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 expression and activity of P-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP1) were analyzed in 178 leukemia samples. Rhodamine-123 (Rho-123) and DiOC(2) were used as substrate to evaluate efflux pump activity. Chronic myeloid leukemia (CML) exhibited a higher percentage of positivity using Rho-123 than DiOC(2) (p=0.000) as compared to other types of leukemia. Moreover, Rho-123 was able to detected Pgp positive cells in a higher proportion of samples than DiOC(2) samples (p=0.004). Similarly, MRP1 positive cells were best detected by Rho-123 as opposed to DiOC(2) (p=0.003). The co-functionality of Rho-123 and DiOC(2) was observed in 26 out of 105 (24.8%) leukemic samples. Co-expression between Pgp and MRP1 was detected in 30 out of 56 (53.6%) samples. As a whole, when the same samples were analyzed, Rho-123 was able to detect Pgp positive cells in a higher proportion of samples than DiOC(2) (p=0.000). Similarly, MRP1 positive cells were best detected by Rho-123 as opposed to DiOC(2) (p=0.007). Our results support the idea that Rho-123 is the substrate of choice for leukemic cells.
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PMID:Contrasting features of MDR phenotype in leukemias by using two fluorochromes: implications for clinical practice. 1697 36

Multidrug resistance (MDR) phenotype is characterized by the over-expression of P-glycoprotein (P-gp) on cell plasma membranes that extrudes several drugs out of cells. Cells that express the MDR phenotype are resistant to the mitochondrial related apoptosis and to several anticancer drugs. This study assessed the presence of P-gp in mitochondria and its role in parental drug-sensitive (P5) and in P5-derived MDR1 cells P1(0.5) hepatocellular carcinoma (HCC) cell lines and in drug-sensitive (PSI-2) and mdr1-transfected (PN1A) NIH/3T3 cells. By using Western blot analysis, confocal laser microscopy, measurements of Rhodamine 123 transport across mitochondrial membranes, MDR1 small interfering RNA and flow cytometry analysis, experiments indicate that P-gp is expressed in mitochondria of P1(0.5) and PN1A cells and it is functionally active. Rho 123 accumulation was largely reduced in mitochondria of P1(0.5) cells as compared to those of P5 cells; the reduced uptake of fluorescence in mitochondria of MDR cells was due to P-gp-mediated Rho 123 efflux. In conclusion, these data demonstrate that functionally active P-gp is expressed in the mitochondrial membrane of MDR-positive cells and pumps out anticancer drugs from mitochondria into cytosol. Therefore, P-gp could be involved in the protection of mitochondrial DNA from damage due to antiproliferative drugs.
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PMID:P-gp localization in mitochondria and its functional characterization in multiple drug-resistant cell lines. 1702 68

The purpose of the present experiment was to examine the effects of D-tartaric acid (TA) on intestinal drug absorption under both in situ and in vitro experimental conditions. In the in vitro diffusion chamber experiments, TA (10 mM) added to the mucosal side of rat colon significantly decreased rhodamine123 (Rho 123) transport from the serosal to mucosal side. Since TA has been shown to change the integrity of the epithelial tight junctions in rat colon at low pH conditions, resulting in improved paracellular drug transport, the effect of TA on membrane resistance was examined at pH 7.4 in the present study. It was found that membrane resistance, an indicator of paracellular integrity, did not change at pH 7.4. In the in situ loop method, TA (20 mM) increased the absorption of Rho123 in both ileum and colon but not in jejunum. TA (20 mM) also increased the absorption of daunorubicin in the ileum, but TA (20 mM) did not change the expression level of P-glycoprotein (P-gp). TA (20 mM) significantly inhibited excretion of i.v.-administered Rho123 and daunorubicin into the ileal lumen. In conclusion, for the first time we demonstrated that TA increases the intestinal absorption of P-gp substrates Rho123 and daunorubicin, possibly by modulating the P-gp function without changing the expression level of P-gp in the rat intestine.
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PMID:Improvement of intestinal absorption of P-glycoprotein substrate by D-tartaric acid. 1707 96

We have tested the ability of two compounds licensed in veterinary medicine: fumagillin and diminazene diaceturate to increase intracellular moxidectin quantity in rat hepatocytes. These compounds significantly increased the quantity of 14C-moxidectin (expressed as area under the time curve concentrations) in cultured rat hepatocytes by 44% and 65% for diminazene and fumagillin treatments respectively. In addition, we have tested these drugs for their interference with P-glycoprotein (P-gp) function in porcine kidney epithelial cells transfected with murine mdr1a (Mdr1a-LLCPK1). We examined the intracellular accumulation of rhodamine 123 (Rho 123) as a functional test to evaluate the effects of these two drugs on P-gp activity. In this model, only fumagillin led to a marked intracellular accumulation of Rho 123. After transforming the data to express the results as a percentage of the accumulation in the presence of the P-gp inhibitor valspodar (VSP), the maximal Rho 123 accumulation was 47% of that with VSP for 100 microm fumagillin. The EC50, the concentration needed to determine 50% of the maximal effect was 34 microm. Fumagillin interacts with P-gp function and appears as a promising compound among registered drugs available, which may optimize the therapeutic use of macrocyclic lactones (MLs).
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PMID:Fumagillin, a new P-glycoprotein-interfering agent able to modulate moxidectin efflux in rat hepatocytes. 1708 52

