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)

Adriamycin is one of the most active anticancer drugs but the development of resistance to this drug hampers its efficacy. In an effort to identify novel genes that confer resistance to adriamycin, we introduced a yeast genomic library into Saccharomyces cerevisiae and selected transformants that grew in the presence of a normally toxic concentration of adriamycin. Detailed examination of a plasmid recovered from these transformants revealed that overexpression of the gene for Ssl2p rendered yeast cells resistant to adriamycin. Ssl2p is a protein that is involved in the initiation of transcription and in DNA repair. Overexpression of Ssl2p did not confer resistance to aclarubicin, an anthracycline anticancer drug, which, like adriamycin, is intercalated into DNA. Both adriamycin and aclarubicin inhibit topoisomerase II and, thus, topoisomerase II might not be a major factor in the acquired resistance to adriamycin that results from overexpression of Ssl2p. We tested several other compounds but the only one to which Ssl2p-overexpressing cells were cross-resistant was actinomycin D. Mammalian cells that overexpress P-glycoprotein, which is a transmembrane protein that is involved in the efflux of certain drugs, are resistant to both adriamycin and actinomycin D but not to aclarubicin. However, overexpression of Ssl2p had little or no effect on the intracellular accumulation of adriamycin. Our results suggest that a novel mechanism might be involved in the sensitivity of yeast to both adriamycin and actinomycin D.
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PMID:Overexpression of Ssl2p confers resistance to adriamycin and actinomycin D in Saccharomyces cerevisiae. 1474 13

The multidrug resistance (mdr) P-glycoprotein is an energy-dependent efflux transporter that protects the brain against a wide variety of neurotoxic compounds. This transmembrane protein is a well-known functional component of the blood-brain barrier and might be present in other brain cells as well. We have developed a riboprobe against the murine mdr1 mRNA recognizing both isoforms of the rodent mdr1 gene to determine the exact localization of P-glycoprotein expression. We have also studied the effects of treatment with a known inducer of P-glycoprotein expression. In situ mRNA hybridization demonstrates that mdr1 mRNA is present in the endothelial cells of brain capillaries throughout the rat brain, indicating that P-glycoprotein is expressed at the endothelial cells forming the blood-brain barrier. Surprisingly, specific mdr1 mRNA expression was also found in neuronal layers of hippocampal fields, particularly in the granule cells of the dentate gyrus. Kainic acid treatment decreased the expression levels of mdr1 mRNA in the dentate gyrus 6 and 24 h after treatment. Our data indicate that P-glycoprotein is expressed by endothelial cells and possibly dentate gyrus neurons The functional role of P-glycoprotein at dentate gyrus neurons is presently unknown.
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PMID:Localization of mRNA expression of P-glycoprotein at the blood-brain barrier and in the hippocampus. 1567 38

The permeability of the blood-brain barrier (BBB) is one of the factors determining the bioavailability of drugs in the brain. The BBB only allows passage of lipophilic drugs by passive diffusion. However, some lipophilic drugs hardly enter the brain. The transmembrane protein P-glycoprotein (P-gp) is one of the carrier systems that is responsible for transportation of drugs out of the brain. P-Glycoprotein affects the pharmacokinetics of many drugs and can be inhibited by administration of modulators or competitive substrates. Identification and classification of central nervous system (CNS) drugs as P-gp substrates or inhibitors are of crucial importance in drug development. Positron emission tomography (PET) studies can play an important role in the screening process as a follow-up of high-throughput in vitro assays. Several rodent studies have shown the potential value of PET to measure the effect of P-gp on the pharmacokinetics and brain uptake of radiolabeled compounds. P-Glycoprotein-mediated effects were observed for two 5-HT(1a) receptor ligands, [(18)F]MPPF vs. [carbonyl-(11)C]WAY100635. Under control conditions, the specific brain uptake of [(18)F]MPPF is five- to eightfold lower than that of [(11)C]WAY100635. After cyclosporin A (CsA) modulation, [(18)F]MPPF uptake in the rat brain increased five- to tenfold. Cerebral uptake of [carbonyl-(11)C]WAY100635 was also increased by modulation, but in general the increase was lower than that observed for [(18)F]MPPF (two- to threefold). Brain uptake of the beta-adrenergic receptor ligands [(11)C]carazolol and [(18)F]fluorocarazolol was increased in P-gp knockout mice and CsA-treated rats. Both the specific and nonspecific binding of [(18)F]fluorocarazolol were doubled by CsA. Cerebral uptake of [(11)C]carazolol in rats was much lower than that of [(18)F]fluorocarazolol and no specific binding was measured. After CsA modulation, the uptake of [(11)C]carazolol increased five- to sixfold, but this uptake was not receptor-mediated. Quantitative PET studies in rodents on P-gp functionality demonstrated a dose-dependent increase of radioligands after administration of CsA. Studies with [(11)C]verapamil and [(11)C]carvedilol showed that complete modulation was achieved at 50 mg/kg CsA. The distribution volume of [(11)C]carvedilol increased from 0.25 in the control study to 1.0 after full modulation with CsA. By quantitative PET measurement of P-gp function, the dose of modulators required to increase the concentration of CNS drugs may be determined, which may result in improved drug therapy.
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PMID:Positron emission tomography studies on binding of central nervous system drugs and P-glycoprotein function in the rodent brain. 1591 74

