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)

Brain edema is an important factor leading to morbidity and mortality associated with primary brain tumors. Dexamethasone, a synthetic glucocorticoid, is routinely prescribed with antineoplastic agents to alleviate pain associated with chemotherapy and reduce intracranial pressure. We investigated whether dexamethasone treatment increased the expression and activity of multidrug resistance (MDR) transporters at the blood-brain barrier. Treatment of primary rat brain microvascular endothelial cells with submicromolar concentrations of dexamethasone induced significantly higher levels of drug efflux transporters such as breast cancer resistance protein (abcg2), P-glycoprotein (P-gp; abcb1a/abcb1b), and MDR protein 2 (Mrp2; abcc2) as indicted by protein and mRNA levels as well as by functional activity. The effect of dexamethasone on transporter function was significant within 6 h of treatment, was dose dependent, and was reversible. Dexamethasone-induced upregulation of Bcrp and P-gp expression and function was partially abrogated by the glucocorticoid receptor (GR) antagonist RU486. In contrast, RU486 had no effect on the dexamethasone-induced upregulation of Mrp2, suggesting a GR-independent regulation of Mrp2, and a GR-dependent regulation of P-gp and Bcrp. In addition to the dexamethasone-induced upregulation of MDR transporters, we measured a dose-dependent and reversible increase in the expression of the nuclear transcription factor pregnane xenobiotic receptor (PXR). Administering dexamethasone to rats caused increased expression of PXR in brain microvessels within 24 h. These results suggest that adjuvant therapy with corticosteroids such as dexamethasone in the treatment of brain tumors may increase the expression of MDR transporters at the blood-brain barrier through pathways involving GR and PXR.
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PMID:Dexamethasone increases expression and activity of multidrug resistance transporters at the rat blood-brain barrier. 1852 38

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain's innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated beta-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-alpha, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.
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PMID:Modulation of P-glycoprotein at the blood-brain barrier: opportunities to improve central nervous system pharmacotherapy. 1856 12

Insect Malpighian tubules actively transport a variety of xenobiotics, and it has been proposed that P-glycoprotein (P-gp), or the multidrug transporter, is involved. To test this idea, we observed the interaction of known P-gp substrates with isolated, living Malpighian tubules from tobacco hornworm (Manduca sexta) larvae. Specifically, the fluorescent drugs daunomycin, rhodamine 123, acridine orange and Hoechst 33342 were applied to the basal side of tubules (proximal portion) in a well of fluid on a coverslip; the subsequent distribution of the drugs was monitored by laser scanning confocal microscopy. Contrary to expectation, none of the drugs appeared in the lumen even after 1-2 h of incubation, although the cells of the tubule were intensely stained within 1 min. For daunomycin, neither verapamil, a P-gp inhibitor, nor nicotine, an alkaloid which appears to be transported by a P-gp-like mechanism in this species, had any effect on the pattern of staining. In sharp contrast to the fast and intense staining of Malpighian tubules, portions of muscle, nerve cord and body fat showed only light staining with daunomycin, and only after prolonged periods. The results suggest that for some drugs, Malpighian tubules act as xenobiotic scavengers, and that this property is unrelated to P-gp-mediated transport.
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PMID:Accumulation of daunomycin and fluorescent dyes by drug-transporting Malpighian tubule cells of the tobacco hornworn, Manduca sexta. 1862 56

An assessment of energetic costs associated with P-glycoprotein (P-gp)-mediated xenobiotic efflux is important in understanding the energy budgets, tradeoffs, and fitness of organisms inhabiting contaminated environments. Here, a functional characterization and determination of the energetic costs associated with doxorubicin (DOX) efflux was examined in isolated hepatocytes of rainbow trout. The accumulation and efflux of DOX were both concentration dependent. The efflux of DOX over a 3 h incubation period resulted in a significant decrease in intracellular ATP concentrations (maximum decrease 25%) compared to control baseline levels, while significant increases in concentrations of ADP (max. 26%), AMP (max. 36%) and inorganic phosphate (max. 11%). were observed. In addition, significant reductions in the adenylate energy charge ([AEC]: max 11%), and phosphorylation potential ([PP]: max. 53%) were shown in cells incubated with DOX compared to control cells. Inhibition of DOX efflux (max. 61%) by the non-competitive P-gp inhibitor tariquidar (XR9576), demonstrated that changes in ATP, ADP, AMP, inorganic phosphate concentrations, AEC and PP in DOX-exposed hepatocytes were mainly due to P-gp activity. Overall, these results indicate that the exposure of trout hepatocytes to DOX increases energetic and metabolic costs that are associated specifically with P-gp efflux activity.
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PMID:Functional and energetic characterization of P-gp-mediated doxorubicin transport in rainbow trout (Oncorhynchus mykiss) hepatocytes. 1866 92