The previous studies from our laboratory reported that benzo(a)pyrene (Bap) influenced efflux transport of rhodamine 123 (Rho-123) by induction of P-glycoprotein (P-gp) in Caco-2 cells. The present study investigated whether induction of P-gp and the enhanced efflux transport of Rho-123 were caused by benzo(e)pyrene (Bep), which has a structure similar to Bap, but is not a carcinogenic compound. In Caco-2 monolayer exposed to 50 microM Bep for 72 h, the ratio of the apparent permeability coefficient (P(app)) of Rho-123 efflux increased significantly compared to that of the control monolayer. Similarly, a significant increase in expression of MDR1 mRNA and of P-gp at the protein level were detected by RT-PCR and by Western blot analysis, respectively, in Caco-2 cells exposed to Bep, compared to that of the control. Caco-2 cells exposed to Bep showed oxidative stress that was detected by fluorescence microscopy using aminophenyl fluorescein. However, the oxidative stress was weaker compared with that of Bap. The cellular GSH content was decreased to 80% or 59% of control cells, respectively, in Caco-2 cells exposed to either Bep or Bap. Our results further show that Bep or Bap-induced P-gp in Caco-2 cells might have been the result of oxidative stress rather than DNA damage.
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PMID:Effects of benzo(e)pyrene and benzo(a)pyrene on P-glycoprotein-mediated transport in Caco-2 cell monolayer: a comparative approach. 1740 18

The purposes of this study were to investigate whether P-glycoprotein (P-GP) is overexpressed in the brain of pentylenetetrazole (PTZ)-kindled rats, and to investigate the effects of P-GP up-regulation on the distribution of phenobarbital (PB) in brain and its antiepileptic effects. Kindled rats were developed using a subconvulsive dose of PTZ (30 mg/kg, once every 2 days, i.p.) for 24 days. P-GP expression and function were measured by Western blot analysis and rhodamine 123 (Rho 123) distribution in brain. Kindled rats received 10 mg/kg of PB alone or co-administration of cyclosporine A (CsA, 5 mg/kg). At 60 min after administration of PB, concentrations of PB in brain and plasma were measured and the tissue-to-plasma concentration ratios of PB were calculated. Anticonvulsive effects of PB (13.2 mg/kg) alone or co-administration of CsA on the kindled rats were observed. The results showed that kindling resulted in 1.7-fold increase of P-GP level in brain, accompanied by significant decrease of tissue-to-plasma concentration ratios of Rho 123 and PB in hippocampus and cortex without affecting their concentrations in plasma. Co-administration of CsA reversed the decrease of PB concentration in brain without affecting PB level in plasma and significantly potentiated the anticonvulsive effects of PB. The present study demonstrated that chronic PTZ-kindling might increase P-GP expression and function in brain of rat, resulting in decrease of Rho 123 and PB levels in brain tissues. Co-administration of CsA increased PB levels in brain and enhanced anticonvulsive effects of PB by inhibiting P-GP function.
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PMID:Increased P-glycoprotein expression and decreased phenobarbital distribution in the brain of pentylenetetrazole-kindled rats. 1784 5

Overexpression of P-glycoprotein may be involved in multidrug resistance of epilepsy, but the mechanisms are not clear. The aim of the studies was to investigate whether chronic exposure of antiepileptic drugs (AEDs) increased P-glycoprotein (P-gp) function and expression in brain of rats. Three drugs phenobarbital (PB), phenytion (PHT) and carbamazepine (CBZ) were orally given to rats twice a day for successive 21 days, P-gp activity in brain was assessed using the brain-to-plasma concentration ratios of rhodamine 123 (Rho 123) at 1 h following intravenous administration of 0.2 mg/kg. Immunohistochemistry was also used to analyze P-gp localization in rat brain regions. P-gp levels in the brain regions were further evaluated using western blot. The results showed 21-day exposure of AEDs resulted in significant decrease of tissue-to-plasma concentration ratios of Rho 123 in cerebral cortex and hippocampus without affecting their concentrations in plasma. Immunohistochemistry result showed that up-regulation of the P-gp mainly occurred in capillary endothelial vessels. Western blot result suggested that the protein level of P-gp in cortex and hippocampus of rats exposed to drugs was significantly higher than that of control rats. The P-gp levels were associated with P-gp activity in corresponding rats. All the results verified the hypothesis that chronic exposure of AEDs may increase P-gp function and level in brain of rats.
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PMID:Effect of 21-day exposure of phenobarbital, carbamazepine and phenytoin on P-glycoprotein expression and activity in the rat brain. 1844 May 57

