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 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

P-gp (P-glycoprotein; ABCB1) protects us by transporting a broad range of structurally unrelated compounds out of the cell. Identifying the regions of P-gp that make up the drug-binding pocket is important for understanding the mechanism of transport. The common drug-binding pocket is at the interface between the transmembrane domains of the two homologous halves of P-gp. It has been shown in a previous study [Loo, Bartlett and Clarke (2006) Biochem. J. 396, 537-545] that the first transmembrane segment (TM1) contributed to the drug-binding pocket. In the present study, we used cysteine-scanning mutagenesis, reaction with an MTS (methanethiosulfonate) thiol-reactive analogue of verapamil (termed MTS-verapamil) and cross-linking analysis to test whether the equivalent transmembrane segment (TM7) in the C-terminal-half of P-gp also contributed to drug binding. Mutation of Phe728 to cysteine caused a 4-fold decrease in apparent affinity for the drug substrate verapamil. Mutant F728C also showed elevated ATPase activity (11.5-fold higher than untreated controls) after covalent modification with MTS-verapamil. The activity returned to basal levels after treatment with dithiothreitol. The substrates, verapamil and cyclosporin A, protected the mutant from labelling with MTS-verapamil. Mutant F728C could be cross-linked with a homobifunctional thiol-reactive cross-linker to cysteines I306C(TM5) and F343C(TM6) that are predicted to line the drug-binding pocket. Disulfide cross-linking was inhibited by some drug substrates such as Rhodamine B, calcein acetoxymethyl ester, cyclosporin, verapamil and vinblastine or by vanadate trapping of nucleotides. These results indicate that TM7 forms part of the drug-binding pocket of P-gp.
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PMID:Transmembrane segment 7 of human P-glycoprotein forms part of the drug-binding pocket. 1681 63

Cyclosporine nephrotoxicity remains a major side effect in solid organ transplantation, and can be exacerbated by concomitant administration of sirolimus. Cyclosporine and sirolimus are P-glycoprotein (Pgp) substrates. We hypothesized that the Pgp activity level may affect cyclosporine cytotoxicity by interfering with the ability of Pgp to remove cyclosporine from within tubular cells, and that an interaction between cyclosporine and sirolimus on Pgp function may explain the enhancement of cyclosporine nephrotoxicity by sirolimus. Cyclosporine cytotoxicity was evaluated in primary cultures of normal human renal epithelial cells (HRECs) by cell viability and cytotoxicity assays. Verapamil, quinine, PSC833, and PGP-4008 were used as Pgp inhibitors. Rhodamine-123 (R-123), a fluorescent substrate of Pgp, was used to assess Pgp-mediated transport. Cellular cyclosporine concentration was measured by high-performance liquid chromatography coupled to tandem mass spectrometry. Pgp expression and function were confirmed in HRECs and cyclosporine and sirolimus were shown to be Pgp inhibitors in this model. Verapamil-induced inhibition of Pgp led to a significant increase in cellular concentration of cyclosporine (P<0.05). Cyclosporine exerted a concentration-dependent cytotoxic effect on HRECs that was significantly increased by inhibition of Pgp activity. Sirolimus exerted an inhibitory effect on R-123 efflux in HRECs and increased cellular cyclosporine concentrations in a dose-dependent manner. These data demonstrate that Pgp plays a critical role in protecting renal epithelial cells from cyclosporine toxicity. The inhibitory effect of sirolimus on Pgp-mediated efflux and the cellular concentration of cyclosporine could explain the exacerbation of cyclosporine nephrotoxicity observed clinically.
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PMID:Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction. 1683 25

