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)

Using cyclosporin A (CsA) to inhibit P-glycoprotein (P-gp) function we showed previously that there was a discordance between the ability of acute myeloid leukemic (AML) blast cells to accumulate daunorubicin and P-gp antigen expression (Xie et al, Leukemia 1995; 9:1882-1887). This discordance suggests that a CsA-sensitive drug efflux mechanism distinct from P-gp is expressed in many clinical samples. In the present study using the ATP depleting agents cyanide, azide, or dinitrophenol to inhibit energy dependent transport processes, we observed even larger increases in daunorubicin accumulation than were seen with CsA. Similar patterns were seen in a wide range of P-gp negative human cancer cell lines. Also the observed cyanide effect did not correlate with the expression of mRNA for multidrug resistance-associated protein (MRP), the only other member of the ABC family of membrane transporters that is known to be capable of effluxing daunorubicin. Thse results suggest that daunorubicin accumulation in many cases of AML is modulated by one or more novel energy-dependent processes that are distinct from P-gp or MRP. We speculate that this novel drug transport mechanism(s) may influence the response of AML patients to daunorubicin and other therapeutic agents.
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PMID:A novel energy dependent mechanism reducing daunorubicin accumulation in acute myeloid leukemia. 900 18

The ATP binding cassette transporter ABC1 is a 220-kDa glycoprotein expressed by macrophages and required for engulfment of cells undergoing programmed cell death. Since members of this family of proteins such as P-glycoprotein and cystic fibrosis transmembrane conductance regulator share the ability to transport anions, we have investigated the transport capability of ABC1 expressed in Xenopus oocytes using iodide efflux and voltage-clamp techniques. We report here that ABC1 generates an anion flux sensitive to glibenclamide, sulfobromophthalein, and blockers of anion transporters. The anion flux generated by ABC1 is up-regulated by orthovanadate, cAMP, protein kinase A, and okadaic acid. In other ABC transporters, mutating the conserved lysine in the nucleotide binding folds was found to severely reduce or abolish hydrolysis of ATP, which in turn altered the activity of the transporter. In ABC1, replacement of the conserved lysine 1892 in the Walker A motif of the second nucleotide binding fold increased the basal ionic flux, did not alter the pharmacological inhibitory profile, but abolished the response to orthovanadate and cAMP agonists. Therefore, we conclude that ABC1 is a cAMP-dependent and sulfonylurea-sensitive anion transporter.
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PMID:ABC1, an ATP binding cassette transporter required for phagocytosis of apoptotic cells, generates a regulated anion flux after expression in Xenopus laevis oocytes. 900 6

The small apical (canalicular) domains of hepatocytes form a luminal meshwork of tubules between adjacent hepatocytes and are the sites of primary bile formation. Organic compounds are transported across this membrane domain against high concentration gradients. It has been recognized in recent years that the hepatocyte is harnessed with a set of canalicular ATP-dependent transport proteins, specialized in this uphill transport. Bile salts, organic anions, cations, and neutral amphipaths are all pumped into the bile via such primary active transporters. Functionally, these transporters resemble ABC transporters overexpressed in cells with the multidrug resistance phenotype. Indeed, those transporters that have been characterized at the molecular level turn out to be new, or already recognized, members of this family. Phospholipid secretion across the canalicular membrane of the mouse is also mediated by a member of this family, mdr2 P-glycoprotein. This was demonstrated by the absence of phospholipid secretion into bile of mice with a disrupted mdr2 gene and by subsequent demonstration of phospholipid translocation in cells that overexpress this protein. The recognition of mdr2 P-glycoprotein as a phospholipid flippase sheds new light on the function of P-glycoproteins and is an important step in understanding the mechanism of biliary lipid secretion.
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PMID:Hepatic canalicular membrane 1: The role of mdr2 P-glycoprotein in hepatobiliary lipid transport. 903 62

Lactic acid bacteria play an essential role in many food fermentation processes. They are anaerobic organisms which obtain their metabolic energy by substrate phosphorylation. In addition three secondary energy transducing processes can contribute to the generation of a proton motive force: proton/substrate symport as in lactic acid excretion, electrogenic precursor/product exchange as in malolactic and citrolactic fermentation and histidine/histamine exchange, and electrogenic uniport as in malate and citrate uptake in Leuconostoc oenos. In several of these processes additional H+ consumption occurs during metabolism leading to the generation of a pH gradient, internally alkaline. Lactic acid bacteria have also developed multidrug resistance systems. In Lactococcus lactis three toxin excretion systems have been characterized: cationic toxins can be excreted by a toxin/proton antiport system and by an ABC-transporter. This cationic ABC-transporter has surprisingly high structural and functional analogy with the human MDR1-(P-glycoprotein). For anions an ATP-driven ABC-like excretion systems exist.
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PMID:The role of transport processes in survival of lactic acid bacteria. Energy transduction and multidrug resistance. 904 23

