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)

The effect of osmotic stress on Cl- permeability in human squamous lung carcinoma epithelial (S1) cells was investigated using a macroscopic 125I efflux assay. Hypotonic challenge of monolayers led to a significant (P < 0.01) dose-related increase in efflux from pre-loaded cells, returning to pre-activation rates within 10 min. A similar magnitude of response could be produced by challenge with an isotonic low chloride-containing solution. Neither 100 mM dideoxy-forskolin nor 100 mM verapamil inhibited the increase in Cl- secretion after hypotonic challenge, whereas 100 mM DIDS inhibited volume-activated Cl- secretion by 55%. Both Northern and Western blot analysis confirmed the absence of MDR1 mRNA and P-glycoprotein in the S1 cells. We conclude that these cells have a volume-regulated Cl- secretory pathway that is independent of the ABC transporter, P-glycoprotein.
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PMID:Lack of inhibition by dideoxy-forskolin and verapamil of DIDS-sensitive volume-activated Cl- secretion in human squamous lung carcinoma epithelial cells. 780 88

P-glycoprotein is a plasma-membrane glycoprotein which confers multidrug-resistance on cells and displays ATP-driven drug-pumping in vitro. It contains two nucleotide-binding domains, and its structure places it in the 'ABC transporter' family. We review recent evidence that both nucleotide-sites bind and hydrolyse Mg-ATP. The two catalytic sites interact strongly. A minimal scheme for the MgATP hydrolysis reaction is presented. An alternating catalytic sites scheme is proposed, in which drug transport is coupled to relaxation of a high-energy catalytic site conformation generated by the hydrolysis step. Other ABC transporters may show similar catalytic features.
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PMID:The catalytic cycle of P-glycoprotein. 854 39

Two distinct Drosophila melanogaster P-glycoprotein (Pgp) gene homologues of different chromosomal origin, MDR49 and MDR65, have been previously identified (38). Most Pgps are implicated in the development of the multidrug-resistance phenotype. Despite intense efforts to identify the molecular mechanism(s) associated with Pgp function, the endogenous substrate(s) of these transport molecules is largely unknown. Recent studies from our laboratory indicate that a murine Pgp homologue (E. H. Abraham, A. G. Prat, L. Gerweck, T. Seneveratne, R. J. Arceci, R. Kramer, G. Guidotti, and H. F. Cantiello. Proc. Natl. Acad. Sci. USA 90: 312-316, 1993) and a related protein, the cystic fibrosis transmembrane conductance regulator (CFTR; I. L. Reisin, A. Prat, E. H. Abraham, J. F. Amara, R. J. Gregory, D. A. Ausiello, and H. F. Cantiello. J. Biol. Chem. 269: 20584-20591, 1994), are novel ATP-permeable ion channels. The common feature of these two proteins is the conserved ATP-binding cassettes (ABC); thus molecules structurally linked to the ABC transporter family may be also functionally associated with ATP channel activity. In this study, MDR65 and MDR49 Pgps were functionally expressed in Sf9 cells, and patch-clamp techniques were applied to assess the role of these proteins in the electrodiffusional movement of ATP. In the presence of intracellular ATP and external NaCl, expression of MDR65 was associated with a linear electrodiffusional pathway that was permeable to both ATP and Cl-. Under symmetrical ATP conditions, only voltage depolarization activated a MDR65-mediated ATP-conductive pathway. Expression of MDR49 was also associated with a voltage-activated ATP conductance in symmetrical ATP, but no apparent permeability to either Cl- or ATP was observed under asymmetrical conditions. The different functional properties of MDR65 and MDR49 may be indicative of distinct physiological roles in this organism. The study indicates, however, that the two Drosophila Pgp homologues share strong functional similarities with their mammalian relatives Pgp and CFTR.
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PMID:Expression of Drosophila melanogaster P-glycoproteins is associated with ATP channel activity. 894 36

