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)

In the kidney, endothelins (ETs) are important regulators of blood flow, glomerular hemodynamics, and sodium and water homeostasis. They have been implicated in the pathophysiology of acute ischemic renal failure, nephrotoxicity by cyclosporine, cisplatin and radiocontrast agents, and vascular rejection of kidney transplants. Here, we used intact killifish renal proximal tubules, fluorescent substrates for Mrp2 (fluorescein-methotrexate, FL-MTX) and P-glycoprotein (a fluorescent CSA derivative, NBD-CSA), and confocal microscopy to reveal a new role for renal ET: regulation of ATP-driven drug transport in proximal tubule. Subnanomolar to nanomolar concentrations of ET-1 rapidly reduced the cell-to-tubular lumen transport of both fluorescent compounds. These effects were prevented by an ET(B) receptor antagonist but not by an ET(A) receptor antagonist. Immunostaining with an antibody to mammalian ET(B) receptors showed specific localization to the basolateral membrane of the fish tubular epithelial cells. ET-1 effects on transport were blocked by protein kinase C-selective inhibitors, implicating protein kinase C in ET-1 signaling. Finally, the nephrotoxic radiocontrast agent iohexol reduced cell-to-lumen FL-MTX and NBD-CSA transport, and these effects were abolished by an ET(B) receptor antagonist. These are the first results linking ET to the control of xenobiotic transport and the first demonstrating control of renal multidrug resistance-associated protein 2 and P-glycoprotein by a hormone.
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PMID:Endothelin B receptor-mediated regulation of ATP-driven drug secretion in renal proximal tubule. 1061 79

Multicellular prostate tumor spheroids develop intrinsic P-glycoprotein (Pgp)-mediated multidrug resistance with the appearance of quiescent cell areas. We have investigated the effect of intracellular reactive oxygen species (ROS) on Pgp expression in large, quiescent and drug-resistant multicellular spheroids (diameter 250 +/- 50microm). Using the ROS-sensitive fluorescence dye 2;7;-dichlorodihydrofluorescein diacetate (H(2)DCFDA), we demonstrated that these tumor spheroids are characterized by reduced intracellular ROS compared with drug-sensitive small spheroids (diameter 60 +/- 20microm) consisting predominantly of proliferating cells. The prooxidants hydrogen peroxide, menadione and glyceraldehyde raised ROS in large tumor spheroids and significantly down-regulated Pgp within 24 hr. Comparable effects were achieved with the known Pgp-reversing agents sodium orthovanadate, quinidine and cyclosporin A but not with verapamil. Consequently, the retention and toxicity of the anthracycline doxorubicin was increased in tumor spheroids treated with prooxidants. Co-administration of prooxidants and the free radical scavenger ebselen did not alter Pgp levels, indicating that down-regulation of Pgp is mediated via ROS. Down-regulation of Pgp by H(2)O(2) was abolished when either forskolin, 8-Br-cAMP or IBMX, which raise intracellular cAMP levels, was co-administered, indicating that Pgp expression is regulated by protein kinase A (PKA). Furthermore, Pgp was down-regulated by the PKA inhibitors Rp-cAMPs and H89. Since prooxidants stimulated the growth of multicellular spheroids and down-regulated the cyclin-dependent kinase inhibitor p27(kip1), we conclude that ROS-mediated Pgp down-regulation may be paralleled by recruitment of drug-resistant quiescent cells in the depth of the tumor tissue for cell-cycle activity.
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PMID:Redox regulation of P-glycoprotein-mediated multidrug resistance in multicellular prostate tumor spheroids. 1062 88

The effects of sodium deoxycholate (Deo-Na), a bile salt, and sodium caprate (Cap-Na), a fatty acid, on the transport of epirubicin were investigated in both the human colon adenocarcinoma (Caco-2) cell line and the everted gut sacs of the rat jejunum and ileum. The possible use of these two potent absorption enhancers as multidrug resistance (MDR) reversing agents also was examined. Epirubicin uptake experiments using a flow cytometer showed that Deo-Na and Cap-Na significantly increased the accumulation of epirubicin in Caco-2 cells. These two enhancers significantly increased apical to basolateral absorption of epirubicin across Caco-2 monolayers and mucosal to serosal absorption of epirubicin in the rat jejunum and ileum. Moreover, the addition of Deo-Na or Cap-Na significantly reduced the basolateral to apical efflux of epirubicin across Caco-2 monolayers. The co-presence of verapamil, one typical P-glycoprotein (P-gp) substrate, and Deo-Na or Cap-Na demonstrated further reduction of epirubicin efflux. The study suggests that inhibition of P-gp or other transporter proteins located in the intestines may be involved, at least partially, in the reduction of epirubicin efflux. In conclusion, the therapeutic efficacy of epirubicin may be improved by the use of such low toxicity excipients as absorption enhancers and MDR modulators in formulations.
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PMID:Effects of sodium deoxycholate and sodium caprate on the transport of epirubicin in human intestinal epithelial Caco-2 cell layers and everted gut sacs of rats. 1067 83

