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)

The human multidrug resistance P-glycoprotein is an active transporter that pumps cytotoxic drugs out of cells. Expression of P-glycoprotein is also associated with a volume-activated chloride channel. Here we address the relationship between these two functions. Drug transport requires ATP hydrolysis while, in contrast, ATP binding is sufficient to enable activation of the chloride channel. The chloride channel and drug transport activities of P-glycoprotein appear to reflect two distinct functional states of the protein that can be interconverted by changes in tonicity. Transportable drugs prevent channel activation but have no effect on channel activity once it has been preactivated by hypotonicity. The transport and channel functions of P-glycoprotein have been separated by directed mutations in the nucleotide-binding domains of the protein. These data provide further evidence that P-glycoprotein is bifunctional with both transport and channel activities. Implications for the design of chemotherapeutic drugs and for the function of the related cystic fibrosis gene product, CFTR, are discussed.
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PMID:Separation of drug transport and chloride channel functions of the human multidrug resistance P-glycoprotein. 138 60

In this review, we will emphasize the role of ATP-dependent membrane transporters in protein export and intracellular protein trafficking in prokaryotic and eukaryotic cells. ATP-binding-cassette (ABC)-transport proteins, also termed "traffic ATPases," belong to a superfamily of ubiquitous ATP-driven membrane transporters that share extensive sequence similarity and highly conserved domain organization. They are implicated in a remarkable variety of transmembrane transport processes, including the transport of ions, heavy metals, sugars, anticancer drugs, amino acids, oligopeptides, and proteins. Bacterial ABC-proteins include the well-characterized periplasmic permeases involved in nutrient uptake, but also include protein secretion systems, such as the exporter for the Escherichia coli enterotoxin hemolysin A. Prominent eukaryotic members of this superfamily include the human P-glycoprotein (which is associated with the phenomenon of multiple drug resistance in tumor cells), the product of the cystic fibrosis gene (CFTR), the gene (pfmdr) implicated in chloroquine resistance of the malarial parasite, putative peptide transporters encoded at the locus for the class II major histocompatibility complex (MHC), and the yeast Ste6 transporter which mediates export of a peptide hormone that lacks a classical hydrophobic signal peptide. The well-established function of prokaryotic ABC-transporters in the secretion of proteins without typical signal sequences, and the example set by the Ste6 transporter, have led to the reasonable hypothesis that certain ABC-proteins in animal cells may be operating by a similar mechanism to mediate the export of a new class of secretory proteins, those lacking a classical hydrophobic signal peptide.
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PMID:Secretion of peptides and proteins lacking hydrophobic signal sequences: the role of adenosine triphosphate-driven membrane translocators. 142 85

We have investigated the polarity of the efflux of the intracellular pH fluorochrome 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) from layers of epithelial Madin-Darby canine kidney (MDCK, Strains I and II) and human intestinal (Caco-2, HCT-8 and T84) cells grown on porous membranes. In Strain I MDCK cells, BCECF efflux was effectively reduced by indomethacin (50% inhibition with 100 microM) and 5-nitro-2-(3-phenylpropyl-amino)-benzoate (NPPB; 50% inhibition with 10 microM). Replacement of external Cl- with bromide, iodide or nitrate did not alter BCECF efflux, while substitution with methanesulphonate resulted in a small but significant reduction. All five cell lines form confluent epithelial layers when grown on porous membranes. Efflux of BCECF from Strain I MDCK epithelial layers into the apical solution was approximately three times greater than into the basal solution. Addition of indomethacin to the apical solution attenuated efflux into the apical but not the basal solution, while basal indomethacin was effective against basal efflux. NPPB has a similar specificity of action. Adrenaline, a stimulant of electrogenic Cl- secretion, did not alter the pattern of BCECF efflux. BCECF efflux was also polarized, with apical efflux greater than basal efflux, in MDCK Strain II and Caco-2 epithelial layers. In contrast, BCECF efflux into the basal and apical media was equivalent in layers formed from HCT-8 and T84 cells. However, indomethacin reduced efflux in all five epithelial lines, although the relative sensitivities of the apical and basal efflux rates to indomethacin varied, as did the sensitivity to the sidedness of application of indomethacin. In MDCK and HCT-8 epithelial layers, transepithelial vinblastine secretion mediated by P-glycoprotein was not inhibited by indomethacin. The data are consistent with the hypothesis that BCECF efflux is a manifestation of a novel ATP-dependent xenobiotic secretory efflux mechanism in renal and gastrointestinal epithelia. The factors regulating the polarity of BCECF efflux, both the indomethacin-sensitive and -insensitive components, have yet to be elucidated.
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PMID:Polarized efflux of 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein from cultured epithelial cell monolayers. 151 Jun 94