Acquired resistance of mammalian cells to multiple chemotherapeutic drugs can result from enhanced expression of the multidrug resistance-associated protein (MRP), which belongs to the ABC transporter superfamily. ABC transporters play a role in the protection of organisms against exogenous toxins by cellular detoxification processes. We have identified four MRP homologues in the soil nematode Caenorhabditis elegans, and we have studied one member, mrp-1, in detail. Using an mrp::lacZ gene fusion, mrp-l expression was found in cells of the pharynx, the pharynx-intestinal valve and the anterior intestinal cells, the rectum-intestinal valve and the epithelial cells of the vulva. Targeted inactivation of mrp-l resulted in increased sensitivity to the heavy metal ions cadmium and arsenite, to which wild-type worms are highly tolerant. The most pronounced effect of the mrp-1 mutation is on the ability of animals to recover from temporary exposure to high concentrations of heavy metals. Nematodes were found to be hypersensitive to heavy metals when both the MRP homologue, mrp-1, and a member of the P-glycoprotein (Pgp) gene family, pgp-1, were deleted. We conclude that nematodes have multiple proteins, homologues of mammalian proteins involved in the cellular resistance to chemotherapeutic drugs, that protect them against heavy metals.
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PMID:Homologues of the human multidrug resistance genes MRP and MDR contribute to heavy metal resistance in the soil nematode Caenorhabditis elegans. 894 35

Multidrug resistance (MDR) to anti-cancer drugs has been associated with the overexpression of P-glycoprotein (P-gp) and the multidrug resistance-associated protein (MRP), both being members of the ATP-binding cassette (ABC) superfamily of transporters. We investigated whether in addition to P-gp and MRP, another ABC transporter, the transporter associated with antigen processing (TAP), is associated with MDR. TAP plays a major role in MHC class I-restricted antigen presentation by mediating peptide translocation over the endoplasmic reticulum membrane. TAP1 and P-gp share a significant degree of homology among their transmembrane domains, which are thought to be the primary determinants of substrate specificity, and both can apparently mediate the translocation of peptides. Using immunocytochemistry and Western blot, TAP was overexpressed in parallel with MHC class I in several MDR human cancer cell lines. TAP was overexpressed more frequently in MRP-positive MDR cell lines (three out of three) than in P-gp positive MDR cells (two out of five). Reversal of resistance resulted in a decrease in TAP levels. Transfection of the TAP genes into TAP-deficient lymphoblastoid T2 cells conferred mild resistance to etoposide, vincristine and doxorubicin (2- to 2.5-fold). Furthermore, etoposide and vincristine inhibited TAP-dependent peptide translocation to the endoplasmic reticulum. Collectively, our results suggest that TAP may modestly contribute to the MDR phenotype, in particular in MRP- overexpressing MDR cells. Further insight into the role of TAP in MDR will require the study of other transfectants, as well as the investigation of TAP expression in P-gp and MRP-negative MDR cancer cell lines.
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PMID:Overexpression of the ABC transporter TAP in multidrug-resistant human cancer cell lines. 898 Mar 97

Natural killer (NK) cells are the first lymphoid population to reconstitute the peripheral blood compartment of immunologically compromised bone marrow transplant (BMT) recipients. Recent data suggest that, among patients transplanted for leukemia, NK cells can prevent or delay disease relapse by mediating a cytotoxic graft vs leukemia (GvL) response. Although the major mechanism by which NK cells mediate target cell lysis involves degranulation and release of cytolytic effector molecules (granzymes, proteoglycans, perforin), accumulating evidence suggests that NK cells possess additional pathways to mediate target cell killing. In fact, it is well recognized that recombinant cytokines such as IL-2 enhance the in vitro cytolytic activity of NK cells. In this study, we observed that the lytic activity mediated by resting and IL-2 activated NK cells against the same target cell appears to occur via two distinct pathways, as distinguished by their differential response to R-verapamil. Specifically, we observed that 25 microM R-verapamil inhibited the lytic activity of resting NK cells against K562 targets by approximately 50%. However, the lytic activity of IL-2 activated NK cells was unaffected by this concentration of R-verapamil. Additional studies suggested that the inhibitory effect of R-verapamil on NK cytotoxic activity was associated with its ability to prevent degranulation of cytotoxic granules. Specifically, R-verapamil inhibited BLT esterase release from resting but not IL-2 activated NK cells. These data suggest that IL-2 activated NK cells can promote target cell lysis by a pathway (possibly degranulation independent) distinct from that used by resting NK cells. We speculate that the target of R-verapamil on resting NK cells is P-glycoprotein (Pgp), an ABC transporter that we recently reported was expressed on NK cells and whose functional activity is known to be inhibited by R-verapamil.
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PMID:Differential sensitivity of resting and IL-2 activated NK cells to R-verapamil. 899 Mar 81

