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)

We show that D- but not L-hexoses modulate the accumulation of radioactive vinblastine in injected Xenopus laevis oocytes expressing the murine Mdr1b P-glycoprotein. We also show that X. laevis oocytes injected with RNA encoding the rat erythroid/brain glucose transport protein (GLUT1) and expressing the corresponding functional transporter exhibit a lower accumulation of [3H]vinblastine and show a greater capacity to extrude the drug than do control oocytes not expressing the rat GLUT1 protein. Cytochalasin B and phloretin, two inhibitors of the mammalian facilitative glucose transporters, can overcome the reduced drug accumulation conferred by expression of the rat GLUT1 protein in Xenopus oocytes but have no significant effect on the accumulation of drug by Xenopus oocytes expressing the mouse Mdr1b P-glycoprotein. These drugs also increase the accumulation of [3H]vinblastine in multidrug-resistant Chinese hamster ovary cells. Cytochalasin E, an analog of cytochalasin B that does not affect the activity of the facilitative glucose transporter, has no effect on the accumulation of vinblastine by multidrug-resistant Chinese hamster cells or by oocytes expressing either the mouse Mdr1b P-glycoprotein or the GLUT1 protein. In all three cases, the drug verapamil produces a profound effect on the cellular accumulation of vinblastine. Interestingly, although immunological analysis indicated the presence of massive amounts of P-glycoprotein in the multidrug-resistant cells, immunological and functional studies revealed only a minor increase in the expression of a hexose transporter-like protein in resistant versus drug-sensitive cells. Taken together, these results suggest the participation of the mammalian facilitative glucose transporter in the development of drug resistance.
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PMID:A possible role for a mammalian facilitative hexose transporter in the development of resistance to drugs. 167 25

Forskolin and 1,9-dideoxyforskolin, an analogue that does not activate adenylyl cyclase, were tested for their ability to enhance the cytotoxic effects of adriamycin in human ovarian carcinoma cells, SKOV3, which are sensitive to adriamycin and express low levels of P-glycoprotein, and a variant cell line, SKVLB, which overexpresses the P-glycoprotein and has the multidrug resistance (MDR) phenotype. Forskolin and 1,9-dideoxyforskolin both increased the cytotoxic effects of adriamycin in SKVLB cells, yet had no effect on SKOV3 cells. Two photoactive derivatives of forskolin have been synthesized, 7-O-[[2-[3-(4-azido-3- [125I]iodophenyl)propionamido]ethyl] carbamyl]-7-deacetylforskolin, 125I-7-AIPP-Fsk, and 6-O-[[2-[3-(4-azido-3- [125I]iodophenyl)propionamido]ethyl]carbamyl]forskolin, 125I-6-AIPP-Fsk, which exhibit specificity for labeling the glucose transporter and adenylyl cyclase, respectively (Morris et al., 1991). Both photolabels identified a 140-kDa protein in membranes from SKVLB cells whose labeling was inhibited by forskolin and 1,9-dideoxyforskolin. There was no specific labeling of proteins in membranes from the SKOV3 cells. The overexpressed 140-kDa protein in SKVLB membranes was identified as the P-glycoprotein by immunoblot analysis and immunoprecipitation using anti-P-glycoprotein antiserum. Total inhibition of photolabeling of the P-glycoprotein was observed with verapamil, nifedipine, diltiazem, and vinbalastine, and partial inhibition was observed with colchicine and cytochalasin B. Forskolin was less effective at inhibiting the photolabeling of the P-glycoprotein than 1,9-dideoxyforskolin or a lipophilic derivative of forskolin. The data are consistent with forskolin binding to the P-glycoprotein analogous to that of other chemosensitizing drugs that have been shown to partially reverse MDR.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of forskolin with the P-glycoprotein multidrug transporter. 167 46

Brain capillaries contain a great variety of membrane proteins involved in the transport of hydrophilic nutrients or in the reception of hormonal signals. The use of Triton X-114 fractionation to purify membrane proteins according to their degree of hydrophobicity was investigated. Analysis by polyacrylamide gel electrophoresis showed a distinct polypeptide composition for each fraction. Most of the proteins (68%) were solubilized by Triton X-114 and, of these proteins, the majority (74%) was found in the detergent-poor phase. Alkaline phosphatase which possesses a glycosyl-phosphatidylinositol anchor partitioned in the pellet of insoluble proteins where it was enriched 2.3-fold. In contrast, gamma-glutamyltranspeptidase, the GLUT1 glucose transporter and P-glycoprotein, three integral membrane proteins, and p21ras and a 42 kDa G protein alpha subunit, both covalently modified by lipids, were efficiently solubilized and fractionated in the detergent-rich fraction where they were enriched 3.5-, 4.8-, 4.4-, 4.5- and 4.7-fold, respectively. Triton X-114 fractionation could therefore be used as a first step in the purification of many blood-brain barrier membrane proteins.
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PMID:Extraction of brain capillary membrane proteins using Triton X-114. 769 79

