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-glycoproteins are responsible for multidrug resistance in tumor cell lines and are thought to have a physiologic role in exporting cellular metabolites. We now report that a P-glycoprotein gene in the H region of the trypanosomatid protozoan Leishmania confers resistance to heavy metals when present in multiple copies. The Leishmania H region is frequently amplified in drug-resistant lines and is associated with metal resistance. Leishmania expression vectors were used to introduce multiple copies of segments of the Leishmania major H region into wild-type L. major promastigotes. Only constructs bearing a segment of L. major DNA containing the P-glycoprotein lmpgpA conferred arsenite resistance. Deletional analysis of the arsenite-resistant construct mapped resistance to the lmpgpA protein coding region. Lines expressing lmpgpA showed resistance to arsenite and trivalent antimonials, but not to pentavalent antimonials, zinc, cadmium, or the typical multidrug-resistant P-glycoprotein substrates vinblastine and puromycin. Transfection of the Leishmania tarentolae P-glycoprotein homologue ltpgpA resulted in a similar resistance profile. Thus, these pgpAs represent a functionally distinct group of P-glycoproteins which exhibit a substrate specificity similar to prokaryotic heavy metal pumps. Additionally, several arguments suggest that pgpAs may play a role in the susceptibility of Leishmania to clinically utilized antimonials.
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PMID:Heavy metal resistance: a new role for P-glycoproteins in Leishmania. 168 Aug 61

The Mr 170,000 to 180,000 membrane glycoprotein associated with multidrug resistance (P-glycoprotein) is involved in drug transport mechanisms across the plasma membrane of multidrug-resistant cells. We have recently reported the purification of P-glycoprotein. The purified P-glycoprotein was found to have an ATPase activity, which might be coupled with the active efflux of anticancer drugs. In the present study, we have further studied the properties of the P-glycoprotein ATPase activity by an immobilized enzyme assay procedure using a P-glycoprotein-antibody-Protein A-Sepharose complex. GTP was also hydrolyzed by the P-glycoprotein, although less efficiently than ATP. The ATPase activity of P-glycoprotein had an optimal pH range around neutrality (pH 6.5-7.4). The detergent concentration of 3-[(3-cholamidopropyl)dimethyl-ammonio]-1-propane sulfonate used for protein solubilization was essential for enzyme recovery. Maximum activity was obtained when 0.1-0.2% 3-[(3-cholamidopropyl)dimethyl-ammonio]-propane sulfonate was used, while higher concentrations markedly inhibited the ATPase activity. The ATPase activity was dependent on Mg2+; maximum activity was obtained at 2-10 mM. Manganese and cobalt could substitute for magnesium as ionic cofactors. Divalent cations such as Ca2+, Zn2+, Ni2+, Cd2+, and Cu2+ inhibited the Mg2+-catalyzed ATP hydrolysis. N-Ethylmaleimide and vanadate inhibited the ATPase activity, while sodium azide or ouabain had no effect. Anticancer agents such as vincristine and Adriamycin did not affect the enzyme activity. In contrast, verapamil and trifluoperazine, agents which inhibit active drug efflux and restore drug sensitivity in resistant cells, caused an increase in the P-glycoprotein ATPase activity suggesting that P-glycoprotein might be the target molecule of these agents.
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PMID:Characterization of the ATPase activity of the Mr 170,000 to 180,000 membrane glycoprotein (P-glycoprotein) associated with multidrug resistance in K562/ADM cells. 290 Jun 77

We have previously demonstrated that glutathione S-transferase pi (GST pi) is overexpressed in SA7 cells, an arsenic resistant cell line derived from Chinese hamster ovary (CHO) cells. Our present results show that SA7 cells accumulate less arsenic than parental CHO cells and partially revertant SA7N cells. The lower levels of arsenic accumulation in SA7 cells resulted from their faster excretion rates. However, the excretion of arsenic from SA7 cells was significantly inhibited by the GST inhibitors ethacrynic acid and Cibacron blue. Furthermore, when GST pi levels in SA7N cells were re-elevated by zinc sulfate pretreatment, arsenic accumulation decreased and arsenic excretion increased to levels similar to those in SA7 cells. These results suggest that GST pi can facilitate the excretion of arsenic. Such facilitation by GST pi is unlikely to be associated with multi-drug resistant P-glycoprotein, since no overexpression of P-glycoprotein was detected in SA7N and SA7 cells.
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PMID:Glutathione S-transferase pi facilitates the excretion of arsenic from arsenic-resistant Chinese hamster ovary cells. 809 79

