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)

Expression of P-glycoprotein, the product of the MDR1 gene, confers multidrug resistance on cell lines and human tumours (reviewed in refs 1,2). P-glycoprotein (relative molecular mass 170,000) is an ATP-dependent, active transporter which pumps hydrophobic drugs out of cells, but its normal physiological role is unknown. It is a member of the ABC (ATP-binding cassette) superfamily of transporters, which includes many bacterial transport systems, the putative peptide transporter from the major histocompatibility locus, and the product of the cystic fibrosis gene (the cystic fibrosis transmembrane regulator, CFTR). CFTR is located in the apical membranes of many secretory epithelia and is associated with a cyclic AMP-regulated chloride channel. At least two other chloride channels are present in epithelial cells, regulated by cell volume and by intracellular Ca2+, respectively. Because of the structural and sequence similarities between P-glycoprotein and CFTR, and because P-glycoprotein is abundant in many secretory epithelia, we examined whether P-glycoprotein might be associated with one or other of these channels. We report here that expression of P-glycoprotein generates volume-regulated, ATP-dependent, chloride-selective channels, with properties similar to channels characterized previously in epithelial cells.
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PMID:Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. 137 98

Chinese hamster pgpl P-glycoprotein (Pgp) is a membrane transport protein that causes multidrug resistance (MDR) by actively extruding a wide variety of cytotoxic agents out of cells. It may also function as a peptide transporter and as a chloride channel. Previously, we have shown that hamster pgpl Pgp is expressed in more than one topological form and that the generation of these structures is modulated by charged amino acids flanking the predicted transmembrane (TM) segments 3 and 4. Different topological structures of Pgp may be involved in different functions. In this study, we examined the role of cytoplasmic components in cell-free translation systems in modulating the topologies of Pgp. By using rabbit reticulocyte lysate (RRL) and wheat germ extract (WGE) expression systems, we showed that WGE contains a soluble, heat-labile, high molecular weight fraction that regulates the membrane topology of truncated Pgp molecules. These results and our previous findings indicate that the membrane topology of a mammalian polytopic membrane protein may be regulated both by the amino acid sequence of the protein and by soluble cytoplasmic component(s). We speculate that Pgp expressed in various cell types may have different topological structures modulated by specific cytoplasmic factors.
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PMID:Involvement of cytoplasmic factors regulating the membrane orientation of P-glycoprotein sequences. 761 15

ATP-binding cassette (ABC) transporters share significant sequence identity within their ATP-binding domains. Degenerate oligonucleotides based on highly conserved portions of the ATP-binding domain genes were used to clone portions of two members of the ABC gene superfamily from Saccharomyces cerevisiae DNA. These genes were designated MDL1 and MDL2 (for multidrug resistance-like). Each MDL gene is predicted to encode a single set of transmembrane domains and a single ATP-binding domain, thus the MDL gene products are 'half-molecule' ABC proteins. The two genes were mapped to precise regions on chromosomes XII and XVI and show a considerable similarity to the mammalian P-glycoprotein/multidrug resistance (MDR) and peptide transporter (TAP) genes. Preliminary analysis of null mutants constructed by gene replacement has indicated that the MDL genes are not essential for viability of yeast. The sequences have been deposited in the GenBank data library under Accession Numbers L16958 (Locus YSCBCSA) and L16959 (Locus YSCBCSB).
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PMID:Mapping and sequencing of two yeast genes belonging to the ATP-binding cassette superfamily. 791 68

P-glycoprotein (pgp) is a membrane transport protein that causes multidrug resistance (MDR) by actively extruding a wide variety of cytotoxic agents out of cells. It may also function as a peptide transporter, a volume-regulated chloride channel, and an ATP channel. Previously, it has been shown that hamster pgp 1 Pgp is expressed in more than one topological form and that the generation of these structures is modulated by charged amino acids flanking the predicted transmembrane (TM) segments 3 and 4 and by soluble cytoplasmic factors. Different topological structures of Pgp may be related to its different functions. In this study, we examined the effects of translation temperature on the membrane insertion process and the topologies of Pgp. Using the rabbit reticulocyte lysate expression system, we showed that translation at different temperatures affects the membrane insertion and orientation of the putative TM3 and TM4 of hamster pgp 1 Pgp in a co-translational manner. This observation suggests that the membrane insertion process of TM3 and TM4 of Pgp molecules may involve a protein conducting channel and/or the interaction between TM3 and TM4, which act in a temperature sensitive manner. We speculate that manipulating temperature may provide a way to understand the structure-function relationship of Pgp and help overcome Pgp-related multidrug resistance of cancer cells.
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PMID:Co-translational effects of temperature on membrane insertion and orientation of P-glycoprotein sequences. 881 6

