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)

By screening a chemical library for the compounds protecting cells from adriamycin (Adr), a series of small molecules was isolated that interfered with the accumulation of Adr in mouse fibroblasts by enhancing efflux of the drug. Isolated compounds also stimulated efflux of Rhodamine 123 (Rho-123), another substrate of multidrug transporters. Stimulation of drug efflux was detectable in the cells expressing P-glycoprotein (P-gp), but not in their P-gp-negative variants, and was completely reversible by the P-gp inhibitors. A dramatic stimulation of P-gp activity against Adr and Rho-123 by the identified compounds was accompanied by suppression of P-gp-mediated efflux of other substrates, such as Taxol (paclitaxel) or Hoechst 33342, indicating that they act as modulators of substrate specificity of P-gp. Consistently, P-gp modulators dramatically altered the pattern of cross-resistance of P-gp-expressing cells to different P-gp substrates: an increase in resistance to Adr, daunorubicin, and etoposide was accompanied by cell sensitization to Vinca alkaloids, gramicidin D, and Taxol with no effect on cell sensitivity to colchicine, actinomycin D, puromycin, and colcemid, as well as to several non-P-gp substrates. The relative effect of P-gp modulators against different substrates varied among the isolated compounds that can be used as fine tools for analyzing mechanisms of drug selectivity of P-gp. These results raise the possibility of a rational control over cell sensitivity to drugs and toxins through modulation of P-gp activity by small molecules.
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PMID:Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein. 1170 75

Immunosuppressive agents such as cyclosporine, tacrolimus, sirolimus, and corticosteroids are substrates for the transmembrane multidrug resistance pump P-glycoprotein (P-gp). Experience in oncologyhas suggested that chronic exposure to P-gp substrates induces upregulation of P-gp activity, which could result in resistance to immunosuppressive drugs. The authors investigated P-gp function in CD4+ and CD8+ T cells from the peripheral blood of solid organ transplant recipients (SOTX). Subjects included 14 stable SOTX (10 liver, 4 lung) and 16 healthy controls. Four-color flow cytometry was used to simultaneously measure intracellular concentration of the fluorescent P-gp substrate Rhodamine 123 (Rh123) and surface expression of CD45RO (nominal memory/effector), CD45RA (naive), and either CD4 or CD8. P-glycoprotein function was measured by a dye efflux assay in which activity was inferred from a decrease in Rh123 fluorescence. CD4+ and CD8+ T cells from patients and control subjects eliminated Rh123, and this activity was inhibited by verapamil, a known P-gp substrate. CD8+ T cells had greater P-gp activity than CD4+ cells, and naive and transitional T cells displayed greater activity than memory T cells. Activity was bimodal in CD8+ CD45RO+ T cells, with a subset of these cells expressing the greatest P-gp activity. Patient CD8+ naive and transitional T cells had upregulated P-gp activity compared to control subjects. We conclude that (1) P-gp activityis significantly upregulated in specific T-cell subsets (CD8+/CD45RA+) in the peripheral blood of SOTX, and (2) the bimodal nature of P-gp response in CD8+ T cells complicates analysis of the effect of chronic administration of P-gp substrates to SOTX.
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PMID:P-glycoprotein (P-gp) is upregulated in peripheral T-cell subsets from solid organ transplant recipients. 1176 54

A microplate screening method has been developed to evaluate the effects of test agents on the accumulation of the fluorescent P-glycoprotein (Pgp) substrates Hoechst 33342, rhodamine 123, and rhodamine 6G in multidrug-resistant (MDR) breast cancer cells that overexpress Pgp. All three substrates exhibit substantially higher accumulation in MCF7 non-MDR cells versus NCI/ADR-RES MDR cells, while incubation with 50 microM reserpine significantly reduces or eliminates these differences. Rhodamine 123 shows the lowest substrate accumulation efficiency in non-MDR cells relative to the substrate incubation level. The effects of several chemosensitizing agents and a series of paclitaxel analogs on the accumulation of each fluorescent substrate suggest that there are distinct differences in the substrate interaction profiles exhibited by these different agents. The described methods may be useful in Pgp-related research in the areas of cancer MDR, oral drug absorption, the blood-brain barrier, renal/hepatic transport processes, and drug-drug interactions.
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PMID:Microplate screening of the differential effects of test agents on Hoechst 33342, rhodamine 123, and rhodamine 6G accumulation in breast cancer cells that overexpress P-glycoprotein. 1189 53

