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)

Direct photoaffinity labeling of liver plasma membrane subfractions enriched in sinusoidal and canalicular membranes using [35S]adenosine 5'-O-(thiotriphosphate) ([35S]ATP gamma S) allows the identification of ATP-binding proteins in these domains. Comparative photoaffinity labeling with [35S]ATP gamma S and with the photolabile bile salt derivative (7,7-azo-3 alpha, 12 alpha-dihydroxy-5 beta-[3 beta-3H]-cholan-24-oyl-2'- aminoethanesulfonate followed by immunoprecipitation with a monoclonal antibody (Be 9.2) revealed the identity of the ATP-binding and the bile salt-binding canalicular membrane glycoprotein with the apparent Mr of 110,000 (gp110). The isoelectric point of this glycoprotein was 3.7. Transport of bile salt was studied in vesicles enriched in canalicular and sinusoidal liver membranes. Incubation of canalicular membrane vesicles with [3H] taurocholate in the presence of ATP resulted in an uptake of the bile salt into the vesicles which was sensitive to vanadate. ATP-dependent taurocholate transport was also observed in membrane vesicles from mutant rats deficient in the ATP-dependent transport of cysteinyl leukotrienes and related amphiphilic anions. Substrates of the P-glycoprotein (gp170), such as verapamil and doxorubicin, did not interfere with the ATP-dependent transport of taurocholate. Reconstitution of purified gp110 into liposomes resulted in an ATP-dependent uptake of [3H]taurocholate. These results demonstrate that gp110 functions as carrier in the ATP-dependent transport of bile salts from the hepatocyte into bile. This export carrier is distinct from hitherto characterized ATP-dependent transport systems.
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PMID:ATP-dependent transport of taurocholate across the hepatocyte canalicular membrane mediated by a 110-kDa glycoprotein binding ATP and bile salt. 191 7

Disruption of the mdr2 gene in mice leads to a complete absence of phospholipid from bile (Smit, J. J. M., et al. 1993. Cell. 75:451-462). We have investigated the control of both mdr2 P-glycoprotein (Pgp) expression and bile salt secretion on biliary lipid secretion in the mouse. Lipid secretion was monitored at various bile salt output rates in wild-type mice (+/+), heterozygotes (+/-), and homozygotes (-/-) for mdr2 gene disruption. In (-/-) mice, phospholipid secretion was negligible at all bile salt output rates. In (+/-) mice, a curvilinear relation between bile salt and phospholipid secretion was observed similar to that in (+/+) mice; however, at all bile salt secretion rates phospholipid secretion was reduced compared to (+/+) mice, indicating that mdr2 Pgp exerts a strong control over secretion. Infusion of increasing amounts of taurocholate up to maximal secretory rate led to a decline in the phospholipid and cholesterol secretion in both (+/+) and (+/-) mice in accordance to what has been observed in other species. In contrast, in (-/-) mice cholesterol secretion increased under these conditions while phospholipid output remained extremely low. The increased cholesterol secretion may represent extraction of cholesterol from the canalicular plasma membrane by taurocholate micelles as opposed to the concomitant secretion of both phospholipid and cholesterol in the presence of a functional mdr2 Pgp. Increased bile flow in (-/-) mice could be attributed completely to an increase in the bile salt-independent fraction and may therefore be caused by the bile duct proliferation in these mice.
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PMID:Regulation of biliary lipid secretion by mdr2 P-glycoprotein in the mouse. 781 32

Cyclosporins are potent tools to inhibit several primary-active, ATP-dependent export carriers. This has been demonstrated in membrane vesicle transport assays for CsA and for its non-immunosuppressive analog PSC 833. Inhibition in the low micromolar and in the nanomolar concentration range is shown for the three distinct ATP-dependent export carriers in the liver canalicular membrane mediating the secretion into bile of leukotrienes (LTC4, other cysteinyl leukotrienes, and related conjugates), bile salts (taurocholate), and amphiphilic, mostly cationic substances (daunorubicin and other P-glycoprotein substrates). Competitive inhibition by cyclosporins is most potent for ATP-dependent taurocholate transport with Ki values of 0.2 and 0.6 microM for CsA and PSC 833, respectively. This inhibition is in agreement with in vivo studies in the rat demonstrating a block at the canalicular membrane in the hepatobiliary elimination of labeled taurocholate. The data suggest that cholestasis, as a side effect during CsA therapy, is largely due to inhibition of the ATP-dependent bile salt export carrier in the canalicular membrane. Inhibition by cyclosporins is less effective with respect to ATP-dependent leukotriene transport, both during biosynthetic release from mastocytoma cells and during hepatobiliary excretion. The Ki values for the former were 4.5 and 30 microM, and the Km/Ki ratios only 0.015 and 0.002 for CsA and PSC 833, respectively. Distinct transporters are inhibited by the cyclosporins with different potency and structurally modified cyclosporins may serve to induce preferential inhibition of a selected transporter. This is illustrated by the inhibition of the multidrug export carrier with daunorubicin as substrate using PSC 833 as inhibitor with a Ki value of 0.3 microM in an in vitro membrane transport system.
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PMID:ATP-dependent export pumps and their inhibition by cyclosporins. 794 82