MDR results from overexpression of P-glycoprotein (Pgp) and multidrug resistance protein (MRP or MRP1) that function as ATP-dependent efflux pumps. Lung resistance related protein (LRP) is also supposed to be involved in MDR. The human canalicular multispecific organic anion transporter (cMOAT) gene that is responsible for the defects in Dubin-Johnson syndrome was isolated. cMOAT is homologous to MRP1 and supposed to be involved in drug resistance. Human cMOAT cDNA transfected LLC-PK1 cells, LLC/cMOAT-1, have increased resistance to vincristine (VCR), 7-ethyl-10-hydroxycamptothecin (SN-38), and cisplatin. The multidrug resistance (MDR)-reversing agents, cyclosporin A (CsA) and PAK-104P, almost completely reversed the resistance to VCR, SN-38 and cisplatin of LLC/cMOAT-1 cells by interacting with the substrate binding site of cMOAT. Treatment of human colorectal carcinoma SW-620 cells with sodium butyrate(NaB) induced LRP in the cells and conferred resistance to Adrianycin(ADM), VCR, VP-16, gramicidin D and taxol. Two LRP-specific ribozymes inhibited the NaB-induced expression of LRP in SW-620 cells and almost completely abolished their acquisition of the MDR phenotype. The accumulation of ADM, VCR and taxol was not decreased in NaB-treated cells, suggesting that ATP-binding cassette transporters are not involved in the MDR of NaB-treated cells. ADM was mainly located in the nuclei of untreated and the cytoplasm of NaB-treated cells. The accumulation level of ADM in the nuclei isolated from untreated cells or those from treated cells in the presence of anti-LRP polyclonal antibody was higher than that from treated cells in the absence of the antibody. Efflux of ADM from nuclei isolated from NaB-treated cells was enhanced compared with those from untreated cells and NaB-treated cells transfected with a LRP-specific ribozyme. The polyclonal antibody against LRP inhibited the enhanced efflux of ADM from nuclei isolated from NaB-treated cells. These findings indicate that LRP is involved in resistance to ADM, VCR, VP-16, taxol and gramicidin D, and has an important role in the transport of ADM from the nucleus to the cytoplasm.
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PMID:[Mechanisms for resistance to anticancer agents and the reversal of the resistance]. 1069 15

A major obstacle for the effective treatment of cancer is the phenomenon of multidrug resistance (MDR) exhibited by many tumor cells. Many, but not all, MDR cells exhibit membrane-associated P-glycoprotein (P-gp), a drug efflux pump. However, most mechanisms of MDR are complex, employing P-gp in combination with other, ill-defined activities. Altered cytosolic pH (pHi) has been implicated to play a role in drug resistance. In the current study, we investigated mechanisms of pHi regulation in drug-sensitive (MCF-7/S) and drug-resistant human breast cancer cells. Of the drug-resistant lines, one contained P-gp (MCF-7/DOX; also referred to as MCF-7/D40) and one did not (MCF-7/MITOX). The resting steady-state pHi was similar in the three cell lines. In addition, in all the cell lines, HCO3- slightly acidified pHi and increased the rates of pHi recovery after an acid load, indicating the presence of anion exchanger (AE) activity. These data indicate that neither Na+/H+ exchange nor AE is differentially expressed in these cell lines. The presence of plasma membrane vacuolar-type H+-ATPase (pmV-ATPase) activity in these cell lines was then investigated. In the absence of Na+ and HCO3-, MCF-7/S cells did not recover from acid loads, whereas MCF-7/MITOX and MCF-7/DOX cells did. Furthermore, recovery of pHi was inhibited by bafilomycin A1 and NBD-Cl, potent V-ATPase inhibitors. Attempts to localize V-ATPase immunocytochemically at the plasma membranes of these cells were unsuccessful, indicating that V-ATPase is not statically resident at the plasma membrane. Consistent with this was the observation that release of endosomally trapped dextran was more rapid in the drug-resistant, compared with the drug-sensitive cells. Furthermore, the drug-resistant cells entrapped doxorubicin into intracellular vesicles whereas the drug-sensitive cells did not. Hence, it is hypothesized that the measured pmV-ATPase activity in the drug-resistant cells is a consequence of rapid endomembrane turnover. The potential impact of this behavior on drug resistance is examined in a companion manuscript.
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PMID:pH and drug resistance. I. Functional expression of plasmalemmal V-type H+-ATPase in drug-resistant human breast carcinoma cell lines. 1079 74