Rhodamine 123 (Rho123), a model substrate of P-glycoprotein (P-gp), was used to evaluate the functional activity of P-gp efflux transporter in the rat placental barrier. The dually perfused rat-term placenta method was used. In our experiments, the materno-fetal transplacental passage of Rho123 did not meet the criteria of the first-order pharmacokinetics, suggesting an involvement of transporter-mediated process. Inhibitors of P-gp, such as [3'-keto-Bmt1]-[Val2]-cyclosporine (PSC833), cyclosporine (CsA), quinidine, and chlorpromazine, increased significantly the materno-fetal transplacental passage of Rho123 in the experiments under steady-state conditions. On the other hand, PSC833, CsA, and quinidine decreased the feto-maternal passage of Rho123. Similarly, in the experiments carried out under nonsteady-state conditions, CsA accelerated the passage of Rho123 in the materno-fetal direction and decreased its passage in the opposite direction. Feto-maternal transplacental clearances of Rho123 were found to be considerably higher than those in the materno-fetal course. Potent P-gp inhibitors, such as PSC833 or CsA, partially canceled the asymmetry. Negligible metabolism of Rho123 into its major demethylated metabolite rhodamine 110 was observed in the rat placenta. Expression of P-gp genes was detected using immunohistochemical, Western blotting, and reverse transcription-polymerase chain reaction methods preferentially in the second rat syncytiotrophoblast layer. In conclusion, these data suggest that P-gp limits the entry of Rho123 into fetuses and at the same time it accelerates the feto-maternal elimination of the model compound. Therefore, it seems plausible that pharmacokinetics of xenobiotics in the rat placental barrier could be controlled by P-gp in both directions.
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PMID:Examination of the functional activity of P-glycoprotein in the rat placental barrier using rhodamine 123. 1262 38

Selective pressures from polluted environments have led to the development of resistance systems in aquatic organisms. Using different techniques, this study examined a cadmium defense mechanism of the freshwater unicellular protozoa Euglena gracilis, and found it to be an efflux pump similar to the multidrug resistance P-glycoprotein. Cd(2+)-treated E. gracilis were able to extrude Rhodamine 123 at 21 degrees C, but not at 4 degrees C. Furthermore, verapamil, a P-glycoprotein modulator, partially blocked the efflux process (at 21 degrees C), and enhanced the Cd(2+) toxic effects on these cells. Western immunoblots of cell lysates, using the anti-P-glycoprotein antibody JSB-1, revealed a 120-KDa protein, which was expressed, in high amounts on Cd(2+)-exposed cells (74% above the control values). Moreover, cells treated with JSB-1 became more sensitive to the harmful effects of cadmium, showing a decreased survival rate. Taken together, these results suggest that a MDR phenotype has evolved in Euglena as one of the mechanisms for cadmium detoxification.
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PMID:P-glycoprotein-like protein contributes to cadmium resistance in Euglena gracilis. 1287 47