Lipophilic cationic compounds accumulate more rapidly in the mitochondria of many carcinoma-derived cells than in non-transformed cells, thus leading to their pronounced cytotoxic effects on carcinoma cells. In this report, in order to measure tumoricidal effects vs cytotoxicity to normal hematopoietic progenitors, we studied the sensitivity of committed human hematopoietic cells in vitro and two human carcinoma cell lines (2008 ovary carcinoma cells and HT29 colon cells) toward two such compounds, rhodamine-123 and phosphonium salt II-41. Continuous exposure of human marrow cells to rhodamine-123 or phosphonium salt II-41 for 7 and 14 days produced dose-related inhibition of colony formation of erythroid burst-forming units (BFU-E), erythroid colony forming units (CFU-E), and CFU-granulocyte/macrophage (CFU-GM). The average values of IC50 for several different human bone marrows are approximately 0.9-1.1 microM for rhodamine-123 toward BFU-E, CFU-E and CFU-GM, and 31-38 microM for phosphonium salt II-41 toward the same hematopoietic progenitors. These IC50 values are similar for each type of hematopoietic progenitors. In each case, rhodamine-123 appears to be at least 30-fold more growth suppressive than phosphonium salt II-41 in these in vitro colony assays. In addition, the sensitivity of these hematopoietic progenitors toward these two compounds is comparable to the inhibition of colony formation for the two human carcinoma cell lines. The lack of differences in the sensitivity among the various hematopoietic progenitors in vitro may disagree with previous studies showing there are vast differences in the state of cell cycle for these hematopoietic progenitor cells. However, these observations about the cytotoxicity in vitro can be explained by assuming that the cytotoxicity of these compounds depends on other factors such as differentiation processes, which result in the appearance of many or very active mitochondria. Alternatively, the lack of differences in the sensitivity of the in vitro colony formation can also be attributed to a reported decrease in expression of P-glycoprotein, a multidrug efflux pump, in the differentiating hematopoietic progeny cells.
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PMID:Sensitivity of committed hematopoietic progenitor cells in vitro (BFU-E, CFU-E, CFU-GM) and two human carcinoma cell lines toward rhodamine-123 and phosphonium salt II-41. 845 Jun 73

Anthracyclines and etoposide have been implicated in the multi-drug resistance phenotype. The mdr 1 gene encodes for the transmembrane protein P-glycoprotein. P-glycoprotein expression was measured in the fresh blast cells from 19 patients with acute myeloid leukemia using three monoclonal antibodies, C219, JSB-1 and MRK 16, and immunocytochemistry with the enzyme alkaline phosphatase as marker. Drug resistance can be identified in vitro using the predictive chemosensitivity test, the MTT (3-4,5-dimethylthiazol-2,5-diphenyl tetrazolium bromide) assay. In order to assess cell viability after drug exposure, this technique utilises the ability of cellular dehydrogenase enzymes to reduce the tetrazolium salt MTT to formazan. In vitro resistance to multi-drug resistance related cytotoxic agents was identified in the blast cells from these patients. This study showed no correlation between the results of the MTT assay and P-glycoprotein expression in this disease, suggesting either that more sensitive techniques are required to measure P-glycoprotein expression or that other drug resistance mechanisms may be involved.
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PMID:Comparison of P-glycoprotein expression with in vitro drug sensitivity in fresh blast cells from acute myeloid leukaemia patients. 852 96

Mice in which the gene for mdr2 P-glycoprotein has been disrupted have a severe deficiency in biliary phospholipid and cholesterol secretion. We studied the relation between mdr2 gene expression and biliary lipid secretion with emphasis on the role of bile salt hydrophobicity. Control mice (+/+), and mice with a homozygous (-/-) or heterozygous (+/-) disruption of the mdr2 gene, were infused with taurodeoxycholate (TDC) or tauroursodeoxycholate (TUDC). In mdr2 (-/-) mice, virtually no phospholipids were secreted into bile, irrespective of the type of bile salt infused. In contrast, cholesterol secretion in (-/-) mice increased upon TDC infusion from less than 0.1 to more than 2 nmol/min . 100 g, which was similar to controls under the same conditions. After infusion of TUDC in (-/-) mice. cholesterol secretion also rose (to 1.8 nmol/min . 100 g) but remained much lower than in controls (8 nmol/min x 100 g). In (+/-) mice, cholesterol secretion was equal to (+/+) mice during secretion of endogenous bile salts and during TDC infusion, but was 50% of control levels during maximal TUDC infusion. We conclude that biliary phospholipid secretion completely depends on mdr2 gene expression but cholesterol can, at least partially, be secreted in an mdr2 Pgp-independent mechanism. The extent to which cholesterol is secreted via this mechanism may depend on the hydrophobicity (i.e., cholesterol-solubilizing capacity) of the secreted bile salt.
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PMID:Uncoupling of biliary phospholipid and cholesterol secretion in mice with reduced expression of mdr2 P-glycoprotein. 872 58

