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 resistant (MDR) cells overexpress a 170-180 kDa membrane glycoprotein, the P-glycoprotein, which is believed to export drugs in an ATP-dependent manner. Plasma membrane vesicles from the MDR CHRC5 cell line, but not the AuxB1 drug-sensitive parent, showed uptake of [3H]colchicine and [3H]vinblastine that was stimulated by the presence of ATP and an ATP-regenerating system. Steady-state uptake of drugs was achieved by 10 min and was stable for greater than 30 min. Non-hydrolysable ATP analogues were unable to support drug uptake, indicating that ATP hydrolysis is essential for transport. ATP-stimulated drug uptake appeared to result from drug transport into inside-out vesicles, since uptake was osmotically sensitive and could be prevented by detergent permeabilization. Steady-state uptake was half-maximal at 100 microM colchicine and 200 nM vinblastine and was inhibited by a 10-100-fold excess of MDR drugs and chemosensitizers, in the order vinblastine greater than verapamil greater than daunomycin greater than colchicine. In addition to being vanadate-sensitive, drug uptake was inhibited by 10-200 microM concentrations of several sulfhydryl-modifying reagents, suggesting that cysteine residues play an important role in drug transport. Vesicular colchicine was rapidly exchanged by an excess of unlabelled drug, demonstrating that drug association is the net result of opposing colchicine fluxes across the membrane.
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PMID:Transport properties of P-glycoprotein in plasma membrane vesicles from multidrug-resistant Chinese hamster ovary cells. 135 67

Reduced drug accumulation is the most common functional change accompanying development of P-glycoprotein-associated multidrug resistance. One of our laboratories showed earlier that the anthracycline analogue 4'-deoxy-4'-iododoxorubicin (DIDOX) was accumulated to identical levels in Ehrlich ascites tumor (EHR2) and daunorubicin (DNR)-resistant EHR2/DNR+ cells (E. Friche, P. B. Jensen, T. Skovsgaard, and N. I. Nissen, J. Cell. Pharmacol., 1:57-65, 1990). In this communication, we show that weekly treatment of EHR2-bearing mice with 4, 8, or 12 mg of DIDOX/kg/week led to the development of three DIDOX-resistant cell lines, EHR2/DIDOX-1, EHR2/DIDOX-2, and EHR2/DIDOX-3. The levels of DIDOX accumulation and retention and its outward transport were similar in the drug-sensitive and three drug-resistant cell lines. By contrast, the accumulation of the active DIDOX metabolite, 13-dihydro-DIDOX (13-OH-DIDOX), the parent compound doxorubicin, and daunorubicin were all decreased in proportion to the resistance of the cells. In EHR2/DIDOX-3 cells, the reduction in daunorubicin accumulation coincided with the development of P-glycoprotein as demonstrated by Western blot and flow cytometry with C219 antibody. DIDOX had no effect on the photolabeling of P-glycoprotein by [3H]azidopine, whereas 13-OH-DIDOX inhibited this labeling in a concentration-dependent manner. Subsequent analysis of topoisomerase II activities and amounts in EHR2/DIDOX-3 cells revealed decreased DNA topoisomerase II catalytic activity. The amounts of immunoreactive DNA topoisomerase II from EHR2/DIDOX-1, EHR2/DIDOX-2, and EHR2/DIDOX-3 cells were about 89%, 73%, and 52%, respectively, of that seen in the drug-sensitive cells. We also found that teniposide stabilized DNA-protein complexes in EHR2/DIDOX-3 but they never reached the level seen in EHR2 cells. Because it has been reported that DIDOX is rapidly metabolized to 13-OH-DIDOX, we postulate that the development of resistance to DIDOX in vivo is due in part to its metabolite, 13-OH-DIDOX, which is a substrate for plasma membrane glycoprotein, and in part to DIDOX, which is an inhibitor of topoisomerase II.
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PMID:Characterization of tumor cell resistance to 4'-deoxy-4'-iododoxorubicin developed in Ehrlich ascites cells in vivo. 135 19

Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. MDR is a complex and multifactorial phenomenon. One important and common mechanism used by cancer cells as a defense against cytotoxic drugs is a 170-kD plasma membrane glycoprotein, P-glycoprotein (P-gp). P-gp confers resistance by actively pumping cytotoxic drugs out of cancer cells. Paradoxically, P-gp overexpression on tumor cells is frequently associated with enhanced susceptibility to lymphokine-activated killer cell activity. This enhanced susceptibility is not observed with P-gp- MDR cells, nor is susceptibility to natural killer cells increased. The physiologic, evolutionary and immunologic concepts with regard to the P-gp and the possible intervention of the function of the P-gp in cancer therapy are reviewed.
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PMID:P-glycoprotein-mediated multidrug resistance and cytotoxic effector cells. 135 93