It has long been thought that intestinal absorption of most of the drugs proceeds by passive diffusion mechanism, in which lipid solubility of the drug molecule is a determinant factor. However, water-soluble natural compounds such as amino acids and sugars can move across cell membranes by the specialized carrier-mediated transport mechanisms. Although some drugs which are structurally analogous to natural compounds have been suggested to be absorbed by such transporters, no clear evidence for the involvement of carrier-mediated transport mechanisms has been obtained. In the present study, through the approach by means of the molecular cloning and functional expression of drug transporters as well as membrane physiological analysis for the drug transport across the intestinal epithelial cell membranes, participation of the carrier-mediated transport mechanisms for the drug absorption was clarified. They include peptide transporter, monocarboxylic acid transporter, anion antiporter, and P-glycoprotein. Most of them have a function for the uptake of drugs into epithelial cells, leading to the increased absorption of drugs, whereas P-glycoprotein excludes drugs into the lumen, thereby decreasing the apparent absorbability of drugs. A rat intestinal monocarboxylic acid-proton cotransporter, MCT1, and an anion antiporter, AE2, were suggested to contribute to the pH-dependent intestinal absorption of monocarboxylic acids such as benzoic acid, lactic acid, nicotinic acid, and valproic acid. An involvement of such pH-dependent transporters in the intestinal absorption of weak organic acids is important, because they may have an alternative mechanism against passive diffusion according to the pH-partition hypothesis. PepT1 cloned from rat intestinal epithelial cells as a peptide transporter was clarified to localize at the intestinal epithelia brush-border membrane and to function for the absorption of beta-lactam antibiotics by the proton-gradient energized mechanism. In contrast, P-glycoprotein functions for the secretion of drugs into the intestinal lumen, thereby decreasing intestinal absorption of an immunosuppressive, cyclosporin A and a 5-HT3 receptor antagonist, azasetron. These lines of studies on the clarification of carrier-mediated drug absorption mechanisms will provide new knowledge for the strategies to the enhancement of intestinal absorption of drugs.
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PMID:[Molecular characterization of intestinal absorption of drugs by carrier-mediated transport mechanisms]. 926 Dec 13

Most antigenic peptides presented to CD8+ T cells are generated from cytosolic precursors and are translocated by TAP into the endoplasmic reticulum, where they associate with MHC class I molecules. TAP-deficient cells exhibit a limited capacity to deliver peptides from cytosolic proteins to class I molecules. One candidate for an alternative peptide transporter is P-glycoprotein, which transports numerous substances, including peptides, across membranes. Elevation of P-glycoprotein expression is partially responsible for the resistance developed by neoplasias to chemotherapeutic drugs. Overexpression of P-glycoprotein has been reported to enhance the expression of class I molecules. Here, we investigated the role of P-glycoprotein in the generation of peptide-MHC complexes. We were unable to detect P-glycoprotein-mediated transport of synthetic peptides into the endoplasmic reticulum of either T2 cells (TAP-deficient) infected with a recombinant vaccinia virus (rVV) expressing P-glycoprotein or drug-resistant cells in which TAP is inactivated by a peptide from the herpes simplex virus ICP47 protein. Expression of rVV-encoded P-glycoprotein in T2 cells was unable to enhance cell surface expression of any of three MHC class I allomorphs tested. rVV-mediated expression of P-glycoprotein enabled T2 cells to produce limited amounts of class I-peptide complexes from cytosolic antigens, but this was not blocked by a drug that inhibits its transporter function, and a similar degree of presentation was mediated by functionally inactive mutated forms of P-glycoprotein. Thus, this was a nonspecific effect that we attributed to diminished membrane integrity resulting from P-glycoprotein overexpression. Taken together, our findings cast serious doubts that P-glycoprotein is a biologically significant transporter of cytosolic peptides.
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PMID:P-glycoprotein plays an insignificant role in the presentation of antigenic peptides to CD8+ T cells. 978 23

The membrane transport processes of drugs are critical issues to determine their absorption, distribution and elimination. Recently, various drug transporters have been identified and characterized. The enterocyte peptide transporter PEPT1 mediates the absorption of peptide-like drugs including beta-lactam antibiotics as well as valacyclovir lacking peptide bond. In the kidney, the basolateral organic anion transporters (OAT1, OAT3) and cation transporters (OCT1, OCT2) mediate renal distribution of hydrophilic anionic and cationic drugs, respectively. The brush-border type OAT-K1/K2 were suggested to be a target transporter for methotrexate-leucovorine rescue therapy. The ATP-driven efflux pump P-glycoprotein appeared to be an interaction site between digoxin and clarithromycin or itraconazole in the kidney. In addition, the intestinal P-glycoprotein was suggested to act as an absorptive barrier for tacrolimus in recipients of liver and small bowel transplantation.
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PMID:[Molecular mechanisms on drug transporters in the drug absorption and disposition]. 1180 41