Generation of bile flow is a regulated, ATP-dependent process and depends on the coordinated action of a number of transporter proteins in the sinusoidal and canalicular domains of the hepatocyte. Dysfunction of any of these proteins leads to retention of substrates, with conjugated hyperbilirubinemia or cholestasis as a result. In recent years many of the transport proteins involved in bile formation have been identified, cloned, and functionally characterized. The hepatocyte sinusoidal membrane contains transport proteins for the hepatic uptake of organic anions and cations and for the uptake of bile acids. The multispecific organic anion transporting polypeptide (OATP) mediates the hepatic uptake of organic anions and a variety of organic amphiphilic compounds, including organic cations. The organic cation transporter OCT1 more specifically transports small organic cations. NTCP is the Na(+)-bile acid cotransporting protein that mediates the hepatic uptake of bile acids. The canalicular transport proteins are able to transport endogenous and exogenous metabolites into the bile against steep concentration gradients. Most of these transporters are members of the large ATP-binding cassette (ABC) superfamily, and their transport function directly depends on the hydrolysis of Mg2+/ATP. At least five ABC transporter proteins have been characterized so far: 1) the human multidrug resistance protein MDR1 mediates the excretion of hydrophobic, mostly cationic, metabolites; 2) MDR3 is involved in phosphatidylcholine secretion; 3) the canalicular bile acid transporter cBAT mediates secretion of monovalent bile salts and provides the molecular basis of bile acid-dependent bile flow; 4) SPGP, product of the P-glycoprotein sister gene, is exclusively expressed in the liver but its function is currently unknown; and 5) the human multidrug resistance protein MRP2 mediates the excretion of multivalent anionic conjugates.
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PMID:Molecular aspects of hepatobiliary transport. 922 63

Multidrug resistance (MDR) describes the phenomenon of simultaneous resistance to unrelated drugs. It has been a decade since the P-glycoprotein (Pgp) gene, which is associated with a form of MDR caused by reduced drug accumulation, was cloned. Thus, this would seem to be an appropriate time to evaluate our understanding of this form of MDR. The two MDR genes identified in humans to date (the MDR-associated protein [MRP] and Pgp genes) are structurally similar and both are members of the ATP-binding cassette (ABC) transporter family. Although the physiological role of MRP is not yet understood, one Pgp gene (mdr1) plays an important role in the blood-tissue barrier and the other (mdr2/3) is involved in phospholipid transport in the liver. A variety of compounds (chemosensitizing agents) can interfere with Pgp and MRP function; such agents may improve the efficacy of conventional therapy when used in combination with such regimens. Determining the roles cellular MDR mechanisms play in patients' response to chemotherapy is a major challenge. Using Pgp and MRP as molecular markers to detect MDR tumor cells is technically demanding, and solid tumors in particular contain heterogeneous cell populations. Since MDR requires Pgp or MRP gene expression, clinically relevant gene expression thresholds need to be established; sequential samples from individual patients are valuable for correlating MDR gene expression with the clinical course of disease. Studies in leukemias, myelomas, and some childhood cancers show that Pgp expression correlates with poor response to chemotherapy. However, in some cases, inclusion of a reversing or chemosensitizing agent such as verapamil or cyclosporin A has improved clinical efficacy. Such agents may inactivate Pgp in tumor cells or affect Pgp function in normal cells, resulting in altered pharmacokinetics. It would be interesting to determine whether patients who fail treatment in the presence of chemosensitizing agents acquire other MDR mechanisms. The ABC transporter superfamily in prokaryotes and eukaryotes is involved in the transport of substrates ranging from ions to large proteins. Of the 15 or more ABC transporter genes characterized in human cells, two (Pgp and MRP) cause MDR. Therefore, it would be relevant to determine the number of such genes present in the human genome; however, extrapolating from the number of ABC transporter genes in bacteria, the human gene probably contains a minimum of 200 ABC transporter superfamily members. Thus, tumor cells can potentially use many ABC transporters to mount resistance to known and future therapeutic agents. The challenge will be to determine which ABC transporters are clinically relevant. Despite the potential of tumor cells to protect themselves, a variety of malignancies can be successfully treated with chemotherapy. This may provide unique insights.
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PMID:Multidrug resistance: molecular mechanisms and clinical relevance. 927 26