The multidrug-resistant (MDR) phenotype is characterized in vitro by the resistance displayed by cell lines to a broad spectrum of natural product cytotoxic agents. This high level of cross-resistance is due to the increased expression of a membrane glycoprotein termed P-glycoprotein. Encoded in humans by the mdr1 gene, P-glycoprotein functions as an energy-dependent efflux pump of these cytotoxic agents. In this report, we demonstrate that the newly characterized immunosuppressant FK506 and its structural analogue, rapamycin, are capable of functioning as MDR reversal agents. FK506 and rapamycin increase both intracellular, cytotoxic drug (daunomycin) accumulation, and the cytotoxicity of chemotherapeutic agents in multidrug-resistant cells. The increase in cytotoxic drug accumulation is observed at concentrations of FK506 and rapamycin 1,000-fold greater than the concentrations required for FK506 and rapamycin to inhibit T-lymphocyte activation and similar to those shown to be effective for other MDR reversal agents such as cyclosporine A (CsA) and verapamil. The effect of FK506 or rapamycin on both intracellular accumulation and cytotoxicity of daunomycin is additive. This is supported by the ability of FK506 and rapamycin to directly compete the binding of the photoaffinity analogue 125I-iodoaryl azidoprazosin to the P-glycoprotein. The data demonstrate that FK506 and rapamycin represent a new class of structurally distinct molecules that can function as MDR reversal agents and suggest a previously unidentified, potential clinical role for these compounds.
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PMID:Immunosuppressants FK506 and rapamycin function as reversal agents of the multidrug resistance phenotype. 138 29

Fluorescence-emission spectra from anthracycline-treated cells suspended in buffer have been used to measure the uptake of three anthracycline derivatives: adriamycin, 4'-O-tetrahydropyranyladriamycin and aclacinomycin in drug-sensitive and drug-resistant K562 cells. The initial rate of uptake and the kinetics of active efflux under the effect of an integral membrane glycoprotein, P-glycoprotein, have been measured as a function of temperature. The activation energies for the passage of the drugs through the plasma membrane have been calculated. In the case of 4'-O-tetrahydropyranyladriamycin, the activation energies for the passive diffusion of the drug equal 45 kJ.mol-1 and 37 kJ.mol-1 for sensitive and resistant cells, respectively. The activation energy for the active efflux of 4'-O-tetrahydropyranyladriamycin equal 25 kJ.mol-1.
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PMID:Kinetic parameters for the uptake of anthracycline by drug-resistant and drug-sensitive K562 cells. 154 Dec 82

Tumor cells exposed in tissue culture to one of several different classes of antineoplastic agents, including anthracyclines, vinca alkaloids, epipodophyllotoxins, and certain antitumor antibiotics, can develop resistance to the selecting agent and cross resistance to the other classes of agents. This phenomena of multidrug resistance is generally associated with decreased drug accumulation and overexpression of a membrane glycoprotein. This membrane protein, referred to as P-glycoprotein, apparently acts as an energy-dependent drug efflux pump. Multidrug resistance in human MCF-7 breast cancer cells selected for resistance to adriamycin (AdrR MCF-7) is associated with amplification and overexpression of the mdr1 gene which encodes P-glycoprotein. A number of other changes are also seen in this resistant cell line including alterations in Phase I and Phase II drug metabolizing enzymes. Similar biochemical changes occur in a rat model for hepatocellular carcinogenesis and are associated in that system with broad spectrum resistance to hepatotoxins. The similar changes in these two models of resistance suggests that these changes might be part of a battery of genes whose expression can be altered in response to cytotoxic stress, thus rendering the cell resistant to a wide variety of cytotoxic agents.
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PMID:Keynote address: multidrug resistance: a pleiotropic response to cytotoxic drugs. 167 83