The objective of this work was to characterize dexloxiglumide biopharmaceutical properties in vitro and relate these characteristics to its in vivo absorption performance, and to assess dexloxiglumide interaction with P-glycoprotein (P-gp) and MRP1 to anticipate its drug interaction potential. Dexloxiglumide aqueous solubility was moderate and pH dependent. Dexloxiglumide exhibited moderate Caco-2 permeability that was polarized, concentration dependent, and pH dependent. The apical-to-basolateral (AP-BL) permeability at pH 5 [14.5 (+/-1.8) x 10(-6) cm/s] was 2-fold higher than at pH 7.5 [7.24 (+/-0.27) x 10(-6) cm/s]. Neutral and ionized dexloxiglumide species displayed permeabilities of 30.8 (+/-8.4) x 10(-6) cm/s and 9.03 (+/-1.31) x 10(-6) cm/s, respectively. The transport of dexloxiglumide across MDR1-MDCK (P-gp overexpressing Madine Darby canine kidney cells) monolayers was polarized, with a BL-AP/AP-BL permeability ratio of 9.35 (+/-0.73), which was reduced to 1.03 (+/-0.03) by P-gp inhibition. Rhodamine 123 efflux was reduced by dexloxiglumide from 4.06 (+/-0.34) to 2.84 (+/-0.15) across Caco-2 monolayers, and from 17.3 (+/-0.9) to 8.26 (+/-1.38) across MDR1-MDCK monolayers, further indicating dexloxiglumide interaction with P-gp. Additionally, P-gp ATPase activity increased with dexloxiglumide concentration. Dexloxiglumide was effluxed from MRP1-NIH3T3 cells (NIH-3T3 cells expressing the multidrug resistance-associated protein 1). Dexloxiglumide increased MRP1-substrate fluorescein uptake 4-fold, and fluorescein increased dexloxiglumide uptake 1.8-fold. Overall, in vitro transport studies indicate dexloxiglumide to be moderately soluble and moderately permeable, which is in agreement with the incomplete oral absorption of dexloxiglumide. In vitro, dexloxiglumide was moderately modulated by P-gp and MRP1, which provides a rationale for the design of drug interaction studies.
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PMID:Characterization of dexloxiglumide in vitro biopharmaceutical properties and active transport. 1450 37

The Lactococcus lactis multidrug resistance ABC transporter protein LmrA has been shown to confer resistance to structurally and functionally diverse antibiotics and anti-cancer drugs. Using a previously characterized photoreactive drug analogue of Rhodamine 123 (iodo-aryl azido-Rhodamine 123 or IAARh123), direct and specific photoaffinity labeling of LmrA in enriched membrane vesicles could be achieved under non-energized conditions. This photoaffinity labeling of LmrA occurs at a physiologically relevant site as it was inhibited by molar excess of ethidium bromide>Rhodamine 6G>vinblastine>doxorubicin>MK571 (a quinoline-based drug) while colchicine had no effect. The MDR-reversing agents PSC 833 and cyclosporin A were similarly effective in inhibiting IAARh123 photolabeling of LmrA and P-glycoprotein. In-gel digestion with Staphyloccocus aureus V8 protease of IAARh123-photolabeled LmrA revealed several IAARh123 labeled polypeptides, in addition to a 6.8kDa polypeptide that comprises the last two transmembrane domains of LmrA.
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PMID:Photoaffinity labeling under non-energized conditions of a specific drug-binding site of the ABC multidrug transporter LmrA from Lactococcus lactis. 1462 28