A major concern regarding the chronic administration of antiretroviral drugs is the potential for induction of drug efflux transporter expression (i.e., P-glycoprotein, P-gp) at tissue sites that can significantly affect drug distribution and treatment efficacy. Previous data have shown that the inductive effect of human immunodeficiency virus protease inhibitors (PIs) is mediated through the human orphan nuclear receptor, steroid xenobiotic receptor (SXR or hPXR). The objectives of this study were to investigate transport and inductive properties on efflux drug transporters of two PIs, atazanavir and ritonavir, at the blood-brain barrier by using a human brain microvessel endothelial cell line, hCMEC/D3. Transport properties of PIs by the drug efflux transporters P-gp and multidrug resistance protein 1 (MRP1) were assessed by measuring the cellular uptake of (3)H-atazanavir or (3)H-ritonavir in P-gp and MRP1 overexpressing cells as well as hCMEC/D3. Whereas the P-gp inhibitor, PSC833, increased atazanavir and ritonavir accumulation in hCMEC/D3 cells by 2-fold, the MRP inhibitor MK571 had no effect. P-gp, MRP1, and hPXR expression and localization were examined by Western blot analysis and immunogold cytochemistry at the electron microscope level. Treatment of hCMEC/D3 cells for 72 hr with rifampin or SR12813 (two well-established hPXR ligands) or PIs (atazanavir or ritonavir) resulted in an increase in P-gp expression by 1.8-, 6-, and 2-fold, respectively, with no effect observed for MRP1 expression. In hCMEC/D3 cells, cellular accumulation of these PIs appears to be primarily limited by P-gp efflux activity. Long-term exposure of atazanavir or ritonavir to brain microvessel endothelium may result in further limitations in brain drug permeability as a result of the up-regulation of P-gp expression and function.
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PMID:Up-regulation of P-glycoprotein by HIV protease inhibitors in a human brain microvessel endothelial cell line. 1885 43

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 ubiquitous presence of pharmaceuticals in aquatic systems is a challenging problem as their potential chronic effects on aquatic organisms remain largely unknown. The ATP-binding cassette (ABC) transport proteins contributing to the multidrug/multixenobiotic resistance (MDR/MXR) phenomenon seem to have an important role in the elimination of xenobiotics in aquatic organisms. Modulation of their efflux activities by contaminants may lead to substantial increase in intracellular accumulation and toxic effects of other xenobiotics. The aim of our work was to analyse a series of pharmaceuticals for their potential to modulate the activity of xenobiotic efflux transporters from the ABCB and ABCC sub-family in the Poeciliopsis lucida hepatoma cell (PLHC-1) fish cell line (PLHC-1/wt) and a doxorubicin (DOX) resistant PLHC-1 subclone (PLHC-1/dox) characterized by an elevated expression of the P-glycoprotein (ABCB1). Cellular accumulation of the model fluorescent substrates calcein-AM and rhodamine123 were used to determine an inhibitory effect on P-gp1 and/or MRP-like efflux transporters. 18 out of 33 tested pharmaceuticals showed MXR inhibitory activity with IC50 values occurring in the lower micromolar to millimolar range. Further, cytotoxic effects of pharmaceuticals were evaluated in PLHC-1/dox cells. Co-exposure of resistant cells to model P-gp1 inhibitor cyclosporine A (CyA) resulted in up to five times increased cytotoxicity of pharmaceuticals. In addition, some pharmaceuticals lead to a marked increase in cytotoxicity of doxorubicin, a model P-gp1 substrate. The modulation of toxicity by MDR inhibitors indicates their role in influencing cellular toxicity. In conclusion, the results of our study revealed significant inhibitory effects of environmentally relevant pharmaceuticals on P-gp1 and MRP-like transporters in fish. Our findings correspond well with data from mammalian systems indicating that the specificity and roles of the related efflux transporters may be similar in fish. Furthermore, due to the presence of active and inducible ABC transport proteins, the PLHC-1 cells appear to be a reliable in vitro system for the investigation of MDR/MXR mechanisms in fish.
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PMID:Human pharmaceuticals modulate P-gp1 (ABCB1) transport activity in the fish cell line PLHC-1. 1895 Aug 75

