Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

P-glycoprotein, a 170-kd glycoprotein encoded by the MDR 1 gene, is a member of a highly conserved superfamily of ATP-binding cassette (ABC) transport proteins. It shares extensive homology with numerous bacterial and eukaryotic ABC transport proteins. P-glycoprotein acts as an energy-dependent efflux pump that appears to transport structurally diverse agents ranging from ions to peptides. P-glycoprotein (P-gP) has been implicated as playing a role in multidrug (MDR) resistance in cancer, chloroquine-resistant Plasmodium falciparum infection, and possibly human immunodeficiency virus-1 (HIV-1) resistance to nucleoside compounds. A number of normal tissues in humans and rodents have been shown to express high levels of P-gp. The expression and function of P-gp in cells of the immune system have been explored in the past 2 years. This review presents a state of the art regarding the expression, regulation, and function of Pgp in cells of the immune system. In addition, its alteration in aging and HIV-1 infection is reviewed. A possible physiologic role of P-gp in cytokine secretion, antigen processing/presentation, and effector functions is also discussed.
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PMID:P-glycoprotein (MDR 1 gene product) in cells of the immune system: its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. 790 61

We describe the selection of 3 new multidrug-resistant cell lines derived from tumor cells of different metastatic phenotypes within the Dunning R3327 model of rat prostatic carcinoma. Cell lines of weak (AT2) and strong (AT3 and MAT-LyLu) metastatic behavior were cultured in vitro and challenged with doxorubicin at progressively increasing concentrations. Chemosensitivity was determined colorimetrically by release of precipitated formazan pigment (MTT assay). Expression of the multidrug-resistance glycoprotein (P-170) was monitored immunocytochemically and by Western blotting using monoclonal antibody C219. The behavior of the parental and resultant drug-resistant cells was assessed by their growth in syngeneic rats. Doxorubicin challenge of the initially drug-sensitive parental prostatic carcinoma cell lines resulted in the rapid development of multidrug resistance together with simultaneous expression of P-glycoprotein. While lung and lymph-node metastases developed in host animals inoculated with parental AT3 and MAT-LyLu cells, no metastases developed in the multidrug-resistant progeny of these cell lines. This study has shown that Dunning rat prostate-carcinoma cell lines, previously sensitive to different cytotoxic agents, rapidly become multidrug-resistant and express P-glycoprotein following exposure to doxorubicin. Furthermore, development of multidrug resistance is associated with a less aggressive tumor phenotype and loss of metastatic potential. Nevertheless, it is unlikely that the non-metastatic phenotype of Dunning rat prostatic carcinoma cells is solely associated with expression of P-glycoprotein. These new multidrug-resistant cell lines exhibiting an altered behavioral phenotype will provide a valuable model with which to analyze the relationship between expression of P-glycoprotein and the metastatic phenotype of prostatic carcinoma cells.
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PMID:Establishment and in vivo characterization of multidrug-resistant dunning R3327 rat prostate-carcinoma cell-lines. 791 Aug 10

Two general approaches to the gene therapy of cancer have been proposed: (1) strategies that use exogenous genes to modify cancer cells so that they are less malignant or more susceptible to host defenses or to killing by exogenous agents; and (2) approaches that modify host cells so that they are more effective in eliminating cancer cells or more resistant to agents that are used to treat cancer. In both cases, the development of vectors that encode in vivo selectable phenotypes, such as drug resistance, would be extremely valuable because of the inherent inefficiency of gene transfer and the potential of such vectors to protect normal tissues against toxic agents. To allow the selection of cells in vivo that have been transduced with vectors for gene therapy, we have utilized the human multidrug resistance (MDR1) gene. The product of this gene is a 170,000-dalton glycoprotein known as P-glycoprotein, which acts as an energy-dependent efflux pump for a great many cytotoxic anticancer drugs, including doxorubicin, daunorubicin, etoposide, teniposide, actinomycin D, and taxol. Vectors encoding an MDR1 cDNA are able to transduce many cell types, including bone marrow cells, with high efficiency to allow selection of drug resistance in vitro and in vivo in mouse models. Thus, it should be possible to protect the bone marrow of patients undergoing intensive chemotherapy by transduction of their bone marrow with MDR1 vectors. Furthermore, the ability to select for the presence of the MDR1 cDNA in vivo means that it can be used to introduce otherwise nonselectable genes into the bone marrow for therapy of cancer and other diseases.
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PMID:Gene transfer of drug resistance genes. Implications for cancer therapy. 791 13