Bacteria have developed many fascinating antibiotic-resistance mechanisms. A protein in Lactococcus lactis, LmrA, mediates antibiotic resistance by extruding amphiphilic compounds from the inner leaflet of the cytoplasmic membrane. Unlike other known bacterial multidrug-resistance proteins, LmrA is an ATP-binding cassette (ABC) transporter. The human multidrug-resistance P-glycoprotein, encoded by the MDR1 gene, is also an ABC transporter, overexpression of which is one of the principal causes of resistance of human cancers to chemotherapy. We expressed lmrA in human lung fibroblast cells. Surprisingly, LmrA was targeted to the plasma membrane and conferred typical multidrug resistance on these human cells. The pharmacological characteristics of LmrA and P-glycoprotein-expressing lung fibroblasts were very similar, and the affinities of both proteins for vinblastine and magnesium-ATP were indistinguishable. Blockers of P-glycoprotein-mediated multidrug resistance also inhibited LmrA-dependent drug resistance. Kinetic analysis of drug dissociation from LmrA expressed in plasma membranes of insect cells revealed the presence of two allosterically linked drug-binding sites indistinguishable from those of P-glycoprotein. These findings have implications for the reversal of antibiotic resistance in pathogenic microorganisms. Taken together, they demonstrate that bacterial LmrA and human P-glycoprotein are functionally interchangeable and that this type of multidrug-resistance efflux pump is conserved from bacteria to man.
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PMID:A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene. 944 Jun 94

ABC transporters are key players in the multidrug resistance of cancer cells and yeast, and they appear to be involved in the drug resistance of various pathogenic protozoa. No member of this ubiquitous protein family has yet been described in Trypanosoma brucei spp., the causative agents of African sleeping sickness and animal trypanosomiases. However, different cases of artificially induced drug resistance were shown to be linked to a reduction in net drug uptake. We used polymerase chain reaction with degenerate oligonucleotide primers corresponding to particularly conserved regions within the ATP-binding cassette to probe the genome of T. brucei spp. for the presence of ABC transporter genes. Three different sequence segments encoding ATP-binding cassettes were identified, which, upon Southern blotting, appeared to belong to distinct genes designated Tbabc1, Tbabc2, and Tbabc3. They appear to be single-copy genes in both drug-susceptible and drug-resistant stocks of T. brucei spp., expressed in bloodstream forms as well as in the procyclic life stage. Whereas Tbabc3 shows moderate homology to various known ABC transporters, Tbabc1 and Tbabc2 are highly homologous to P-glycoprotein A of Leishmania tarentolae and to the multidrug resistance protein 1 of L. donovani, respectively.
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PMID:Identification of three ABC transporter genes in Trypanosoma brucei spp. 949 8


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