Imazalil (IMA) is a widely used imidazole-antifungal pesticide and, therefore, a food contaminant. This compound is also used as a drug (enilconazole). As intestine is the first site of exposure to ingested drugs and pollutants, we have investigated the effects of IMA, at realistic intestinal concentrations, on xenobiotic-metabolizing enzymes and efflux pumps by using Caco-2 cells, as a validated in vitro model of the human intestinal absorptive epithelium. For comparison, other conazole fungicides, i.e. ketoconazole, propiconazole and tebuconazole, were also studied. IMA induced cytochrome P450 (CYP) 1A1 activity to the same extent as benzo(a)pyrene (B(a)P) or 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in a dose- and time-dependent manner. Cell-free aryl hydrocarbon receptor (AhR) binding assay and reporter gene assay suggested that IMA is not an AhR-ligand, implying that IMA-mediated induction should involve an AhR-independent pathway. Moreover, IMA strongly inhibited the CYP3A4 activity in 1,25-vitamin D(3)-induced Caco-2 cells. The other fungicides had weak or nil effects on CYP activities. Study of the apical efflux pump activities revealed that ketoconazole inhibited both P-glycoprotein (Pgp) and multidrug resistance-associated protein 2 (MRP-2) or breast cancer resistance protein (BCRP), whereas IMA and other fungicides did not. Our results imply that coingestion of IMA-contaminated food and CYP3A4- or CYP1A1-metabolizable drugs or chemicals could lead to drug bioavailability modulation or toxicological interactions, with possible adverse effects for human health.
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PMID:CYP1A1 induction and CYP3A4 inhibition by the fungicide imazalil in the human intestinal Caco-2 cells-comparison with other conazole pesticides. 1907 Jun 57

Pharmacotherapy of central nervous system (CNS) disorders is impaired by the drug efflux transporter, P-glycoprotein, which limits drug penetration across the blood-brain barrier into the CNS. One strategy to increase brain drug levels is to modulate P-glycoprotein regulation. This approach requires understanding of the mechanisms that control transporter expression and function. One mechanism through which P-glycoprotein is regulated is the nuclear receptor, pregnane X receptor (PXR). Xenobiotics including drugs activate PXR and induce P-glycoprotein, which potentially affects pharmacokinetics/pharmacodynamics of coadministered drugs. Because rodent models are not suitable to predict xenobiotic interactions with human PXR, in a porcine model, we studied functional similarities between pig and human PXR. We used brain capillary endothelial cells from pig to study the effect of PXR activation on P-glycoprotein. To activate PXR, we used the PXR ligands, rifampicin, hyperforin, and pregnenolone-16alpha-carbonitrile (PCN), and measured abcb1 mRNA with quantitative polymerase chain reaction, P-glycoprotein expression with Western blotting, and P-glycoprotein transport activity with a calcein assay. We provide first proof of principle that the human PXR ligands, rifampicin and hyperforin, but not the rodent PXR ligand, PCN, activate pig PXR at the blood-brain barrier and induce mRNA, protein expression, and transport activity of P-glycoprotein. Our data indicate functional similarities between human and pig PXR that suggest the pig model could be useful for predicting xenobiotic-PXR interactions in humans. Because PXR is crucial in controlling drug efflux transporters, our findings will contribute to a better understanding of the regulation of blood-brain barrier function, which could potentially have important clinical implications for the treatment of CNS disorders.
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PMID:Pregnane X receptor (PXR) regulates P-glycoprotein at the blood-brain barrier: functional similarities between pig and human PXR. 1914 57

While P-glycoprotein (PGP, ABCB1) is known to play an important role in drug exclusion at the blood brain barrier (BBB), less is known about the contribution of other members in the ATP-binding cassette (ABC) transporter family to BBB drug efflux, or whether these transporters are expressed differently in humans and in mammalian species of pharmacological interest. We used quantitative real-time PCR to determine mRNA expression levels for the majority of ABC family members in brain and in isolated brain microvessel endothelial capillary cells (BMEC) from human, rat, mouse, pig and cow. We confirmed BBB expression of several well-characterized ABC family members that are implicated in xenobiotic exclusion from the brain, including ABCB1 (PGP), ABCG2 (BCRP), ABCC1 (MRP1), ABCC4 (MRP4), and ABCC5 (MRP5). In addition, we detected high expression and enrichment in BMEC of several less well-characterized ABC transporters in one or more species, including ABCA2-4, ABCB4, ABCB6-8, ABCB10, ABCC3, ABCC6, ABCC10, and ABCE1. We also uncovered species differences in the expression of a number of transporters, including ABCG2 and ABCC4. This study identifies several additional ABC family members that may contribute to xenobiotic efflux at the human BBB, and compares the expression of a broad array of efflux transporters between human and four other species relevant to pharmacological research.
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PMID:Comparative gene expression profiles of ABC transporters in brain microvessel endothelial cells and brain in five species including human. 1942 73


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