The MRP gene (Cole et al., Science (Washington DC), 258: 1650-1654, 1992) encodes a membrane-bound glycoprotein the expression of which correlates with non-P-glycoprotein-mediated multidrug resistance in a variety of cultured human cell lines. Using an RNA-polymerase chain reaction assay, expression of this gene was examined in the highly chemoresistant pediatric malignancy, neuroblastoma. MRP expression was observed in 5 human neuroblastoma cell lines and in all 25 primary neuroblastoma tumors of stage I through IVS. Tumors with amplification of the N-myc oncogene were found to have significantly higher MRP expression that those with no amplification (P = 0.0016). Expression of the MRP gene in the tumor specimens was highly correlated with expression of the N-myc gene (P = 0.0009), while expression of the MDR1 gene, encoding P-glycoprotein, was not related to expression of either the N-myc or MRP genes. Decreased expression of the N-myc oncogene in neuroblastoma cell lines SH-SY5Y and BE(2)-C, following treatment with retinoic acid, was paralleled by down-regulation of MRP gene expression, contrasting with increased expression of the MDR1 gene. Expression of the MRP gene is thus common in both primary neuroblastoma tumors and cultured cell lines, and correlates with amplification and overexpression of the N-myc oncogene, which is central to the malignant phenotype of this disease.
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PMID:Expression of the multidrug resistance-associated protein (MRP) gene correlates with amplification and overexpression of the N-myc oncogene in childhood neuroblastoma. 792 12

The expression of drug resistance antigens in mononuclear inflammatory cells was studied in transbronchial lung biopsy specimens of lung allograft recipients who experienced steroid-sensitive and steroid-resistant bouts of acute rejection and bronchiolitis obliterans. Immunostains for C494 and C219 epitopes of p-glycoprotein and human metallothionein revealed that (1) mononuclear cells expressing these antigens are present in the lung allograft during rejection, (2) that steroid-resistant acute rejection is associated with increased percentages of C494 and metallothionein-positive cells as compared to steroid-sensitive cases, (3) that bronchiolitis obliterans was associated with a higher percentage of cells with drug-resistant antigen expression, and (4) that steroid-resistant bronchiolitis obliterans is associated with the highest percentage of C494 and metallothionein-positive cells in the five clinical situations studied. P-glycoprotein and metallothionein expression may be a marker of aggressive or persistent cases of acute rejection and bronchiolitis obliterans.
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PMID:Multidrug resistance in lung allograft recipients: possible correlation with the development of acute and chronic rejection. 809 60

In this study we report detection of mdr1 gene expression in the liver metastases of 7/11 patients with colon carcinoma and characterise the MDR phenotype associated with a panel of 19 human colon carcinoma cell lines. Within this panel, mdr1 mRNA biosynthesis and surface localisation of Pgp were assessed with respect to MDR functionality where the cell lines are representative of different clinical stages of tumour progression, metastatic potential and differentiation. The data indicates that constitutive levels of mdr1 mRNA/Pgp expression may not necessarily result in the functional expression of the MDR phenotype. While low levels of mdr1 mRNA/Pgp were detected in 5/8 well differentiated colon cell lines, only 2/8 were functionally MDR. In contrast, 10/11 moderate and poorly differentiated lines expressed mdr1 mRNA/Pgp and of these, 9/11 were functionally MDR. The phosphorylation status of the mature 170 kD P-glycoprotein and the surface localisation of this glycoprotein showed the strongest correlation with functionality. Analysis of cell lines for cross-resistance and chemosensitivity profiles against a battery of chemotherapeutic drugs suggests multiple mechanisms, in addition to Pgp, contribute to the overall resistance of colorectal cancer.
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PMID:Constitutive expression of multidrug resistance in human colorectal tumours and cell lines. 809 14

HL60 cells isolated for resistance to Adriamycin (HL60/ADR) overexpress a 190-kDa ATP binding protein which has a minor sequence homology with P-glycoprotein. It has also been observed that HL60/ADR overexpress the MRP gene which was first identified as a component of a non-P-glycoprotein mediated multidrug resistance of H69/ADR cells [Cole et al., Science (Washington DC), 258: 1650, 1992]. A complementary DNA of MRP has been cloned and based on the deduced sequence encodes a member of the superfamily of proteins which bind ATP and function in various transport processes [Cole et al., Science (Washington DC), 258: 1650, 1992]. In view of this it was of interest to identify the protein encoded by MRP and determine if it may be related to p190. In the present study we have prepared antisera against three synthetic peptides which correspond to the deduced sequence of the MRP protein. Proteins reactive with the antisera have been examined in HL60/ADR cells using Western blot analysis. All antisera react with a 190 kDa protein contained in membranes of resistant but not sensitive cells. One antiserum used for further studies is not reactive with P-glycoprotein contained in membranes of HL60 cells isolated for resistance to vincristine. Analysis of subcellular fractions demonstrates that p190 is present primarily in the endoplasmic reticulum with lower levels also present in plasma membranes. Treatment of HL60/ADR cells with tunicamycin results in the appearance of a 165-kDa resistance associated protein which reacts with the antipeptide serum. The results of this study therefore demonstrate that the MRP gene encodes a 190-kDa membrane bound glycoprotein.
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PMID:The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. 810 65