An important problem in the treatment of children with acute lymphoblastic leukaemia (ALL) is pre-existent or acquired resistance to structurally and functionally unrelated chemotherapeutic compounds. Various cellular mechanisms can give rise to multidrug resistance (MDR). Best studied is the transmembrane protein-mediated efflux of cytotoxic compounds that leads to decreased cellular drug accumulation and toxicity. Several MDR-related efflux pumps have been characterised, including P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), breast cancer resistance protein (BCRP) and lung resistance protein (LRP). P-gp expression and/or activity has been associated with unfavourable outcome in paediatric ALL patients, whereas MRP1 and BCRP do not seem to play a major role. LRP might contribute to drug resistance in B-lineage ALL, but larger studies are needed to confirm these results. The present review summarises the current knowledge concerning multidrug resistance-related proteins and focuses on the clinical relevance and prognostic value of these efflux pumps in childhood ALL.
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PMID:Prognostic significance of multidrug resistance-related proteins in childhood acute lymphoblastic leukaemia. 1632 33

P-glycoprotein (p-gp) is a transmembrane protein functioning as a drug-efflux pump in the intestinal epithelium. Human patients with inflammatory bowel disease (IBD) who fail to respond to treatment with steroids express high levels of p-gp in lamina propria lymphocytes. The purpose of this study was to investigate p-gp expression in duodenal biopsy samples of dogs with chronic enteropathies and to evaluate the expression of p-gp after treatment with a known inducer of p-gp (prednisolone). Duodenal biopsy samples from 48 dogs were evaluated immunohistochemically with the mouse monoclonal antibody C219 for expression of p-gp in lamina propria lymphocytes. Biopsy samples were available from 15 dogs after treatment with prednisolone and 16 dogs after dietary therapy alone ("elimination diet"). Treatment with prednisolone resulted in an increase in p-gp expression (P=0.005). In contrast, dietary treatment alone produced no significant change in p-gp expression (P=0.59). A low p-gp score before initiation of steroid treatment was significantly associated with a positive response to treatment (P=0.01). These results indicate that lamina propria lymphocyte expression of p-gp is upregulated after prednisolone treatment in dogs with IBD, and that mucosal expression of p-gp may be of value in predicting the response to therapy.
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PMID:P-glycoprotein expression in lamina propria lymphocytes of duodenal biopsy samples in dogs with chronic idiopathic enteropathies. 1632 44

The blood-brain barrier (BBB) impedes the influx of intravascular compounds from the blood to the brain. The elements composing the BBB are endothelial cells, pericytes and the end-feet of astrocytes. Among them, the endothelial cell barrier line is the most critical for preventing toxic substances from entering the brain. In this review, we focus on the ultrastructural distribution of important components in the intracellular junction and cytoplasm of brain endothelial cells. The ultrastructural distribution of tight junction-specific integral membrane proteins such as occludin, junctional adhesion molecules, claudin, peripheral zonula occludens protein-1 (ZO-1), adherens junction-specific transmembrane protein cadherin, and adherens junction-associated peripheral proteins alpha-catenin, beta-catenin, and p120 catenin is reviewed. P-glycoprotein and some other transporters recently discovered in endothelial cells prevent several compounds from entering the brain parenchyma. It is likely that the transient inhibition of P-glycoprotein by antidepressants enables other medicines to enter the brain. Vesicular transport with clathrin-mediated or adsorptive endocytosis through endothelial cells is also critical for transportation of blood-born substances from the bloodstream to the brain. How medicines pass the BBB to reach the brain parenchyma is discussed.
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PMID:Molecular anatomy of the brain endothelial barrier: an overview of the distributional features. 1750 40