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

Over-expression of P-glycoprotein (P-gp) in lymphocytes is implicated in the failure of immunosuppressant therapy. We investigated P-gp function in peripheral-blood CD3+, CD4+, and CD8+ cells of 14 healthy subjects and 12 patients with systemic lupus erythematosus (SLE). P-gp function was estimated by the transporter activity of the cells based on the efflux of Rhodamine-123 (Rh123) from the cells in the presence or absence of a P-gp inhibitor, cyclosporine A. P-gp function in the CD8+ cells of the healthy subjects was significantly higher than that of the SLE patients (p=0.0318), whereas the function in CD3+ cells and CD4+ cells were not significantly different between the healthy subjects and the SLE patients. The patients were divided into two subgroups according to their clinical response to glucocorticoid (GC) therapy, i.e., a high-response group (HR) (n=6) and a low-response group (LR) (n=6). In contrast, P-gp function in CD4+ cells of the LR group was significantly higher than that of the HR group (p=0.0432). Further, no significant differences in the P-gp function in CD3+ and CD8+ cells were observed between the two groups. The data showed a relationship between clinical sensitivity to GC therapy and P-gp function of CD4+ cells in SLE patients. Thus, the estimation of P-gp function in peripheral-blood CD4(+) cells might be useful for the estimation of clinical response to GC therapy.
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PMID:P-glycoprotein functions in peripheral-blood CD4+ cells of patients with systemic lupus erythematosus. 1845 10

Tyroservatide (YSV) is an active, low-molecular-weight polypeptide that has been shown to have antitumor effects on human hepatocellular carcinoma BEL-7402 cells in vitro and in vivo. Multi-drug resistance (MDR) represents a major obstacle to the success of cancer chemotherapy. To enhance the chemosensitivity of tumor cells, attention has been focused on MDR modulators. In this study, we evaluated the reversal effect of YSV on MDR, and explored its mechanism of action in vitro. Administration of YSV reversed the multi-drug resistance of human hepatocellular carcinoma BEL-7402/5-FU cells significantly. The intracellular accumulation of doxorubicin and Rhodamine-123 (Rh123) were increased, which implied that the function of the P-glycoprotein (P-gp) efflux pump was inhibited by YSV. Moreover, the mRNA and protein expression of multi-drug resistance gene (MDR1) were also decreased by YSV. We observe that lung-resistance protein (LRP) and multi-drug resistance-associated protein (MRP1) each contribute to MDR in BEL-7402/5-FU cells as well. The mRNA and protein expression of LRP were decreased by YSV. No significant change was observed in mRNA expression of MRP1. However, we observe that the MRP1 protein level was reduced after treatment with YSV. These data demonstrate that YSV effectively reverses MDR in BEL-7402/5-FU cells, and that its mechanism of action is associated with the down-regulation of MDR1, MRP1 and LRP expression, as well as the inhibition of P-gp function.
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PMID:Reversal effect of tyroservatide (YSV) tripeptide on multi-drug resistance in resistant human hepatocellular carcinoma cell line BEL-7402/5-FU. 1853 71

The multixenobiotic resistance (closely related to multidrug resistance) system controls transport across the plasma membrane as a defense against toxic molecules. Multixenobiotic resistance system consists of an efflux pump, ABCB1 (also named P-glycoprotein, P-gp), and/or a molecule of the ABCC family (also named multiple resistance associated protein, MRP). ABCB1 is able to increase efflux of many low-molecular foreign molecules. Measuring system induction may be used as a biomarker of cell/organism exposure to foreign substances. Various established cell lines were tested for constitutive and induced multixenobiotic resistance proteins by Western blotting immunodetection. The pumping function was indirectly assayed with Rhodamine B by visualization of cell fluorescence in the presence of verapamil. Changes in ABC proteins were measured by flow cytometry after exposition to various perfluorinated carboxylic acids. MCF7 and HeLa cells were found to contain the highest constitutive level of both ABCB1 and ABCC1. HEK293 exhibited much less ABCB1 and no activity of pumping out Rhodamine B. The pumping activity was found to be related to the amount of the cell-type specific 170 kDa ABCB1 protein. An 8-day exposure to 10(-4) M perfluorononanoic acid resulted in about 2-2.5-fold increase of ABCB1 level. That was confirmed also for short times by flow cytometry of cells exposed to perfluorinated acids and its natural congeners. Both ABCB1- and ABCC1-related fluorescence increased along with the carbon chain in acids from C(6) up to C(9) and decreased for C(10). Measuring of multixenobiotic resistance changes in vitro induced by chemicals may be a convenient test for screening for their potential toxicity.
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PMID:Induction of the multixenobiotic/multidrug resistance system in various cell lines in response to perfluorinated carboxylic acids. 1856 Jun 6