The blood-testis barrier is believed to be constituted by tight junctions between Sertoli cells in seminiferous tubules and possibly by myoid cells that encircle these tubules. We now show that testis microvessels are endowed with several markers of barrier properties of brain microvessels, such as the glucose transporter, P-glycoprotein, and gamma-glutamyl transpeptidase. Quantitative EM studies show that the endothelium in testis, as in brain, is continuous and has long junctional profiles and few vesicles. However, a small proportion of testis capillaries have expansions in their junctional clefts suggestive of patent paracellular channels, which may explain their higher permeability. Because barrier features are thought to be induced and/or maintained in brain microvessels by astrocytes, we assessed whether astrocyte-like cells exist in the testis. We found that the intertubular Leydig cells, adjacent to microvessels, express the astrocyte markers: glial fibrillary acidic protein, glutamine synthetase, and S-100 protein. We suggest that the testis endothelium contributes to the blood-testis barrier and that these endothelial barrier features are influenced by Leydig cells. We believe that the endothelial and the epithelial (Sertoli) components of the blood-testis barrier are "in series" and complement each other in achieving a stable milieu for spermatogenesis.
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PMID:Barrier properties of testis microvessels. 790 79

The blood-brain barrier is formed by the cerebral capillary endothelial cells, joined together by tight junctions. These cells express the general endothelial cell markers as well as specific markers found on endothelial cells forming physiological barriers such as gamma-glutamyltranspeptidase, the glucose transporter Glut1 and the neutral amino-acid transporter. Using the monoclonal antibodies C219 and MRK16, we have revealed by Western blot and immuno-histochemistry the expression of the multidrug resistance P-glycoprotein on isolated rat cerebral cortex capillaries. On the other hand, P-glycoprotein was not detectable in brain cortex homogenates. P-glycoprotein thus appears to be a blood-brain barrier endothelium-specific marker which could regulate brain penetration of xenobiotics and thus participate in the neuroprotection of the brain.
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PMID:Detection of the multidrug resistance of P-glycoprotein in healthy tissues: the example of the blood-brain barrier. 873 93

Vascular endothelial cells (EC) exhibit organ-to-organ heterogeneity in their functions and morphologies. In particular, brain capillary EC have unique characteristics exemplified by the blood-brain barrier (BBB). The formation and the maintenance of BBB have been ascribed to EC responses to inductive signal(s) or factor(s) from astrocytes that encircle microvessels in the central nervous system. These EC responses were demonstrated in numerous in vivo studies, exemplified by those of Janzer and Raff (Nature 325:253, 1987) and Tout et al. (Neuroscience 55:291, 1993) showing that transplanted astrocytes induced BBB properties in non-neural vascular EC. In this study, we constructed a heterologous co-culture system, in which rat fetal brain astrocytes were cultivated on one surface of a porous membrane and human umbilical vein EC on the opposite surface. Electron microscopic examination revealed that astrocytes passed their endfeet through the pores, making contact with EC. In this system, gamma-glutamyltranspeptidase (gamma-GTP) activity in EC was found to be significantly increased by contacting astrocytes in a density- and time-dependent manner, but not when the astrocyte feeder layer was apart from EC or replaced by COS cells; astrocyte-derived extracellular matrix partially activated gamma-GTP. mRNAs for some of the representative BBB markers, including transferrin receptor, P-glycoprotein, brain-type glucose transporter (GLUT-1), and gamma-GTP were also demonstrated by reverse transcription-polymerase chain reaction to be upregulated in EC co-cultured with astrocytes. Astrocyte inductions of close membrane apposition resembling a zonula occludens and of an increase in the content of mitochondria in EC were also noted in electron micrographs. Furthermore, an increased barrier activity against inulin was conferred on EC when they were lined with astrocytes. The results obtained with this heterologous co-culture system thus indicate that through contact with their feet, astrocytes are capable of transdifferentiating non-neural EC into the brain type, endowing them with the BBB properties.
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PMID:Induction of various blood-brain barrier properties in non-neural endothelial cells by close apposition to co-cultured astrocytes. 898 64

