition of virus production by the MDR1 transporter. 1069 67

P-glycoprotein was initially isolated due to its role in multidrug resistance to cancer chemotherapeutics. Recent work, however, makes it increasingly apparent that this transporter is also involved in the pharmacokinetics of many drugs. P-gp is strategically expressed in the luminal epithelial cells of organs often associated with drug absorption and disposition, for example, hepatocyte canalicular membrane, renal proximal tubules, and the intestinal mucosa. P-gp is also expressed in the endothelial cells comprising the blood-brain barrier. This localization clearly suggests the potential for this protein to serve as a protective mechanism against entry of toxic xenobiotics and also suggests that P-gp is well situated to participate in the removal of therapeutic agents. Numerous investigations with drugs such as digoxin, etoposide, cyclosporine, vinblastine, Taxol, loperamide, dom-peridone, and ondansteron demonstrate that P-gp has an important role in determining the pharmacokinetics of substrate drugs. Pharmacological modulation of P-gp function to increase drug bioavailability, both on a organismal and a cellular level, is one approach currently being explored to enhance therapeutic effectiveness. This approach is not without potential collateral consequences given the wide tissue distribution of P-gp. While animals deficient in P-gp are viable and without obvious abnormalities, the pharmacokinetics and toxic consequences of several compounds are significantly altered in these animals. Thus blockade of the protective P-gp barrier in humans may have adverse effects on substrate drugs. In particular, this situation may arise when several compounds which may be substrates compete for P-gp-mediated transport. Additional multidrug transporters, notably MRP and family members, have been identified and may also determine the fate of pharmaceuticals. Further understanding the physiological role of each of the multidrug transporters is critical for determining their role in pharmacokinetics and for evaluating the consequences of modification of their activities. Such information is also important in the development of novel drugs which may be substrates for these transporters.
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PMID:Multidrug-resistance transporters. 1074 82

The multidrug resistance protein 2 (MRP2, symbol ABCC2) transports anionic conjugates and certain amphiphilic anions across the apical membrane of polarized cells. Human hepatoma Hep G2 cells retain hepatic polarity and form apical vacuoles into which cholephilic substances are secreted. Immunofluorescence microscopy showed that human MRP2 was expressed in the apical vacuole membrane of polarized Hep G2 cells, whereas the isoform MRP3 was localized to the lateral membrane. Expression of both MRP2 and MRP3 was confirmed by immunoblotting and reverse transcription PCR. Fluo 3 secretion into the apical vacuoles was inhibited by cyclosporin A but not by selective inhibitors of multidrug resistance 1 P-glycoprotein. In addition, carboxyfluorescein, rhodamine 123, and the fluorescent bile salt derivatives ursodeoxycholyl-(Nepsilon-nitrobenzoxadiazolyl)-lysine and cholylglycylamido-fluorescein were secreted into the apical vacuoles; the latter two probably via the bile salt export pump. We conclude that MRP2 mediates fluo 3 secretion into the apical vacuoles of polarized Hep G2 cells. Thus the function of human MRP2 and the action of inhibitors can be analyzed by the secretion of fluorescent anions such as fluo 3.
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PMID:MRP2, a human conjugate export pump, is present and transports fluo 3 into apical vacuoles of Hep G2 cells. 1076 5

Infection of HeLa cells with adenovirus-carrying HSF1(+) cDNA, which encodes a mutated form of HSF1 with constitutive transactivation capacity, increased multidrug resistance 1 (MDR1) mRNA level and P-glycoprotein (P-gp) cell surface content and stimulated rhodamine 123 accumulation and vinblastine efflux activity. On the other hand, infection with adenovirus-carrying HSP70 and HSP27 cDNAs did not increase MDR1/P-gp expression. HSF1 regulates MDR1/P-gp expression at the transcriptional level, since HSF1(+) bound the heat-shock consensus elements (HSEs) in the MDR1 gene promoter and also activated the expression of an MDR1 promoter-driven reporter plasmid (pMDR1(-1202)). In addition, heat-shock increased pMDR1(-1202) promoter activity but not the activity of a similar reporter plasmid with point mutations at specific HSEs, and the heat-induced increase was totally inhibited by co-transfection with an expression plasmid carrying HSF1(-), a dominant negative mutant of HSF1. The stress inducers arsenite, butyrate, and etoposide also increased pMDR1(-1202) promoter activity, but the increase was not inhibited (in the case of butyrate) or was only partially inhibited (in the case of arsenite and etoposide) by HSF1(-). These results demonstrate that HSF1 regulates MDR1 expression, and that the HSEs present in the -315 to -285 region mediate the heat-induced activation of the MDR1 promoter. However, other factors may also participate in MDR1 induction by stressing agents.
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PMID:Regulation of multidrug resistance 1 (MDR1)/P-glycoprotein gene expression and activity by heat-shock transcription factor 1 (HSF1). 1081 97


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