The bidirectional permeation characteristics of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein (P-gp), across monolayers of MDCK cells transfected with the human MDR1 gene (MDCK-MDR1) were investigated. The ratios of the apparent permeability coefficients (P(app)) of rhodamine 123 and Hoechst 33342 flux measured in the basolateral (BL) to apical (AP) direction versus the flux in the AP-to-BL direction (P(app BL-to-AP)/P(app AP-to-BL)) were 115 and 177, respectively. The P-gp inhibitor GF-120918 could significantly reduce the polarized efflux of both rhodamine 123 and Hoechst 33342. Rhodamine 123 appeared to "stimulate" the polarized efflux of Hoechst 33342 across MDCK-MDR1 cell monolayers. In contrast, Hoechst 33342 partially inhibited the polarized efflux of rhodamine 123 across these cell monolayers whereas daunorubicin partially inhibited the polarized efflux of both rhodamine 123 and Hoechst 33342. The uptake characteristics of rhodamine 123 and Hoechst 33342 in MDCK-MDR1 cells were measured in the absence and presence of GF-120918 and known P-gp substrates (Hoechst 33342, rhodamine 123, and daunorubicin). The uptake of rhodamine 123 and Hoechst 33342 in MDCK-MDR1 cells was enhanced more than twofold by inclusion of GF-120918 (2 microM) in the incubation medium. Daunorubicin (160 microM) increased the relative fluorescence unit (RFU) values of cytoplasm-associated rhodamine 123 by up to 30%. However, daunorubicin (40 microM) and rhodamine 123 (5 microM) decreased the RFU values of cell membrane-associated Hoechst 33342 by 70% and 40%, respectively. To further explore what appears to be a "stimulatory" effect of daunorubicin and rhodamine 123 on the uptake of Hoechst 33342 and a stimulatory effect of daunorubicin on Hoechst 33342 transport across cell monolayer, uptake of Hoechst 33342 into liposomes in the presence and absence of GF-120918, daunorubicin, and rhodamine 123 was determined. GF-120918 exhibited no effect on the RFU values of liposome-associated Hoechst 33342. In contrast, rhodamine 123 and daunorubicin decreased the fluorescence of liposome-associated Hoechst 33342 suggesting these molecules were either quenching the fluorescence of this chemical probe or displacing it from the lipid bilayer. In conclusion, these bidirectional transport data indicate that rhodamine 123 and Hoechst 33342 are excellent substrates of P-gp in MDCK-MDR1 cells. The ability of Hoechst 33342 to partially inhibit the polarized efflux of rhodamine 123 is consistent with these substrates binding to the same site on P-gp. In contrast, the ability of rhodamine 123 to apparently "stimulate" the efflux of Hoechst 33342 in both the transport and uptake experiments suggests the substrates might bind to different sites on P-gp. However, experimental results using liposomes suggested that this "stimulation" phenomenon by rhodamine 123 on Hoechst 33342 uptake and efflux might simply be an artifact. Thus, the use of Hoechst 33342 to probe the binding sites on a membrane-bound protein such as P-gp might be problematic.
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PMID:Bidirectional transport of rhodamine 123 and Hoechst 33342, fluorescence probes of the binding sites on P-glycoprotein, across MDCK-MDR1 cell monolayers. 1506 95

P-glycoprotein (pgp), an efflux transporter localized in a variety of tissues including the intestinal mucosa, renal tubules and bile canaliculi, is known to participate in the disposition of a variety of chemicals, including steroid hormones. This study examined the relationship of pgp to the movement into the bile of the hormone estradiol (E2), and the potential for transport interactions between the environmental pollutant nonylphenol ethoxylate (NPE) and E2. Biliary-cannulated in situ-prepared isolated perfused livers were used to assess pgp transport function. E2, in competitive transport preparations with Rhodamine 123 (Rho123), a pgp substrate, demonstrated significant decreases in Rho123 transport into bile, as did the prototypic inhibitor and substrate verapamil. [3H]E2 (0.28 nM) transport into bile was significantly reduced with either 20 M NPE or verapamil. These results suggest that E2 is a substrate and/or modulator for the catfish biliary pgp transporter, and that NPE potentially influences biliary transport and excretion of E2.
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PMID:Inhibition of P-glycoprotein transport: a mechanism for endocrine disruption in the channel catfish? 1517 33

The overexpression of P-glycoprotein (P-gp) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Combined therapy with MDR-related cytotoxins and MDR modulators is a promising strategy to overcome clinical MDR. This study was designed to screen potent MDR modulators from imidazole derivatives. Cytotoxicity was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The intracellular accumulation of doxorubicin (Dox) was detected by fluorescence spectrophotometry. The function of P-gp was examined by Rhodamine 123 accumulation detected with flow cytometry (FCM). Among imidazole derivatives, FG020326, FG020327, and FG020318 were found to possess three- to fourfold stronger reversal MDR activity than verapamil, a well-known positive MDR modulator. Imidazole derivatives significantly increased the Dox accumulation and inhibited P-gp function exhibited by the increase of Rhodamine accumulation in MDR cells. The fold reversal of MDR was relative with the increase of Rhodamine accumulation. FG020326, FG020327, and FG020318 showed potent MDR reversal activity in vitro. Their mechanism of MDR reversal is associated with the inhibition of P-gp function and the increase of anticancer accumulation. These results suggest FG020326, FG020327, and FG020318 are promising to further study and develop.
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PMID:Screening novel, potent multidrug-resistant modulators from imidazole derivatives. 1530 26


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