A high-performance liquid chromatographic assay with fluorescence detection has been developed for the determination of doxorubicin and its metabolite doxorubicinol in plasma of cancer patients. Quantitative extraction was achieved by a single protein-precipitation step of 1-ml samples with 500 microl of acetone in the presence of 100 microl of zinc sulfate [70% (w/v) in water]. Doxorubicin and doxorubicinol were separated isocratically on a column packed with Inertsil ODS-80A material and a mobile phase composed of water:acetonitrile:tetrahydrofuran (76:24:0.5, v/v/v). The related compound daunorubicin was used as internal standard. The column effluent was monitored fluorimetrically at an excitation wavelength of 480 nm and an emission wavelength of 560 nm, with a band width of 40 nm. The calibration graphs of doxorubicin and doxorubicinol were linear over a range of 1.0 to 100 and 0.50 to 50. 0 ng/mL, respectively, with lower limits of quantitation of 1.0 and 0.50 ng/ml. Results obtained from a 4-day validation study demonstrated excellent accuracy (91.0-106%) and precision (0.90-10. 2%) across the calibration ranges for both compounds. The developed method has been applied extensively to a clinical study to examine the pharmacokinetics and metabolism of doxorubicin in patients cotreated with a potent inhibitor of MDR1 P-glycoprotein activity, GF120918.
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PMID:Determination of doxorubicin and doxorubicinol in plasma of cancer patients by high-performance liquid chromatography. 988 78

The purpose of this work was to elucidate the transport pathways of zinc insulin across the Calu-3 cell monolayer, an in vitro model of the human airway epithelium. Calu-3 cells grown in liquid-covered conditions formed a confluent monolayer with a high transepithelial electrical resistance value of 1000 +/- 150 Omega small middle dot cm(2). The cell monolayer was characterized by a low mannitol permeability of 4.7 +/- 0.5 10(-7)cm/s. Transport of zinc insulin (donor concentration 1 U/mL) in Dulbecco's modified phosphate buffer saline at 37 degrees C was found to be higher in the basolateral (BL) to apical (AP) (P(app) = 3.0 +/- 0.2 10(-8) cm/s), than in the AP to BL direction (P(app) = 0.41 +/- 0.02 10(-8) cm/s). P-glycoprotein efflux or specific enzymatic degradation did not appear to contribute toward this asymmetric transport. Insulin receptors, though apparently more abundant on the BL side than on the AP side of Calu-3 cells, did not mediate the direction-dependent transport of insulin. However, transport of a monomeric human insulin analog, Asp(B10)des(B28-30), across the Calu-3 cell monolayer was similar in both directions (BL to AP and AP to BL). The corresponding permeability, P(app) = 2.9 +/- 0.2 10(-8) cm/s, was not significantly different from the permeability of zinc insulin in the BL to AP direction. The paracellular pathway seems to play a major role in the insulin transport across the Calu-3 cell monolayers. We hypothesize that the transport of zinc insulin oligomers is restricted at the AP surface by the presence of the tight junctional complexes. From the BL side, oligomers may undergo dissociation in the intercellular space and diffuse readily as monomers to the AP surface of the membrane.
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PMID:Insulin aggregation and asymmetric transport across human bronchial epithelial cell monolayers (Calu-3). 1194 52

ZNRD1, a new zinc ribbon gene, has been previously identified as an upregulated gene in a multidrug-resistant gastric cancer cell line SGC7901/VCR comparing to its parental cell SGC7901 by subtractive hybridization and RT-PCR. The antisense nucleic acid for ZNRD1 could enhance adriamycin accumulation in SGC7901/VCR cells and sensitize SGC7901/VCR cells to vincristine. The present study aims to explore the role of ZNRD1 in multidrug resistance in gastric cancer cells. Upregulation of ZNRD1 protein in SGC7901/VCR cells was confirmed by Western blot and immunocytochmical staining. ZNRD1 was genetically overexpressed in SGC7901 cells by gene transfection. It was found that overexpression of ZNRD1 could sensitize SGC7901 cells to P-glycoprotein (P-gp)-related anticancer drugs (vincristine, adriamycin, etoposide) but not to P-gp-nonrelated drugs (5-fluorouracil and cisplatin), which was accompanied with significantly decreased adriamycin accumulation and retention and increased adriamycin releasing in SGC7901 cells. Verapamil, an inhibitor for P-gp, could reverse the effects of ZNRD1 on drug sensitivity and drug accumulation in SGC7901 cells to a great extent. Western blot and Northern blot revealed that overexpression of ZNRD1 could upregulate P-gp at both protein and mRNA levels. Together, these results suggest that overexpression of ZNRD1 could promote multidrug-resistant phenotype of gastric cancer cells through upregulation of P-gp.
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PMID:Overexpression of ZNRD1 promotes multidrug-resistant phenotype of gastric cancer cells through upregulation of P-glycoprotein. 1497 23