Expression of P-glycoprotein was studied in formalin-fixed tissue sections from 75 materials with an immunoperoxidase (ABC) method using the monoclonal antibody MRK-16. Specimens examined were from three monkey fetuses, eight autopsy cases, and 64 neuroblastoma patients, 25 of whom were underwent mass screening for diagnosis. P-glycoprotein test results were positive in fetal lung alveolar tissue and in the adrenal medulla of three of seven adult autopsy cases. Expression of P-glycoprotein was demonstrated in 22 of 35 cases (63%) in a group of neuroblastoma patients younger than 12 months of age, as compared with 9 of 20 (31%) who were older than 12 months of age at diagnosis. P-glycoprotein positivity was higher in patients who were alive (25 of 40, 63%) than in those who had died (6 of 24, 25%). Previous studies on P-glycoprotein expression in neuroblastoma were carried out using specimens mainly from older children, and the results were not analyzed with reference to the findings in normal tissues. The present study has clearly shown that positive P-glycoprotein expression in neuroblastoma patients should be evaluated carefully in infant cases because it stains frequently in normal adrenal glands.
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PMID:Expression of multidrug resistance-related P-glycoprotein shows good prognosis in neuroblastoma. 909 7

Fluoroaluminate in combination with nucleotide inhibited ATPase activity of P-glycoprotein (Pgp) in plasma membranes and in pure reconstituted form. Low nucleotide concentrations were effective, e.g., half-maximal inhibition was obtained with 10 microM MgATP. With MgATP or MgADP, reactivation occurred with t1/2 = 7 min at 37 degrees C. With 8-azido-ATP, UV irradiation of inhibited Pgp gave specific photolabeling of both nucleotide sites. Fluoroaluminate therefore provides a valuable tool for functional and structural characterization of P-glycoprotein and probably of other ABC transporters. 2-Azido-ATP, in combination with vanadate, fluoroaluminate, or beryllium fluoride, inhibited Pgp ATPase activity. Low concentrations of 2-azido-ATP were effective. However, after UV irradiation of the inhibited Pgp species, in no case was there evidence of covalent labeling of nucleotide sites. Therefore in the Pgp catalytic sites, under conditions of nucleotide trapping, there is no suitable amino acid side chain adjacent to the photoactivated 2-position of bound 2-azido-nucleotide, and 8-azido-ATP is the preferred photolabeling analog.
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PMID:Inhibition of P-glycoprotein ATPase activity by procedures involving trapping of nucleotide in catalytic sites. 914 65

The ABC superfamily of transporters includes the mammalian P-glycoprotein family (Class I and Class II P-gps), the multidrug resistance-associated protein (MRP), the Pgh-1 product of Plasmodium falciparum gene pfmdr1, all of which are associated with cellular pleiotropic drug resistance phenomena. STE6, the yeast transporter for the farnesylated peptide pheromone a, is also a member of this family. Structural similarities in this family translate into functional homology as expression of mouse Mdr3S (P-gp), P. falciparum Pgh-1, and human MRP partially restore mating in a sterile yeast mutant lacking a functional STE6 gene. The demonstration that Class II P-gps function as phosphatidylcholine (PC) translocators raise the possibility that other ABC transporters may also interact with physiological lipids. We report the identification of the synthetic lipid and PC analog ET-18-OCH3 (edelfosine) as a substrate for not only Class II P-gp but also for Class I P-gps and surprisingly for the other ABC transporters MRP, Pgh-1, and STE6. Expression of these proteins in the yeast Saccharomyces cerevisiae JPY201 was found to confer cellular resistance to cytotoxic concentrations of this lipid by a factor of 4-20-fold in a growth inhibition assay. The noted activity of ABC transporters toward this synthetic lipid was specific as a mutant variant of Mdr3 (Mdr3F) with reduced activity could not convey cellular resistance to ET-18-OCH3. ET-18-OCH3 was also found capable of blocking a-peptide pheromone transport and STE6 complementation by these ABC proteins. The inhibitory effect of ET-18-OCH3 on cell growth and a-factor transport could be abrogated by incubation with the lipid acceptor protein BSA or by enzymatic cleavage by microsomal alkylglycerol mono-oxygenase (MAMO). MAMO and BSA reversal of the ether lipid effect was only seen in the presence of a functional transporter. These results suggest that the group of cytotoxic synthetic PC analogs studied reveal possible structural and functional aspects common to the ABC transporters tested. Furthermore, the studies with BSA and MAMO suggest that the mechanism of transport of ET-18-OCH3 by these ABC transporters may be related to the flippase mechanism of PC transport by Mdr2.
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PMID:Functional interactions between synthetic alkyl phospholipids and the ABC transporters P-glycoprotein, Ste-6, MRP, and Pgh 1. 1009 17

