Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Juliano and Ling initially reported the expression of a 170 kDa glycoprotein in the membrane of Chinese hamster ovarian cells in 1976, and named this glycoprotein P-glycoprotein (P-gp) based on its predicted role of causing "permeability" of the cell membrane. After much research on anthracycline-resistance, this P-gp was finally characterized as a multidrug-resistant protein coded by the mdr1 gene. Multidrug resistance associated protein (MRP) was initially cloned from H69AR, a human small cell-lung carcinoma cell line which is resistant to doxorubicin (DXR) but does not express P-gp. MRP also excretes substrates through the cell membrane using energy from ATP catabolism. The substrate of MRP is conjugated with glutathione before active efflux from cell membrane. Recently, membrane transporter proteins were re-categorized as members of "ATP-Binding Cassette transporter"(ABC-transporter) superfamily, as shown at http://www.med.rug.nl/mdl/humanabc.htm and http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.html. A total of ABC transporters have been defined, and MDR1 and multidrug resistance associated protein 1 (MRP1) were reclassified as ABCB1 and ABCC1, respectively. Their associated superfamilies include 11 and 13 other protein, in addition to ABCB and ABCC, respectively. Lung resistance-related protein (LRP) is not a member of the superfamily of ABC transporter proteins, because it shows nuclear membrane expression and transports substrate between nucleus and cytoplasm. LRP was initially cloned from a non-small cell lung carcinoma cell line, SW1573/2R120 which is resistant to DXR, vincristine, etoposide and gramicidin D and does not express P-gp. The mechanisms of resistance remains unclear, and why some resistant cell lines express P-gp and others express MRP and/or LRP is likewise unclear.
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PMID:Resistant mechanisms of anthracyclines--pirarubicin might partly break through the P-glycoprotein-mediated drug-resistance of human breast cancer tissues. 1179 Nov 27

Multidrug resistance associated proteins (MRPs) and P-glycoprotein (P-gp) are involved in hepatobiliary transport of various compounds. Our aim was (1) to define transporter specificity of the cholescintigraphic agents 99mTc-HIDA and 99mTc-MIBI, which are used clinically for myocardial perfusion measurements; and (2) to deduce MRP and P-gp functions in vivo from hepatic 99mTc kinetics. Accumulation of radioactivity was measured in the human tumor cell lines GLC4, GLC4/ADR150x (MRP1-overexpressing/P-gp-negative) and GLC4/P-gp (P-gp-overexpressing). Bile secretion was quantified in untreated and in glutathione-depleted control and MRP2-deficient (GY/TR-) rats. Hepatobiliary transport was measured using a gamma camera in both types of rats. 99mTc-HIDA accumulated 5.8-fold less in GLC4/ADR150x calls than in GLC4 or GLC4/P-gp cells. In GLC4/ADR150x, the cellular 99mTc-HIDA content was increased 3.4-fold by the MRP1,2 inhibitor MK571 (50 microM), while MK571 had no measurable effect in GLC4 and GLC4/P-gp cells. 99mTc-MIBI accumulated less in GLC4/P-gp and GLC4/ADR150x cells than in GLC4 cells. Bile secretion of 99mTc-HIDA was impaired in GY/TR- compared to control rats and not affected by glutathione depletion in GY/TR- rats. Hepatic secretion of 99mTc-HIDA was slower in GY/TR- (t1/2 40 min) than in control rats (t1/2 7 min). Bile secretion of 99mTc-MIBI was similar in both rat strains and impaired by glutathione depletion in control rats only, indicating compensatory activity of additional transporter(s) in GY/TR- rats. 99mTc-HIDA is transported only by MRP1,2 only, while 99mTc-MIBI is transported by P-gp and MRP1,2. The results indicate that hepatic P-gp and MRP1,2 function can be assessed in vivo by sequential use of both radiopharmaceuticals.
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PMID:In vivo imaging of hepatobiliary transport function mediated by multidrug resistance associated protein and P-glycoprotein. 1511 37

Fluorescent dyes and inhibitor compounds are commonly used to detect activity of multixenobiotic resistance (MXR) efflux pumps in marine invertebrates. We here address the question whether compounds acting as specific inhibitors of certain mammalian transporters can be used in dye efflux assays to distinguish different transporter activities in gill tissue from a marine mussel. We quantified effects of PSC833, a specific inhibitor of mammalian P-gp (P-glycoprotein, ABCB1), and MK571, which blocks MRP (Multidrug resistance associated protein, ABCC) type transporters, on calcein-am efflux in gill tissue of Mytilus californianus. Calcein-am acts as a substrate of both P-gp and MRP. Effects of single compounds and mixtures were determined and combined effect models predicting independent action (IA) and concentration addition (CA) of the chemicals were applied. Effect values predicted by IA showed better correspondence with the experimentally obtained data. This indicates that the inhibitor compounds target different mechanisms of calcein-am efflux and points to P-gp and MRP activities in mussel gills. Our approach could be a simple way for identifying the efflux transporter types targeted by chemosensitizers, including environmentally relevant compounds, in native tissues from marine invertebrates.
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PMID:Teasing apart activities of different types of ABC efflux pumps in bivalve gills using the concepts of independent action and concentration addition. 1839 25

It has become clear that almost any drug or chemical substance administered to the mother is able to cross the placenta to some extent, unless it is metabolized or altered during passage, or else its molecular size and low lipid solubility do not allow transplacental transfer. A number of transport systems have been identified in the placenta, which recognizes a wide variety of pharmacological active drugs as substrates. In recent years, research on human placental transporters has been developing due to the increase of knowledge technology in pharmacology. In this review we will focus on the main placental transporters which are known today. The P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP/ABCG2) and Multidrug resistance associated protein 2 (MDR2) transporters are expressed at the apical surface of the syncytiotrophoblast, and have a protective effect. Transporters for 5-HT (SERT) and NE (NET) are also expressed at the apical surface and regulate extracellular concentrations of monoamines. The physiologic function of Multidrug resistance associated protein (MRP) transporters (which is expressed at the basal surface of the syncytiotrophoblast) may be the removal of metabolic end products from the fetus. Some of the members of the organic anion transporters are also expressed at the basolateral surface of the syncytiotrophoblast.
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PMID:Drug transport across the placenta. 2134 26

Multidrug resistance (MDR) is an unwanted phenomenon, that may cause therapy failure in several neoplasms including hematological malignancies. The purpose of any type of laboratory MDR assay is to reliably identify such patients and to provide useful data to clinicians with a relatively short turnaround time. MDR can be multicausal and several previous data identified a group of transmembrane proteins - the ATP-binding casette (ABC) proteins - that may be involved in MDR in various hematological malignancies. The prototype of these proteins is the P-glycoprotein (Pgp, MDR1, ABCB1) that is a seven-membrane spanning transmembrane protein capable of extruding several cytotoxic drugs that are of key importance in the treatment of hematological disorders. Similarly other ABC proteins - Multidrug resistance associated protein 1 (ABCC1) and breast cancer resistance protein (ABCG2) are both capable of pumping out cytotoxic drugs. Here, we present flow cytometric methods to identify MDR proteins by antigen and activity assays. The advantage of flow technology is the short turnaround time and its relative easiness compared to nucleic acid based technologies. However, for the activity assays, it should be noted, that these functional tests require live cells, thus adequate results can only be provided if the specimen transport can be completed within 6 hours of sample collection. Identification of MDR proteins provides prognostic information and may modulate therapy, thus signifies a clinically useful information in the evaluation of patients with leukemias.
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PMID:Prediction of Therapy Response and Prognosis in Leukemias by Flow Cytometric MDR Assays. 2768 27