Filterfeeders, such as bivalves, are highly affected during toxic cyanobacterial blooms, as they are non-selective and may use the cyanobacteria as main nutrition source. The freshwater mussel Dreissena polymorpha, living in lakes and rivers coexisting with cyanobacteria, was exposed to 100 microg L(-1) microcystin-LR (MC-LR) for up to three days. MC-LR concentration in mussel tissue and surrounding media was quantified by HPLC-PDA during uptake and depuration phase, revealing an immediate, continuous uptake, and release of non-metabolized toxin, and occurrence of reincorporation. The involvement of multi-xenobiotic-resistance protein (P-glycoprotein, P-gp) on the excretion of MC-LR was evidenced by efflux and accumulation version of the Rhodamine Assay as well as on P-gp gene expression. P-gp expression was enhanced after 1 h exposure but no changes were detected after longer (72 h) exposure. P-gp enzyme activity showed a significant increase with exposure time, supporting the hypothesis that P-gp is involved in the excretion of MC-LR. Induction of biotransformation enzyme such as pi-class glutathione S-transferase (piGST) and antioxidant enzyme catalase (CAT) was immediately inhibited and returned to control values only after more than 72 h expose time. Heat shock protein 70 (hsp70) and protein phosphatase 2A (PP2A) gene expression was not changed due to the treatment with cyanobacterial toxin MC-LR.
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PMID:Multi-xenobiotic-resistance a possible explanation for the insensitivity of bivalves towards cyanobacterial toxins. 1893 Jul 53

The purpose of the present study was to evaluate the effect of kainic acid (KA)-induced acute seizures on the pharmacokinetic profiles of antiepileptic drug, carbamazepine (CBZ) in mice. Experimental acute seizure in mice was induced by intraperitoneal injection of KA (30 mg/kg), and mice were provided for experiments after 48 h of KA treatment. The portal plasma concentrations of CBZ and its metabolite carbamazepine-10,11-epoxide (CBZ-epo) had trends to decrease as compared to the control mice, whereas the brain CBZ and CBZ-epo concentrations was actually lower in KA treated mice. On the other hand, the exsorption of CBZ from blood to the intestinal lumen via P-glycoprotein (P-gp) in KA treated-mice was significantly increased in parallel with that of Rhodamine-123 (Rho123), a P-gp substrate. Western blotting analysis for intestinal and cerebral P-gp showed that the P-gp expression was induced in the KA-treated mice. The apparent brain-to-plasma concentration ratio (Kp) of CBZ in the KA-treated mice showed significant decrease but that of CBZ-epo did not. Moreover, in the KA-treated mice, the percentage of protein binding was significantly increased, and found to be an inverse proportion in the relationship between the Kp and protein binding of CBZ. In conclusion, the mechanism responsible for a decreased brain CBZ concentration in the KA-induced seizure mice is based on the up-regulation of P-gp function in tissues and plasma protein binding of CBZ.
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PMID:Evaluation of carbamazepine pharmacokinetic profiles in mice with kainic acid-induced acute seizures. 1904 17

The present study was aimed to investigate the effects of polyoxyethylene (40) stearate (PS), a non-ionic surfactant, on the activity of P-glycoprotein (P-gp) and six major cytochrome P450 (CYP) isoforms. An in vitro diffusion chamber system was utilized to estimate the effects of PS concentration on the transport characteristics of Rhodamine 123 (R123) and Rhodamine 110 (R110), a standard P-gp substrate and nonsubstrate, respectively, across the excised intestinal segments of rat. Caco-2 cells were cultured to investigate the mechanisms by estimating the effects of PS on intracellular ATP levels, P-gp ATPase activity and membrane fluidity. The obtained results showed that PS inhibited P-gp mediated efflux in a concentration-dependent manner mainly by modulating substrate-stimulated P-gp ATPase activity. On the other hand, human liver microsomes were utilized to examine the inhibitive potential of PS on six major CYP isoforms. Inhibitive potential on two of these CYP2C9 and CYP2C19 was found to be clinically significant. In conclusion, PS is potentially useful as a pharmaceutical ingredient to improve the oral bioavailability of coadministered P-gp substrates and substrates for certain CYP isoforms.
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PMID:Effects of polyoxyethylene (40) stearate on the activity of P-glycoprotein and cytochrome P450. 1944 20


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