In CFTR, a member of the ABC superfamily and a chloride channel, amino acid substitutions in its transmembrane domains 1 and 6 (TM1, TM6) have been reported to modulate the anion selectivity or ion conductance of the ion channel. In P-glycoprotein, no amino acid substitution in TM1, but some in TM6, have been reported to modify the substrate specificity of this protein. In this work, we demonstrated the involvement of His61, which is in the middle of the predicted TM1, in the function of P-glycoprotein. His61 was replaced by all other amino acid residues, and each of the mutant cDNAs was introduced into drug-sensitive human carcinoma cells, KB3-1. The drug-resistance profile of cells stably expressing each mutated P-glycoprotein was investigated by comparing their relative resistance to vinblastine, colchicine, VP16, and adriamycin. The resistance to vinblastine was increased by replacing His61 by amino acids with smaller side chains, while it was lowered by replacing by amino acids with bulkier side chains. The reverse effect was observed for resistance to colchicine and VP16. The resistance to adriamycin was increased by replacing by amino acids with bulkier side chains except Lys or Arg, which have a basic side chain. We also showed that the replacement of His61 by Phe and Lys greatly impaired the efflux of calcein AM, while the replacement had no effect on the efflux of rhodamine 123. These results suggest that an amino acid residue at position 61 in TM1 is important in deciding the substrate specificity of P-glycoprotein.
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PMID:Alteration of substrate specificity by mutations at the His61 position in predicted transmembrane domain 1 of human MDR1/P-glycoprotein. 922 Sep 75

One of the major causes of multidrug resistance in human cancers is expression of the P-glycoprotein multidrug transporter, which acts as a drug efflux pump. P-Glycoprotein is a member of the ABC superfamily of membrane proteins, and is composed of 12 hydrophobic membrane-spanning segments and 2 cytoplasmic nucleotide binding domains. Membrane lipids are known to play an important role in the function of P-glycoprotein. In the present study, purified P-glycoprotein of high specific ATPase activity was reconstituted into defined bilayers of dimyristoylphosphatidylcholine (DMPC), and its effects on lipid thermodynamic properties were then investigated using differential scanning calorimetry. P-Glycoprotein had a large perturbing effect on DMPC bilayers, even at relatively high lipid:protein ratios. The gel to liquid-crystalline phase transition temperature, Tm, was lowered on inclusion of P-glycoprotein in the bilayer, and the cooperativity of the transition was markedly reduced. The phase transition enthalpy, DeltaH, declined in a linear fashion with increasing P-glycoprotein content for lipid:protein ratios between 63:1 and 16:1 (w/w). Evaluation of these data using two different analytical methods indicated that P-glycoprotein perturbed either 375 or 485 phospholipids, withdrawing them from the phase transition. The DeltaH value for those lipids undergoing melting was similar to that of pure DMPC, which implies that their thermodynamic properties are essentially unchanged in the presence of P-glycoprotein. At lipid:protein ratios below 16:1 (w/w), transition enthalpy increased with higher P-glycoprotein content, until the DeltaH value reached that of pure DMPC. However, the lipid remained highly perturbed, as indicated by a very broad phase transition peak. This behavior may arise from either aggregation/oligomerization of P-glycoprotein within the bilayer or changes in the interaction of the transporter with the membrane at high density.
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PMID:Interaction of P-glycoprotein with defined phospholipid bilayers: a differential scanning calorimetric study. 924 13

Among the genetic and metabolic alterations that cancer cells undergo, several allow their survival under extreme environmental conditions. The resulting aberrant metabolism is compatible with tumor progression at the expenses of high energy needs, especially for maintaining high division rate. When treated with chemotherapeutic drugs many cancer cells take advantage of their ability to develop a resistance phenotype, as part of an adaptative mechanism. Two main actors of this multidrug phenotype (MDR) are represented by the P-glycoprotein and by the more recently discovered multidrug-resistance associated protein (MRP), two membrane proteins of the ABC superfamily of transporters that can extrude chemotherapeutic drugs under an ATP-dependent mechanism. We will briefly review the major metabolic aberrations that several cancers develop, followed by the molecular, genetic, structural, and functional aspects related mainly to P-glycoprotein, with a concern for the regulation of mdr gene expression. We will point out the role that membrane cholesterol may play in the MDR phenotype, relate this phenotype to bioenergetic considerations, and review the ways of modulating it by the use of new therapeutic approaches.
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PMID:Biochemical, genetic, and metabolic adaptations of tumor cells that express the typical multidrug-resistance phenotype. Reversion by new therapies. 938 1


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