Resistance of human cancer cells to multiple cytotoxic hydrophobic agents (multidrug resistance) is due to overexpression of the MDR1 gene whose product is the ATP-dependent multidrug transporter, P-glycoprotein. We have previously reported that plasma membrane vesicles partially purified from multidrug-resistant human KB carcinoma cells, but not from drug-sensitive cells, accumulated [3H]vinblastine in an ATP-dependent manner (Horio, M., Gottesman, M.M. and Pastan, I. (1988) Proc. Natl. Acad. Sci. USA 85, 3580-3584). Certain calcium-channel blockers, quinidine, and phenothiazines are able to overcome multidrug resistance in cultured cells. In this work, the effect of these reversing agents on ATP-dependent vinblastine (VBL) transport by vesicles from drug-resistant KB cells has been characterized. Azidopine was the most potent inhibitor of ATP-dependent VBL uptake tested (ID50: concentration of inhibitor such that the transport of vinblastine is inhibited by 50%, less than 1 microM). Verapamil, quinidine, and the tiapamil analogue RO-11-2933 were potent but less effective inhibitors (ID50 less than 5 microM). Diltiazem, nifedipine and trifluoperazine were even less effective. These agents had no effect on Na(+)-dependent and Na(+)-independent L-leucine uptake by the vesicles, indicating that the inhibition of ATP dependent VBL transport by these agents is not a non-specific effect, as might result from leaks in the vesicle membrane. Verapamil, quinidine, azidopine and trifluoperazine increased the apparent Km value of vinblastine transport, suggesting that these agents may be competitive inhibitors of vinblastine transport.
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PMID:Agents which reverse multidrug-resistance are inhibitors of [3H]vinblastine transport by isolated vesicles. 167 42

The mechanism of the synthetic isoprenoid N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine (SDB-ethylenediamine) in potentiating antitumor drug action against multidrug-resistant cells was comparatively studied with other potentiators such as verapamil and cepharanthine. SDB-ethylenediamine increased the accumulation of [3H]daunorubicin (DNR) in Chinese hamster V79 (V79/S) and its multidrug-resistant mutant (V79/ADM) cells. Even after SDB-ethylenediamine was removed from the medium, its effect continued. But when verapamil was removed from the medium, its effect disappeared immediately. Unlike verapamil and cepharanthine, SDB-ethylenediamine did not greatly inhibit the efflux of [3H]DNR from V79/ADM, the binding of [3H]vinblastine to membrane vesicles of V79/ADM, or the binding of [3H]azidopine to P-glycoprotein in the cytoplasmic membrane of V79/ADM. It did stimulate the influx of [3H]DNR into the ATP-depleted cells of V79/S and V79/ADM. Thus, SDB-ethylenediamine uniquely potentiates antitumor drugs. The increased intracellular accumulation of antitumor drugs in the presence of SDB-ethylenediamine is due not only to the inhibition of active efflux but also to the stimulation of the influx of antitumor drugs.
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PMID:Novel mechanism of N-solanesyl-N,N'-bis(3,4-dimethoxybenzyl)ethylenediamine in potentiation of antitumor drug action on multidrug-resistant and sensitive Chinese hamster cells. 167 55

Overexpression of P-glycoprotein genes is a well-established cause of one form of multidrug resistance. P-glycoproteins are plasma membrane proteins containing two ATP-binding sites and twelve putative transmembrane segments. P-glycoproteins are thought to act as ATP-dependent drug efflux pumps, actively extruding a range of structurally different, hydrophobic drugs from the cell. This simple model can account for the properties of multidrug resistant cells, even those that seem to require more complex explanations. The structure and function of P-glycoprotein genes has been studied in mammals and in several lower eukaryotes. These studies are helping to delineate the range of drugs that can be transported by P-glycoproteins; the genetic mechanisms that can lead to elevated cellular P-glycoproteins levels; and the evolution of the versatile and prolific P-glycoprotein gene family. The physiological function of the human P-glycoproteins encoded by the MDR1 and MDR3 (or MDR2) genes remains a matter of speculation.
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PMID:Multidrug resistance mediated by P-glycoproteins. 168 Apr 93