P-glycoprotein (P-gp) is a highly-conserved membrane protein expressed in various multidrug-resistant cell lines. P-glycoprotein was detected in capillaries isolated from human, beef and rat brains with a Western immunoblotting procedure using the monoclonal antibody C219 (mAb C219) specific for P-gp. The mAb C219 detected a 180 kDa protein in brain capillaries isolated from all three species. The largest amount of antigen was detected in capillaries isolated from human brain. Specific binding was assessed by competitive inhibition of mAb C219 binding by the synthetic epitope VQEALD. The glycoprotein nature of the brain capillary proteins was confirmed by its sensitivity to N-glycanase treatment, which reduced their apparent molecular mass by 5 to 10 kDa. In addition, immunohistochemical studies using the antibodies C219, JSB-1 and C494 were performed. Bovine and rat capillaries showed reactivity only with the mAb C219. Heavy staining of human brain capillaries was observed with both antibodies C219 and JSB-1, while only weak staining was observed with antibody C494. These results clearly show that P-glycoprotein is strongly expressed at the blood-brain barrier (BBB) site and suggest that this protein may play a physiological role in regulating the access of certain molecules to the central nervous system, or in the secretory functions of the BBB.
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PMID:High levels of P-glycoprotein detected in isolated brain capillaries. 810 51

Among the mechanisms by which cancer cells evade chemotherapy, multidrug resistance (MDR) is certainly the best known. MDR is characterised by cross-resistance between numerous natural products used in cancer treatment, especially antibiotics and plant alkaloids. MDR results from a defect in cell accumulation of the drugs, which are actively effluxed from cells by a plasma membrane pump, which is a high molecular weight glycoprotein termed P-glycoprotein. This protein is encoded by a gene called mdr1, and can be inhibited by a variety of pharmacological compounds. The activation of the mdr1 gene can occur via numerous types of stimulation, especially anticancer drugs themselves, which can induce mdr1 gene transcription. P-glycoprotein is an ATPase transporter which is believed to extrude xenobiotics from the plasma membrane rather than from cytoplasm. Although potential sites of interaction of P-glycoprotein with its various ligands have been identified, especially at the level of putative transmembrane domains, the exact mechanism for drug pumping has never been elucidated. Reversal of MDR in vitro is easy to obtain and to characterise. An important development aims at identifying substances able to reverse MDR in the clinical setting, that are devoid of any pharmacological properties other than interaction with P-glycoprotein. Other targets can be postulated for these MDR modulators, whose combination could well lead to a synergistic reversal of drug resistance.
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PMID:[Multidrug resistance and its reversal. General review of fundamental aspects]. 873 88

Inherent or acquired resistance to multiple natural product drugs is a major obstacle to the success of chemotherapy. Two proteins have been shown to cause this type of multidrug resistance in human tumour cells, the 170 kDa P-glycoprotein and the 190 kDa multidrug resistance protein (MRP). Overexpression of these N-glycosylated phosphoproteins in mammalian cells is associated with reduced drug accumulation. Both MRP and p-glycoprotein belong to the ATP-binding cassette superfamily of transmembrane transport proteins, but they share only 15% amino acid identity. Furthermore, their predicted membrane topologies differ considerably, with MRP containing three multispanning transmembrane domains compared with the two that are present in P-glycoprotein. The drug cross-resistance profiles of cells that overexpress MRP or P-glycoprotein are similar but not identical. For example, lower levels of taxol resistance are associated with overexpression of MRP than with overexpression of P-glycoprotein. There also appear to be fundamental differences in the mechanisms by which the two proteins transport chemotherapeutic drugs. P-glycoprotein-enriched membrane vesicles have been shown to directly transport several chemotherapeutic drugs, whereas vincristine transport by MRP-enriched membrane vesicles is demonstrable only in the presence of reduced glutathione. Several potential physiologic substrates of MRP including leukotriene C4 and 17 beta-estradiol-17-(beta-D-glucuronide) have been identified. In contrast, these conjugated organic anions are transported poorly, if at all, by P-glycoprotein. Finally, agents that reverse P-glycoprotein-associated resistance are usually much less effective in MRP-associated resistance. Antisense oligonucleotide-mediated suppression of MRP synthesis offers a highly specific alternative approach to circumventing resistance mediated by this novel drug resistance protein.
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PMID:Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. 883 15


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