Multidrug resistance (MDR) is associated with the overproduction of the 170-kDa transmembrane protein P-glycoprotein (MDR1) caused by transcriptional activation. However, the activity of the MDR1 promoter in response to different doses of ionizing radiation has not been investigated. In this study, two squamous cell carcinoma oral cavity cell lines, T-167 and T-409, were exposed to either a standard clinical dose of 2 Gy or low-dose fractionated radiation therapy (LDFRT), delivered as 0.5 Gy in four fractions. MDR1 gene expression and degree of cell death were assessed. Clinically relevant 2-Gy dose of radiation resulted in increased expression of MDR1 by reverse transcription-PCR and luciferase reporter assays in both cell lines (T-167 and T-409), whereas LDFRT did not. LDFRT caused enhanced apoptosis when compared with the 2-Gy dose in T-167 and T-409 cells as assessed by terminal nucleotidyl transferase-mediated nick end labeling (TUNEL) assays. Transcription of the MDR1 gene is regulated by numerous transcription factors, which include nuclear factor-kappaB (NF-kappaB), NF-Y, SP1, YB1, MEF1 (MDR1 promoter-enhancing factor 1), p53, and NF-R1. Interestingly, 2 Gy robustly induced both NF-kappaB and NF-Y in T-167 and T-409 cells, but did not show induction when exposed to LDFRT. Silencing the expression of the DNA binding subunit of NF-kappaB, p50, by small interfering RNA vector resulted in a decrease of MDR1 function by rhodamine 123 efflux assay in T167 cells exposed to 2 Gy. Together, these results provide evidence for the lack of induction of P-glycoprotein expression by LDFRT, which has important implications in combinatorial cancer therapy, including the use of LDFRT as an adjuvant for chemotherapy.
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PMID:Lack of P-glycoprotein expression by low-dose fractionated radiation results from loss of nuclear factor-kappaB and NF-Y activation in oral carcinoma cells. 1823 65

Cancer patients who receive chemotherapy often experience intrinsic or acquired resistance to a broad spectrum of chemotherapeutic agents. The phenomenon, termed multidrug resistance (MDR), is often associated with the over-expression of P-glycoprotein, a transmembrane protein pump, which can enhance efflux of a various chemicals structurally unrelated at the expense of ATP depletion, resulting in decrease of the intracellular cytotoxic drug accumulation. The MDR has been a big threaten to the human health and the war fight for it continues. Although several other mechanisms for MDR are elucidated in recent years, considerable efforts attempting to inverse MDR are involved in exploring P-glycoprotein modulators and suppressing P-glycoprotein expression. In this review, we will report on the recent advances in various strategies for overcoming or circumventing MDR mediated by P-glycoprotein.
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PMID:Strategies to overcome or circumvent P-glycoprotein mediated multidrug resistance. 1828 2

P-glycoprotein (Pgp) is a transmembrane protein that actively exports lipophilic chemotherapeutics from the cells causing multidrug resistance. Pgp molecules are partially localized in TX-100-resistant rafts, and the activity of the transporter is highly sensitive to the presence of cholesterol. To better understand these relationships, the influence of membrane cholesterol content on Pgp function, as measured via calcein accumulation, was studied in correlation with changes elicited in membrane structure. Membrane cholesterol was modulated by heptakis(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) and the cholesterol inclusion complex of DIMEB (Chol-DIMEB). Changes in membrane cholesterol level were reflected by alterations in the overall lipid packing as measured by Merocyanine 540 (MC540) staining and were also accompanied by changes in the raft association of the pump. DIMEB and Chol-DIMEB treatments have also lead to increased permeability of the cell membrane in both directions, raising the possibility that the effects on pumping efficiency reflect leakage of ATP also from the non-permeabilized cells. However, the treatments did not influence the intracellular ATP levels of the non-permeabilized cells. Our data suggest that Pgp inhibition by cyclodextrin treatments arises through modulation of its membrane microenvironment, rather than as a result of concomitant cytotoxicity.
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PMID:P-glycoprotein inhibition by membrane cholesterol modulation. 1853 42

P-glycoprotein (Pgp) is a transmembrane protein pump involved in drug resistance in canine and human lymphoma. There are no published clinical studies evaluating Pgp expression in feline lymphoma. The purpose of this study is to evaluate the level of Pgp expression in feline lymphoma and correlate it with clinical outcome. Two human Pgp monoclonal antibodies, C219 and C494, were used to detect Pgp expression in tissue samples from 63 cats with lymphoma. Demographic results appear comparable to recently published feline lymphoma studies. The Kaplan-Meier median remission and survival times were 164 and 571 days, respectively. Fourteen cats had positive expression of Pgp using MAb C219, and 40 were positive with C494. Variables statistically associated with survival included bone marrow involvement, stage, substage, and use of radiation therapy as a part of treatment. Pgp expression as assessed by MAb C219 and C494 is not predictive of remission or survival time in cats with lymphoma.
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PMID:Evaluation of P-glycoprotein expression in feline lymphoma and correlation with clinical outcome. 1917 80


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