Increased expression of P-glycoprotein (Pgp) has been demonstrated to cause multidrug resistance (MDR) in vitro, and it may be responsible for chemotherapy failure in a number of human cancers. Pgp is a plasma membrane protein thought to function as an energy-dependent drug transporter. From its deduced protein sequence the topology of Pgp was proposed to contain 12 transmembrane domains with six extracellular loops and two cytoplasmic ATP-binding sites. To investigate further the membrane orientation of Pgp, we have expressed a full length cDNA of mouse mdr1, as well as its truncated forms, in a cell-free system supplemented with dog pancreatic microsomal membranes (RM). We determined which domains of the in vitro-synthesized Pgp had transversed the RM membranes by analyzing their resistance to protease digestion and their glycosylation state. To our surprise, this system revealed that a significant portion of in vitro-synthesized Pgp molecules has an additional glycosylated domain in the C-terminal half. Previously, only the first predicted extracellular loop near the N terminus had been thought to be glycosylated. Furthermore, we discovered that Pgp has at least two functional signal recognition particle/docking protein dependent signal sequences, one at the N-terminal half and the other at the C-terminal half. These findings suggest a new topological model for in vitro synthesized P-glycoprotein which may be relevant to its in vivo topology.
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PMID:Study of membrane orientation and glycosylated extracellular loops of mouse P-glycoprotein by in vitro translation. 168 Aug 60

The role of P-glycoprotein in mediating the drug-resistance phenotype in multidrug resistant cells is now well documented. It is thought to function as an energy-dependent drug-efflux pump of broad specificity. Structurally, P-glycoprotein is an internally duplicated molecule containing two large multi-spanning transmembrane domains and two cytoplasmic ATP binding domains. In this report we demonstrate that monoclonal antibodies C219, C494, and C32 directed against short linear regions of the P-glycoprotein molecule inhibit ATP binding to P-glycoprotein in vitro. We also provide direct evidence that both predicted ATP-binding domains bind ATP and that there is co-operativity between the two sites. In addition, the capacity of P-glycoprotein to bind the calcium channel blocker, azidopine, is inhibited differentially by the antibodies. These observations are the first evidence linking specific perturbations of the P-glycoprotein molecule with ATP and drug binding.
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PMID:Modulation of ATP and drug binding by monoclonal antibodies against P-glycoprotein. 168 Aug 71

P-glycoprotein, a hydrophobic 170-kDa integral protein overexpressed in the plasma membrane of multidrug-resistant cells, is proposed to function as an ATP-dependent drug efflux pump. Plasma membrane preparations highly enriched in P-glycoprotein were isolated from multidrug-resistant cells by discontinuous sucrose gradient and Ca2+ precipitation methods. Several strategies were used for P-glycoprotein purification, with the goal being to achieve both good yields and purity, while keeping experimental manipulation to a minimum. P-glycoprotein was solubilized from the plasma membrane using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate. Immunoaffinity chromatography using C219 monoclonal antibody produced low yields of moderately pure protein. Sequential lectin affinity chromatography on RCA-120 followed by lentil lectin resulted in a P-glycoprotein preparation that showed a single band on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. A fraction of P-glycoprotein did not bind to RCA-120, most likely as a result of heterogeneous glycosylation. A combination of chromatography on RCA-120 followed by immunoaffinity chromatography on C219 resulted in low yields of very pure P-glycoprotein.
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PMID:Strategies for the purification of P-glycoprotein from multidrug-resistant Chinese hamster ovary cells. 168 82

Drug resistance has been shown to be associated with the expression of P-glycoprotein (P-gp), the product of mdr-1 gene. One of the suggested mechanisms for the phenomenon called Multidrug Resistance (MDR) is related to the overexpression and amplification of the mdr-1 gene. The product of this gene is called P-gp and it has been considered as a potential marker for drug resistance. Transfection of the mdr-1 gene into drug-sensitive cells confers the role of mdr-1 gene in developing MDR phenotype. Structural analysis of homologous cDNA, responsible for production of transport proteins, from: MDR cell lines, bacteria and yeast, revealed high similarity. Molecular structure analysis indicate that P-gp has nucleotide binding sites. It has been established that P-gh has an internal ATP-ase activity, thus it can act as energy dependent transport protein. The expression of P-gp has been found in neoplastic and normal tissues (as adrenal glands, kidney, liver, pancreas, jejunum and large intestine), as well as in several cell lines which have been induced to become resistant to cytostatics. The aim of present study was to review the role of P-gp expression in laboratory and clinic.
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PMID:[P glycoprotein and multidrug resistance]. 168 69


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