The hypothesis that P-glycoprotein plays a functional role at the brain capillary endothelium, which makes up the blood-brain barrier in vivo, is based largely on immunocytochemical studies showing immunoreactive P-glycoprotein localized to either isolated brain microvessels or microvessels within tissue sections. The present studies use the MRK16 monoclonal antibody to human P-glycoprotein to demonstrate that the pattern of immunolocalization of P-glycoprotein in microvessels of human or primate brain is similar to the pattern of immunolocalization of an astrocyte protein, glial fibrillary acidic protein. In contrast, the discontinuous staining pattern of MRK16 is not colocalized with the continuous immunostaining of the brain endothelial GLUT1 glucose transporter. The MRK16 antibody was radiolabeled with [125I]-iodine, and 125I-MRK16 avidly bound isolated human brain capillaries via a saturable mechanism. However, the 125I-MRK16 antibody was not taken up by primate brain capillaries in vivo following intravenous injection. In conclusion, these studies provide evidence that P-glycoprotein does not play a functional role at the luminal membrane of the brain capillary endothelium in vivo, and that a principal site of immunoreactive P-glycoprotein in brain microvasculature is localized to astrocyte foot processes.
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PMID:Brain microvascular and astrocyte localization of P-glycoprotein. 904 75

The blood-brain barrier is formed by the endothelial cells of the brain capillaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic activity. Essential nutrients are delivered to the brain by selective transport mechanisms, such as the glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion through the endothelial cells depending on their lipophilicity, degree of ionization, molecular weight, relative brain tissue and plasma bindings, some others can use specific endogenous transporters. In such cases, binding competition on the transporter with endogenous products or nutrients can occur and limits drug transfer. The blood-brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many drugs are unable to reach this organ at therapeutic concentrations. Various attempts have been made to overcome the limiting access of drugs to the brain, e.g. chemical modification, development of more hydrophobic analogs or linking an active compound to a specific carrier. Transient opening of the blood-brain barrier in humans has been achieved by intracarotid infusion of hypertonic mannitol solutions or of bradykinin analogs. Another way to increase or decrease brain delivery of drugs is to modulate the P-glycoprotein (P-gp) whose substrates are actively pumped out the cell into the capillary lumen. Many P-gp inhibitors or inducers are available to enhance the therapeutic effects of centrally acting drugs or to decrease central adverse effects of peripherally active drugs.
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PMID:Drug transfer across the blood-brain barrier and improvement of brain delivery. 1002 84

Sites of immunoreactive P-glycoprotein associated with human brain microvasculature were identified by labeling of unfixed isolated human brain capillaries, allowing visualization of the three-dimensional capillary structure by confocal microscopy. Capillaries isolated from human autopsy brain were dual-labeled with the MRK16 mouse monoclonal antibody (against human P-glycoprotein) and rabbit polyclonal antisera against the human brain microvascular glucose transporter (GLUT1), or glial fibrillary acidic protein (GFAP) on astrocyte foot processes. MRK16 and GLUT1 dual-labeling showed no signal overlap, identical to the staining pattern observed for dual-labeling with anti-GFAP and anti-GLUT1 antibodies: both GFAP and MRK16 labeling were discrete, discontinuous, and not co-localized with continuous GLUT1 labeling of capillary endothelium. In contrast, complete overlap of MRK16 and GFAP labeling demonstrated P-glycoprotein localization on astrocyte foot process remnants at the abluminal face of the brain microvasculature.
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PMID:P-Glycoprotein on astrocyte foot processes of unfixed isolated human brain capillaries. 1008 69

The blood-brain barrier is formed by the endothelial cells of the brain capillaries. Its primary characteristic is the impermeability of the capillary wall due to the presence of complex tight junctions and a low endocytic activity. Essential nutrients are delivered to the brain by selective transport mechanisms, such as glucose transporter and a variety of amino acid transporters. Although most drugs enter the brain by passive diffusion through the endothelial cells depending of their lipophilicity, degree of ionization, molecular weight, relative brain tissue and plasma bindings--some of them can use specific endogenous transporters. In these cases, binding competition on the transporter with endogenous products or nutrients can occur and limit the drug transfer. The blood-brain barrier can be a major impediment for the treatment of diseases of the central nervous system, since many drugs are unable to reach this organ at therapeutic concentrations. Various attempts have been made to overcome the limiting access of drugs to the brain: chemical modification of drugs, development of more hydrophobic analogs or linking an active compound to a specific carrier. Transient opening of the blood-brain barrier has been achieved by intracarotid infusion of hypertonic mannitol solutions or of bradykinin analogs in humans. Another way to increase or decrease brain delivery of drugs is to modulate the P-glycoprotein (P-gp) whose substrates are actively pumped out the cell into the capillary lumen. We actually dispose of many P-gp inhibitors or inducers in order to enhance the therapeutic effects of centrally acting drugs or to decrease central adverse effects of peripheric drugs.
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PMID:[Mechanisms of nutrient and drug transfer through the blood-brain barrier and their pharmacological changes]. 1037 Aug 86


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