Transport proteins have critical physiological roles in nutrient transport and may be utilized as a mechanism to increase drug absorption. However, we have little understanding of these proteins at the molecular level due to the absence of high-resolution crystal structures. Numerous efforts have been made to characterize the P-glycoprotein efflux pump, the peptide transporter (PepT1) and the apical sodium-dependent transporter (ASBT) which are important not only for their native transporter function but also as drug targets to increase absorption and bioactivity. In vitro and computational approaches have been applied to gain some insight into these transporters with some success. This represents an opportunity for optimizing molecules as substrates for the solute transporters and providing a further screening system for drug discovery. Clearly the future growth in knowledge of transporter function will be led by integrated in vitro and in silico approaches.
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PMID:Modeling of active transport systems. 1192 51

We investigated whether the uptake of a specific antipsychotic agent, sulpiride, in Caco-2 cells is mediated by a carrier-mediated system. Caco-2 cell monolayers were cultured in plastic culture dishes and uptake and efflux studies were conducted. The determination of sulpiride was performed by HPLC. At 37 degrees C, sulpiride uptake in pH 6.0 was twice as much as in pH 7.4. At 4 degrees C, however, no significant difference was observed between pH 6.0 and 7.4. The uptake at 4 degrees C was markedly lower than that obtained at 37 degrees C. The subtraction of the uptake at 4 degrees C from the uptake at 37 degrees C indicated a saturable process, and the result of the Eadie-Hofstee plot analysis indicated that the uptake consists of two or more saturable components. The uptake was significantly inhibited by uncoupler, protonophore, amino acid modifying agent and proteinase. Sulpiride efflux was temperature-dependent and was significantly inhibited by uncoupler and amino acid modifying agent. These findings indicate that sulpiride uptake and efflux in Caco-2 cells are carrier-mediated. Furthermore, the uptake was significantly decreased by some substrates and inhibitors of peptide transporter, PEPT1, and organic cation transporters, OCTN1 and OCTN2, and was significantly increased by preloading with them. The uptake was also significantly increased by a typical substrate of P-glycoprotein. From these findings, we presumed that peptide transporter PEPT1 and organic cation transporters OCTN1 and OCTN2 are involved with this uptake. P-glycoprotein may also contribute to the efflux of sulpiride.
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PMID:Studies on intestinal absorption of sulpiride (1): carrier-mediated uptake of sulpiride in the human intestinal cell line Caco-2. 1213 63

The objectives of this study were (1) to investigate the transporter inhibition activity of three nonionic surfactants on P-glycoprotein, the human intestinal peptide transporter, and the monocarboxylic acid transporter in Caco-2 cell monolayers, and (2) to evaluate the role of membrane fluidity and protein kinase C in surfactant-induced transporter inhibition. All three surfactants inhibited P-glycoprotein (P-gp). Over a range from 0 to 1 mM, Tween 80 and Cremophor EL increased apical-to-basolateral permeability (AP-BL) and decreased basolateral-to-apical (BL-AP) permeability of the P-gp substrate rhodamine 123. Vitamin E TPGS's effect was equally large, but essentially only reduced the BL-AP permeability of rhodamine 123, and did so at a vitamin E TPGS concentration of only 0.025 mM. These P-gp inhibition effects would appear to be related to these excipients' modulation of membrane fluidity, where Tween 80 and Cremophor EL fluidized cell lipid bilayers, while vitamin E TPGS rigidized lipid bilayers. However, among the three surfactants, only Tween 80 inhibited the peptide transporter, as measured by glycyl sarcosine permeability. Likewise, only Cremophor EL inhibited the monocarboxylic acid transporter, as measured by benzoic acid permeability. Nevertheless, at least one of these three surfactants inhibited each P-gp, the human intestinal peptide transporter, and the monocarboxylic acid transporter. A common functional feature of these three surfactants was their ability to modulate fluidity, although results indicate that even strong membrane fluidity modulation alone was not sufficient to reduce transporter activity. N-octyl glucoside, a nonionic surfactant that did not modulate membrane fluidity, did not affect transporter functioning. Protein kinase C inhibitors failed to affect rhodamine 123 and glycyl sarcosine permeability, suggesting protein kinase C inhibition was not the mechanism of transporter inhibition. These results suggest that surfactants can inhibit multiple transporters but that changes in membrane fluidity may not be a generalized mechanism to reduce transporter activity.
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PMID:Effects of nonionic surfactants on membrane transporters in Caco-2 cell monolayers. 1220 53


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