The basic distinguishing feature of all cells expressing functional P-glycoprotein-multidrug resistance (P-gp-MDR) is a decrease in steady-state accumulation drug levels as compared to drug-sensitive controls. In an attempt to identify mechanism(s) by which MDR can be circumvented, we examined the cellular accumulation, in resistant cells, of 4'-O-tetrahydropyranyl-doxorubicin (pirarubicin) alone and in conjunction with various molecules belonging to three different classes: the crown ethers, the tetraalkylammonium salts, and the polyoxethylene amphiphiles. The present study was performed using a spectrofluorometric method which enabled us to follow the uptake and release of fluorescent molecules by living cells while the cells were being incubated with the drug. Erythroleukemia K562 cell lines were used. Our data show that the compounds of these three completely different classes were able to increase the incorporation of pirarubicin provided they had a minimum degree of lipophilicity. Study of the growth inhibitory activity of these compounds revealed that cross-resistance to the tetraalkyl ammonium salt increased with the lipophilicity and was equal to 58 for tetraoctylammonium salt, the most lipophilic compound of this series. This demonstrates that neither the presence of a positive charge nor an aromatic moiety is required for MDR recognition.
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PMID:The effect of crown ethers, tetraalkylammonium salts, and polyoxyethylene amphiphiles on pirarubicin incorporation in K562 resistant cells. 884 34

Mdr2 P-glycoprotein is expressed in the canalicular membrane of the mouse hepatocyte and is responsible for phospholipid secretion into bile. It is our hypothesis that it functions as a flippase in the translocation of phosphatidylcholine from the inner leaflet to the outer leaflet of the canalicular membrane. We have investigated the influence of different types of bile salts on the expression levels of mdr2 Pgp. Feeding mice a cholate-supplemented diet results in an increased mdr2 mRNA level, and this is accompanied by an increased biliary phospholipid secretion capacity. Cholate is a more hydrophobic bile salt than the main endogenous bile salt, muricholate. The induction of mdr2 gene expression and concomitant increase in phospholipid secretion are in line with the function of biliary phospholipids to inactivate the detergent action of hydrophobic bile salts.
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PMID:Influence of bile salts on hepatic mdr2 P-glycoprotein expression. 886 55

The phosphatidyl translocating activity of the mdr2 P-glycoprotein (Pgp) in the canalicular membrane of the mouse hepatocyte is a rate-controlling step in the biliary secretion of phospholipid. Since bile salts also regulate the secretion of biliary lipids, we investigated the influence of the type of bile salt in the circulation on mdr2 Pgp expression and activity. Male mice were led a purified diet to which either 0.1% (w/w) cholate or 0.5% (w/w) ursodeoxycholate was added. This led to a near-complete replacement of the endogenous bile salt pool (mainly tauromuricholate) by taurocholate or tauroursodeoxycholate respectively. The phospholipid secretion capacity was then determined by infusion of increasing amounts of tauroursodeoxycholate. Cholate feeding resulted in a 55% increase in maximal phospholipid secretion compared with that in mice on the control diet. Northern blotting revealed that cholate feeding increased mdr2 Pgp mRNA levels by 42%. Feeding with ursodeoxycholate did not influence the maximum rate of phospholipid output or the mdr2 mRNA content. Female mice had a higher basal mdr2 Pgp mRNA level than male mice, and this was also correlated with a higher phospholipid secretion capacity. This could be explained by the 4-fold higher basal cholate content in the bile of female compared with male mice. Our results suggest that the type of bile salts in the circulation influences the expression of the mdr2 gene.
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PMID:Regulation of mdr2 P-glycoprotein expression by bile salts. 902 Aug 71

One of the major problems in cancer chemotherapy is the development of tumor resistance to drug treatment. In in vitro experiments, the stepwise selection of cancer cells resistant to a single antineoplastic agent may lead to resistance to multiple agents (multidrug resistance). One of the well known mechanisms leading to multidrug resistance is the over-expression of the mdr1 gene product, the 170 kDa membrane P-glycoprotein which is an ATP-driven efflux pump of xenobiotics. We studied the effects of dextran-conjugated doxorubicin in combination with colchicine, vinblastine and free doxorubicin respectively on the killing of human KB 3-1 carcinoma cells and its multidrug resistant subclone KB-V-1 cells. Cell survival was quantified by the tetrazolium salt MTT assay Cytotoxicity studies were designed so that data could be analyzed by the medium-effect principle and the calculated Combination Indices at different cell survival levels. When added alone conjugated doxorubicin was not as effective as doxorubicin in cell killing. When conjugated doxorubicin was combined with free doxorubicin or colchicine at high (over 75%) killing rates, a significant degree of synergism was observed in the killing of multidrug resistant KB-V1 cells. This synergism was not observed in non-resistant KB-3-1 cells nor when conjugated doxorubicin was combined with vinblastine.
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PMID:Partial synergism between dextran-conjugated doxorubicin and cancer drugs on the killing of multidrug resistant KB-V1 cells. 904 56


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