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)

P-glycoprotein (P-gp) is expressed not only in tumour cells but also in some normal tissues including brain capillaries. We investigated whether or not P-gp was expressed in the capillary endothelial cells of a rat focal ischaemic brain. The brains were immunohistochemically studied for Factor VIII, glial fibrillary acidic protein (GFAP), and P-gp. Endothelial gamma-glutamyl transpeptidase (gamma-GTP) activity, which is thought to be induced by glial cells, was also studied histochemically. The P-gp positive endothelial cells disappeared in the ischaemic lesion by post-ischaemic day 3. Factor VIII-positive regenerating capillaries were first observed on day 3 without P-gp expression. The P-gp positive endothelial cells began to reappear on day 5, and were detected in all the endothelial cells by day 8. The P-gp expression in endothelial cells showed a similar pattern as that of gamma-GTP, and seemed to correlate with GFAP-positive reactive astrocytes. The newly-formed brain capillaries thus appeared to have a potential to express P-gp in abnormal pathogenic conditions as cerebral infarction, and our present study also suggested that P-gp in the brain capillaries might therefore be expressed in conjunction with glial cells.
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PMID:P-glycoprotein expression in brain capillary endothelial cells after focal ischaemia in the rat. 793 92

We investigated the time kinetics of P-glycoprotein (P-gp), a membrane bound drug efflux pump for many anti-cancer drugs in multidrug resistant cells, using a rat ischemic brain model. Frozen sections of the brain were studied immunohistochemically with anti-Factor VIII antibody for endothelial cells, with anti-glial fibrillary acidic protein (GFAP) antibody for reactive astrocytes, and with MC6-4 monoclonal antibody for P-gp. A putative blood-brain barrier (BBB) marker, gamma-glutamyl transpeptidase (gamma-GTP), and the progression of the brain edema were also studied. P-gp positive endothelial cells disappeared in the ischemic lesion by post-ischemic Day 3. Factor VIII-positive regenerating capillaries were first observed on Day 3 without P-gp expression when the brain edema reached a maximum. P-gp positive endothelial cells began to reappear on Day 5, and were detected in all endothelial cells by Day 8. The time kinetics of P-gp expression in the endothelial cells showed a similar pattern as that of gamma-GTP, and its induction is associated with GFAP-positive reactive astrocytes. These results suggest that P-gp might play an important role in maintaining the BBB function in conjunction with glial cells.
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PMID:P-glycoprotein expression in brain capillary endothelial cells after focal ischemia in rat. 797 60

(1) In vitro models of the BBB have been developed from cocultures between bovine, porcine, rodent or human brain capillary endothelial cells with rodent or human astrocytes. Since most in vivo BBB studies have been performed with small laboratory animals, especially rats, it is important to establish a rat brain endothelial (RBE) cell culture system that will allow correlations between in vitro and in vivo results. The present review will constitute a brief description of the best characterized RBE cell lines (RBE4, GP8/3.9, GPNT, RBEC1, TR-BBBs and rBCEC4 cell lines) and will summarize their recent and important contribution to our current knowledge of the BBB transport functions and permeability to blood-borne solutes, drugs, and cells. (2) In most cases, primary cultures of RBE cells were transduced with an immortalizing gene (SV40 or polyoma virus large T-antigen or adenovirus E1A), either by transfection of plasmid DNA or by infection using retroviral vectors. In one case however, the conditionally immortalized TR-BBB cell line was derived from primary cultures of brain endothelial cells of SV40-T-expressing transgenic rats. (3) All cell lines appear to have an endothelial morphology. The absence of foci formation would mean that the cells are not transformed. The endothelial origin is shown by the expression of Factor VIII-related antigen. Immortalized RBE cells express all the enzymes and transporters that are considered as specific for the blood-brain barrier endothelium, with similar characteristics to those expected from in vivo analyses, but at a significantly lower level. Some RBE cell lines are responsive to astroglial factors, such as RBE4 cells, rBEC4, and TR-BBB cells. None of the immortalized RBE cell lines appear to generate the necessary restrictive paracellular barrier properties that would allow to use them in transendothelial permeability screening. (4) RBE cell lines have been used to demonstrate that transporters such as organic cation transporter/carnitine transporter, serotonin transporter, and the ATA2 system A isoform are expressed in rat brain endothelium. When the transporter is shown to be expressed with the same properties in the immortalized RBE cells as in vivo, regulation studies may be initiated even if the transporter is down-regulated. Pharmacological applications have been proposed with well-characterized transporters such as monocarboxylic acid transporter-1, large neutral amino acid tansporter-1, nucleoside carrier systems, and P-glycoprotein. RBE cell monolayers have also been used to investigate the mechanism of the transendothelial transport of large molecules, such as immunoliposomes or nanoparticles, potentially useful as drug delivery vectors to the brain. (5) RBE4 and GP8 cell lines have been extensively used to demonstrate that intercellular adhesion molecule-1 (ICAM-1) engagement in brain endothelial cells triggers multiple signal transduction pathways. Using functional assays, it was established that ICAM-1 signaling is intimately and actively involved in facilitating lymphocyte infiltration. (6) Several RBE cell lines have been described, which constitute tentative in vitro models of the rat BBB. The major limitation of these models generally appears to be due to their relatively high paracellular permeability to small molecules, thus limiting their use for permeability studies. The strategies developed for the production of these RBE cell lines will enable the characterization of still more efficient permeability models, as well as the immortalization of human brain endothelial cells.
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PMID:Rat brain endothelial cell lines for the study of blood-brain barrier permeability and transport functions. 1596 8

Multidrug transporters, such as P-glycoprotein (P-gp), multidrug-resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP), are associated with multidrug resistance in cancers; other molecules, such as major vault protein (MVP), have a similar association with drug-resistant cancer. These proteins are postulated to generate drug resistance in epilepsy. They have been shown individually to be up-regulated in epileptogenic brain tissue. In any consideration of the function, inhibition or evasion of the activity of such proteins, the colocalization of such proteins needs to be understood. We systematically determined the presence of such colocalization, focusing on microvascular endothelium from epileptogenic human brain tissue. Double labelling immunofluorescence and confocal laser scanning microscopy were used to determine colocalization of P-gp, MRP1, BCRP and MVP in one case of hippocampal sclerosis and two cases of focal cortical dysplasia type IIb. Endothelial colocalization was examined with double labelling using antibodies to CD34 and Factor VIII. The presence of P-gp, BCRP and MVP in microvascular endothelium was confirmed. P-gp, BCRP and MVP colocalized in microvascular endothelium, though not all proteins appeared to be identically distributed within this tissue. MRP1 did not colocalize to endothelium. These findings were not unexpected but required formal confirmation. The demonstrated colocalization of P-gp, BCRP and MVP in microvascular endothelium in epileptogenic human brain tissue has important implications for functional experiments (including single knock-out mice studies), work with specific and broad-spectrum inhibitors of transport function, and any eventual trials of treatment of refractory epilepsy involving modulation of the function of these proteins.
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PMID:Vascular colocalization of P-glycoprotein, multidrug-resistance associated protein 1, breast cancer resistance protein and major vault protein in human epileptogenic pathologies. 1640 53