Hematopoietic stem cells (HSC) can be identified by the expression of the CD34 molecule. CD34+ cells are found in bone marrow (BM), umbilical cord blood (UCB) and in mobilized peripheral blood (PB). CD34+ cells express P-glycoprotein (Pgp), a product of the multidrug resistance (MDR) gene. Pgp activity can be measured by the efflux of the dye Rhodamine 123 (Rho 123) and can be blocked by verapamil. Transport activity in HSC suggests that Pgp could have a functional role in stem cell differentiation. This study compared the number of CD34+ cells with Pgp activity measured by efflux of Rho 123 in the hematopoietic population obtained from different sources. Samples were analysed for their content of CD34+ cells, and BM had a significantly higher amount of CD34+ cells compared to UCB, mobilized PB and normal PB. When the frequency of Rholow cells was studied among the CD34+ population, an enrichment of cells with Pgp activity was observed. The frequency in BM was significantly lower than that in UCB and mobilized PB. The low retention of Rho 123 could be modified by verapamil, indicating that the measurements reflected dye efflux due to Pgp activity. Although UCB and mobilized PB had a lower number of CD34+ cells compared to BM, the total number of CD34+ cells with Pgp activity was similar in the three tissues. The different profiles may indicate the existence of subpopulations of stem cells or different stages of cellular differentiation detected by the extrusion of the dye Rho 123.
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PMID:Rhodamine 123 efflux in human subpopulations of hematopoietic stem cells: comparison between bone marrow, umbilical cord blood and mobilized peripheral blood CD34+ cells. 1863 79

The Rho signaling has an essential function in human immunodeficiency virus (HIV)-1-mediated disruption of the integrity of the blood-brain barrier (BBB). However, it is unknown how membrane domains, such as lipid rafts, can influence HIV-1-mediated activation of the Rho pathway and how these processes can affect the expression of the efflux transporters at the BBB level. This study is focused on the function of HIV-1 protein Tat in activation of the Rho signaling and upregulation of P-glycoprotein (P-gp) in human brain endothelial cells. Treatment with Tat markedly elevated GTP-RhoA levels and the potential downstream effectors, such as myosin phosphatase target subunit 1 and myosin light chain. In addition, Tat upregulated expression and promoter activity of P-gp as well as its efflux function. Inhibition of the Rho signaling cascade effectively blocked P-gp overexpression at the level of promoter activity. Disruption of lipid rafts by depletion of membrane cholesterol by methyl-beta-cyclodextrin, but not caveolin-1 silencing, also abolished Tat-mediated RhoA activation and P-gp upregulation. The present data indicate the critical function of intact lipid rafts and the Rho signaling in HIV-1-mediated upregulation of P-gp and potential development of drug resistance in brain endothelial cells.
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PMID:Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells. 1979

Given the widespread use of formulations combining anthelmintics which are possible P-glycoprotein interfering agents, the understanding of drug interactions with efflux ABC transporters is of concern for improving anthelmintic control. We determined the ability of 14 anthelmintics from different classes to interact with abcb1a (mdr1a, P-glycoprotein, Pgp) by following the intracellular accumulation of rhodamine 123 (Rho 123), a fluorescent Pgp substrate, in LLC-PK1 cells overexpressing Pgp. The cytotoxicity of the compounds that are able to interfere with Pgp activity was evaluated in cells overexpressing Pgp and compared with parental cells using the MTS viability assay. Among all the anthelmintics used, ivermectin (IVM), triclabendazole (TCZ), triclabendazole sulfoxide (TCZ-SO), closantel (CLOS) and rafoxanide (RAF) increased the intracellular Rho 123 in Pgp overexpressing cells, while triclabendazole sulfone, albendazole, mebendazole, oxfendazole, thiabendazole, nitroxynil, levamisole, praziquantel and clorsulon failed to have any effect. The concentration needed to reach the maximal Rho 123 accumulation (E(max)) was obtained with 10 microM for IVM, 80 microM for CLOS, 40 microM for TCZ and TCZ-SO, and 80 microM for RAF. We showed that for these five drugs parental cell line was more sensitive to drug toxicity compared with Pgp recombinant cell line. Such in vitro approach constitutes a powerful tool to predict Pgp-drug interactions when formulations combining several anthelmintics are administered and may contribute to the required optimization of efficacy of anthelmintics.
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PMID:Interaction of anthelmintic drugs with P-glycoprotein in recombinant LLC-PK1-mdr1a cells. 2051 41


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