Multidrug resistance describes an experimental observation which appears to explain cross-resistance to certain structurally unrelated cytotoxic agents, including anthracyclines, vinca alkaloids and podophyllotoxins. It is now clear that a major factor responsible for its development is increased expression of a membrane glycoprotein--P-glycoprotein, which functions as an energy-dependent efflux pump. Recent data, particularly in haematological malignancies such as acute non-lymphocytic leukaemia, myeloma and non-Hodgkin's lymphoma, indicate that P-glycoprotein may be involved in the development of clinical drug resistance. The potential therefore exists for new therapeutic studies aimed at circumventing resistance which develops through this mechanism, by using modulators, such as verapamil, quinidine and several others, which prevent cellular drug efflux by competitive binding to P-glycoprotein.
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PMID:Multidrug resistance: clinical relevance in haematological malignancies. 167 35

The most consistantly reported alteration of multidrug-resistant carcinoma cells is the overexpression of a membrane glycoprotein, termed P-glycoprotein. In this study we examined whether the strong intrinsic chemotherapy resistance of glial tumors might be related to the expression of the MDR1 gene which codes for P-glycoprotein. Fourteen glial tumors were examined immunohistochemically using the monoclonal antibody C219. In addition, RNA samples of 11 of these tumors were analysed using a sensitive Northern blot assay. P-glycoprotein is expressed in all 14 glial tumors; the number of stained tumor cells, however, varied considerably ranging from 0.3% to 15%. There was no correlation between the number of MDR1-positive cells and the histological malignancy. Varying amounts of MDR1 mRNA were detectable in 7 from 11 examined tumors. The results of our study show that the MDR1 gene is expressed in human glial tumors and suggest that the multidrug transporter may contribute to the clinical non-responsiveness of these tumors to chemotherapy.
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PMID:The multidrug-resistance gene MDR1 is expressed in human glial tumors. 172 31

Direct photoaffinity labeling of liver plasma membrane subfractions enriched in sinusoidal and canalicular membranes using [35S]adenosine 5'-O-(thiotriphosphate) ([35S]ATP gamma S) allows the identification of ATP-binding proteins in these domains. Comparative photoaffinity labeling with [35S]ATP gamma S and with the photolabile bile salt derivative (7,7-azo-3 alpha, 12 alpha-dihydroxy-5 beta-[3 beta-3H]-cholan-24-oyl-2'- aminoethanesulfonate followed by immunoprecipitation with a monoclonal antibody (Be 9.2) revealed the identity of the ATP-binding and the bile salt-binding canalicular membrane glycoprotein with the apparent Mr of 110,000 (gp110). The isoelectric point of this glycoprotein was 3.7. Transport of bile salt was studied in vesicles enriched in canalicular and sinusoidal liver membranes. Incubation of canalicular membrane vesicles with [3H] taurocholate in the presence of ATP resulted in an uptake of the bile salt into the vesicles which was sensitive to vanadate. ATP-dependent taurocholate transport was also observed in membrane vesicles from mutant rats deficient in the ATP-dependent transport of cysteinyl leukotrienes and related amphiphilic anions. Substrates of the P-glycoprotein (gp170), such as verapamil and doxorubicin, did not interfere with the ATP-dependent transport of taurocholate. Reconstitution of purified gp110 into liposomes resulted in an ATP-dependent uptake of [3H]taurocholate. These results demonstrate that gp110 functions as carrier in the ATP-dependent transport of bile salts from the hepatocyte into bile. This export carrier is distinct from hitherto characterized ATP-dependent transport systems.
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PMID:ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt. 191 7

The most frequently reported alteration of multidrug resistance (MDR) is the overexpression of the 170 kd membrane glycoprotein. An increased expression of the MDR-gene in pre-neoplastic and neoplastic liver lesions produced experimentally by different carcinogens has been reported. As shown in rat liver by stop experiments, specific carcinogen-induced alterations can be separated from non-specific, toxic changes. Therefore, we induced rat hepatocellular carcinomas with N-nitrosomorpholine and investigated whether expression of the MDR-gene also takes place in hepatocellular carcinomas after withdrawal of the carcinogen. Using mAb C219 against P-glycoprotein, both normal liver and hepatocellular carcinomas show specific immunoreactivity by means of immunofluorescence and immunohistochemistry. In hepatocellular carcinomas, however, the reaction is increased if compared to normal liver of untreated control animals. These results were confirmed by immunoblotting. Using the cDNA probe 1.5, a significant increase in MDR-gene transcripts was found in hepatocellular carcinomas as compared to normal liver.
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PMID:Overexpression of P-glycoprotein in rat hepatocellular carcinomas induced with N-nitrosomorpholine. 196 29


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