The GTPases Rho regulate the assembly of polymerized actin structures. Their C-terminal sequences end with the CAAX motif that undergo a lipidation of the cysteine residue. Analogs to the C-terminal ends of Rho proteins, N-acetyl-S-all-trans, trans-farnesyl-L-cysteine and N-acetyl-S-all-trans-geranylgeranyl-L-cysteine, wereused to analyze the role of prenylation in their membrane association. Silver-stained gels indicated that N-acetyl-S-all-trans-geranylgeranyl-L-cysteine treatment released only a few proteins of 20, 46, and 60 kDa. Western blot analysis showed that N-acetyl-S-all-trans-geranylgeranyl-L-cysteine released RhoB (10%), RhoA (28%), and Cdc42 (95%) from membranes, whereas N-acetyl-S-all-trans and trans-farnesyl-L-cysteine did not. Rab1, which possesses two geranylgeranyl groups, was also strongly extracted by N-acetyl-S-all-trans-geranylgeranyl-L-cysteine, whereas Ras, which is farnesylated, was not. Furthermore, N-acetyl-S-all-trans-geranylgeranyl-L-cysteine was very efficient (95%) in dissociating actin and tubulin from membranes but not integral membrane protein P-glycoprotein and sodium/phosphate cotransporter NaP(i)-2. The extraction of Rho and cytoskeletal proteins occurred below the critical micellar concentration of N-acetyl-S-all-trans-geranylgeranyl-L-cysteine. Membrane treatments with 0.7 m KI totally extracted actin, whereas 70% of Cdc42 was released. Actin was, however, insoluble in Triton X-100-treated membranes, whereas this detergent extracted (80%) Cdc42. These data show that Rho proteins and actin are not physically bound together and suggest that their extraction from membranes by N-acetyl-S-all-trans-geranylgeranyl-L-cysteine likely occurs via different mechanisms.
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PMID:Modulation of Rho and cytoskeletal protein attachment to membranes by a prenylcysteine analog. 1080 40

Western immunoblots of whole cell lysate and crude membrane extract of an in vitro selected sodium m-arsenite-resistant L. donovani strain revealed a 230-kDa protein identified by an anti-P-glycoprotein (Pgp) antibody. Immunofluorescence microscopy, using the same antibody, detected putative Pgp on resistant parasites. Overexpression of the putative Pgp was down-regulated by verapamil. These results provided, possibly, the first evidence that (i) overexpression of Pgp-like protein occurs in arsenite-resistant Leishmania that are cross-resistant to structurally and functionally unrelated drugs and (ii) verapamil regulates drug sensitivity possibly by down-regulating Pgp expression in the arsenite-resistant Leishmania.
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PMID:Putative P-glycoprotein expression in arsenite-resistant Leishmania donovani down-regulated by verapamil. 1081 10

A multixenobiotic resistance mechanism (MXR) related to the P-glycoprotein multidrug transporter protein (p-gp) has been identified and characterized in several marine invertebrates. p-gp activity and protein titer is induced by exposure to toxins, supporting the suggestion that the role for this transporter is protection from xenobiotics by reducing accumulation of toxins in cells. In this study, we report on the specificity of the induction of the transporter by various chemical and physical stressors. p-gp substrates (including the pesticides pentachlorophenol and chlorthal) as well as non-substrates (including DDE and sodium arsenite) induced p-gp activity and protein titer in the gill tissues of the mussel Mytilus californianus. Similarly, mussels exposed to heat shock of 20 degrees C or 25 degrees C exhibited increased p-gp titer and activity compared to mussels held at ambient (12 degrees C) temperature seawater. Some of the same treatments that induced an increase in p-gp caused a concomitant increase in hsp70, but hsp induction was not always associated with induction of the p-gp protein. These findings suggest that p-gp induction in mussels may be part of a general cellular stress response. This response, however, does not appear to be always coupled with the hsp70 response in mussels.
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PMID:Induction of the multixenobiotic defense mechanism (MXR), P-glycoprotein, in the mussel Mytilus californianus as a general cellular response to environmental stresses. 1081 9