Multixenobiotic resistance mechanisms (MXR) related to the mammalian P-glycoprotein multidrug transporter protein (P-gp) are known to occur in several marine invertebrates. In the present work, we report on the induction of an MXR protein by various heavy metals in the gills of the freshwater clam Corbicula fluminea. The evaluation of the MXR protein level was assessed by Western blot using a specific monoclonal antibody raised against the human P-gp (C219). A field transplantation experiment, where clams were caged in a gradient relative to an industrial site, demonstrated a positive relationship between MXR levels and (a) metal pollution (Cd and Zn) in the environment and (b) metal bioaccumulation in the gills. To establish this correlative relationship, clams were exposed to different levels of cadmium (15-60 microg l(-1)) for up to 15 days in a controlled laboratory experiment. MXR protein levels increased in time for all treatments (including the control). However, the highest levels of MXR protein titer were expressed in clams that had been exposed to the lowest dose of cadmium. The causes for this observed inverse relationship between the exposure dose and the MXR induction is discussed. MXR protein titer was also shown to be induced by other heavy metals (zinc, inorganic mercury, and copper).
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PMID:Induction of a multixenobiotic resistance protein (MXR) in the Asiatic clam Corbicula fluminea after heavy metals exposure. 1508 11

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.
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PMID:Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. 1536 99

Here, we investigated the role of zinc ribbon domain-containing 1 (ZNRD1) in multidrug resistance (MDR) of leukemia cells and the possible underlying mechanisms. ZNRD1 was found overexpressed in the vincristine-induced MDR leukemia cell HL-60/vincristine moreso than its parental cell HL-60. Up-regulation of ZNRD1 expression could confer resistance of both P-glycoprotein (P-gp)-related and P-gp-nonrelated drugs on HL-60 cells and suppress Adriamycin-induced apoptosis accompanied by decreased accumulation and increased releasing amount of Adriamycin. ZNRD1 could significantly up-regulate the expression of P-gp, Bcl-2, and the transcription of the MDR1 gene but not alter the expression of MDR-associated protein, glutathione S-transferase activity, or intracellular glutathione content in leukemia cells. In addition, inhibition of ZNRD1 expression by RNA interference or P-gp inhibitor could partially reverse ZNRD1-mediated MDR. The further study of the biological functions of ZNRD1 may be helpful for understanding the mechanisms of MDR of leukemia and developing possible strategies to treat leukemia.
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PMID:Zinc ribbon domain-containing 1 (ZNRD1) mediates multidrug resistance of leukemia cells through regulation of P-glycoprotein and Bcl-2. 1637 8

This review focuses on drug-drug interactions with three major groups of antimicrobial agents: macrolides (including azalides and ketolides), quinolones, which are widely used for the treatment of bacterial infections, and azoles, which are used for antifungal therapy. Macrolides and the ketolide telithromycin are potent inhibitors of CYP3A4 and thus interfere with the pharmacokinetics of many other drugs that are metabolised by this enzyme. In contrast, although closely related, azithromycin is not a cytochrome inhibitor. All quinolones form complexes with di- and trivalent cations and, therefore, the absorption of quinolones can be dramatically reduced when given concomitantly with mineral antacids, zinc or iron preparations. Ciprofloxacin exhibits an inhibitory potential for the cytochrome isoenzyme 1A2, resulting in an inhibition of theophylline metabolism. Other quinolones, such as levofloxacin or moxifloxacin, do not interfere with theophylline metabolism. The systemic azoles, such as ketoconazole, itraconazole, fluconazole and voriconazole, are inhibitors of CYP isoenzymes, such as CYP3A4, CYP2C9 and CYP2C19, to varying degrees. In addition, some are substrates of the MDR-1 gene product, P-glycoprotein. These features are the basis for most of the interactions occurring during azole therapy (e.g., in severely ill patients in the hospital who are treated with multiple drugs).
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PMID:Drug interactions during therapy with three major groups of antimicrobial agents. 1655 82


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