The aim of this study was to characterize the transport of organic cations at the intestinal level, by studying the characteristics of the transport of 1-methyl-4-phenylpyridinium (MPP+) in Caco-2 cells. Transepithelial flux as well as cellular accumulation of [3H]MPP+ were quantitatively similar when substrate was applied from the basolateral or apical cell membrane. Verapamil (100 microM) and rhodamine123 (10 microM) significantly reduced [3H]MPP+ transepithelial flux in the apical-to-basolateral direction. When cells were grown on plastic supports, [3H]MPP+ was rapidly accumulated in the cells, both by saturable and nonsaturable mechanisms. The kinetic parameters of the saturable component were: Km: 449 microM and Vmax: 2,249 pmol per mg protein and 5 min. Uptake of [3H]MPP+ was metabolic energy-dependent and Na+-, pH- and potential-independent. It was inhibited by several organic cations (verapamil, rhodamine123, daunomycin, vinblastine, tetrabutylammonium and vecuronium) but not by others (tetraethylammonium and N-methylnicotinamide). Decynium22 and corticosterone inhibited [3H]MPP+ uptake into the cells. The P-glycoprotein antibody UIC2 (20 microg/ml) had no effect. In conclusion, [3H]MPP+ is efficiently transported by Caco-2 cells in both basolateral-to-apical (secretion) and apical-to-basolateral (absorption) directions. Absorption of [3H]MPP+ at the apical membrane seems to occur through a carrier-mediated mechanism belonging to the Amphiphilic Solute Facilitator (ASF) family of transporters, but distinct from the known members of this family.
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PMID:Characterization of the transport of the organic cation [3H]MPP+ in human intestinal epithelial (Caco-2) cells. 1083 4

20 (S) Camptothecin was discovered in the early 60's as a result of the intensive screening of natural products by the NCI. Camptothecin lactone was poorly water soluble and was administered as the sodium salt in phase I trials. Despite some encouraging responses in early studies, continued evaluation of this compound revealed severe and unpredictable toxicities such as haemorrhagic cystitis and diarrhoea. The reversible opening of the lactone ring of a camptothecin is pH-dependent and yields a ring-opened carboxylate form which has greatly reduced activity in vivo and in vitro. Under physiological conditions, the carboxylate form predominates, but the exact position of this equilibrium in vivo also depends on other factors such as protein-binding and differential metabolism and elimination. The site of action of camptothecin is a complex formed by the nuclear enzyme topoisomerase I and DNA, which represents a novel target for cancer chemotherapy. The principal role of topoisomerase I is the relaxation of DNA required for transcription and replication. The transient covalent complexes formed by the linking of the enzyme and the 3' extremity of a nicked DNA strand are stabilised in the presence of camptothecin and involved in collisions with replication forks. The ensuing arrest of the fork is accompanied by the generation of permanent double-strand breaks which are thought to be responsible for the antiproliferative properties of camptothecin. The acquisition of resistance to camptothecin in cell culture appears, in general, to be due to a reduction in content and activity of topo-isomerase I. Single-point mutations of the gene of the enzyme have been detected in a number of these resistant variants. Camptothecin appears to be a poor substrate of P-glycoprotein and its intracellular accumulation is not appreciably reduced in cells expressing the multidrug-resistant phenotype. Several water soluble and active derivatives of camptothecin have been synthetized of which CPT-11 and topotecan are the most advanced in clinical trials. These compounds represent two different approaches to the problem of the poor water solubility of camptothecin lactone. CPT-11 is a soluble prodrug which is converted in vivo to the highly active SN-38, whereas topotecan itself is water-soluble due to the presence of a tertiary amine substitution which is charged at physiological pH. These two compounds present different pharmacological properties in the clinical setting.
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PMID:[Pharmacology of camptothecin and its derivatives]. 1084 37


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