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:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multidrug resistance transporters (MDRs) are excellent candidates for molecular-level biomonitoring - they function in exporting xenobiotic compounds and their expression is inducible. However, currently available MDR sequence information from aquatic invertebrates is partial and mostly biased towards the conserved ATPase domain. In the present study, two genes belonging to the MDR/TAP (ABCB) family were cloned and characterized from the bivalve Brachidontes pharaonis, which thrives in rocky environments along the Israeli Mediterranean coast. One of these is a complete sequence of a 'half'ABCB, probably belonging to the ABCB10 subfamily, while the second is a 'full'ABCB1 transporter. A quantitative RT-PCR protocol for biomonitoring was tested in laboratory experiments. Bivalves exposed to diesel showed significant increase in B1 expression levels, while the expression of B10 was suppressed. These results suggest that B. pharaonis features an MDR1 homologue that is induced by pollution and may serve as a sentinel organism for routine biomonitoring programs. However, our findings also exemplify that not all MDRs are equally suitable for this purpose and sequence information must be expanded beyond the ATPase domain for correct classification of cloned genes.
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PMID:Cloning and expression of MDR transporters from marine bivalves, and their potential use in biomonitoring. 1671 20

The MDR1 transporter mediated efflux of different xenobiotics out of the cells serves as the most important mechanisms of the multidrug resistance in cancer cells, thus inhibition of the MDR1 transporter may increase the efficiency of anticancer drugs in the therapy. Here we describe some new phenothiazine derivatives, which possess strong in vitro MDR1 inhibitory activity. The effectiveness of the compounds on the MDR1 mediated calcein-AM efflux, ATPase activity, and colchicine resistance was proven by microplate assays and flow cytometry using recombinant and control cell lines. Some of these derivatives were more active than verapamil and one of them was at least as active as cyclosporin A. According to our results the new structural elements built in these phenothiazine type compounds increased their MDR1 inhibitory activity, which may serve as a basis of the development of an effective MDR1 inhibitor drug.
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PMID:Inhibition of the MDR1 transporter by new phenothiazine derivatives. 1675 Jan 72

The death-inducing cytokine TRAIL is a promising agent for anticancer therapy since it preferentially kills cancer versus normal cells; however, some cancer cells are TRAIL-resistant. We initially explored whether overexpression of the MDR1 gene product P-glycoprotein (P-gp), which causes multidrug resistance (MDR) in cancer cells, also contributes to TRAIL-resistance. Surprisingly, our results revealed that P-gp-overexpression enhances TRAIL-induced apoptosis not only in neoplastic cells transfected with the MDR1 gene but also in MDR variants selected with cytotoxic anticancer agents. Mechanistic analysis of TRAIL-induced apoptosis in the MDR1-transfected MCF-7 breast cancer cell line BC-19 revealed that TRAIL-triggered significantly more apoptosis in these cells compared with parental MCF-7 cells by binding to the TRAIL receptor DR5. DR5 but not DR4 engagement by TRAIL attenuated cellular ATP levels by robustly stimulating P-gp ATPase activity, and thus triggered P-gp-dependent apoptosis by depletion of the cellular ATP pool. In addition to hyperactive P-gp-mediated ATP hydrolysis, TRAIL-induced, P-gp-potentiated apoptosis was associated with activation of caspases-6, -7, -8, and -9; Bid cleavage; and mitochondrial depolarization. P-gp interacted with the TRAIL receptors DR4, DR5, and DcR1 in plasma membranes and enhanced TRAIL binding to DR5. Interestingly, the decreased level of the decoy TRAIL receptor, DcR1, in BC-19 cells further sensitized these cells to TRAIL. Therefore, both extrinsic and intrinsic apoptosis pathways are involved in this process. These findings for the first time reveal that TRAIL treatment preferentially causes apoptosis in P-gp-overexpressing MDR cells, and suggests significant clinical implications for the use of TRAIL in treating neoplasms that have failed chemotherapy.
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PMID:P-glycoprotein enhances TRAIL-triggered apoptosis in multidrug resistant cancer cells by interacting with the death receptor DR5. 1675 35

Based on the topoisomerase IIalpha catalytic inhibitory activity of a previous hit compound, NSC35866, we screened 40 substituted purines or purine-like compounds from the National Cancer Institute repository for their ability to inhibit the ATPase activity of human topoisomerase IIalpha. Several compounds, including NSC348400, NSC348401 and NSC348402, were inhibitory at submicromolar concentrations. Three-dimensional quantitative structure-activity relationship models using comparative molecular field and comparative molecular similarity indices analyses were constructed using 24 of these compounds. The ability of 10 selected compounds to inhibit the complete DNA strand passage reaction of topoisomerase IIalpha correlated well with their potency as ATPase inhibitors. None of the 40 compounds significantly increased levels of the topoisomerase IIalpha-DNA covalent complex, suggesting that they functioned as catalytic topoisomerase II inhibitors and not as topoisomerase II poisons. Although some of these compounds could antagonize the effect of etoposide on the level of topoisomerase IIalpha-DNA covalent complex formation in vitro, in contrast to NSC35866, they were not capable of antagonizing etoposide-induced cytotoxicity and DNA strand breaks in cells. Two independently selected human SCLC cell lines with reduced topoisomerase IIalpha expression displayed cross-resistance to NSC348400, NBSC348401, and NSC348402, whereas an MDR1 line was fully sensitive. These results suggest that topoisomerase IIalpha is a functional cellular target for most of these substituted purine compounds and that these compounds do not display MDR1 liability.
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PMID:A three-dimensional quantitative structure-activity relationship study of the inhibition of the ATPase activity and the strand passing catalytic activity of topoisomerase IIalpha by substituted purine analogs. 1688 Feb 87

Identifying molecules that interact with P-glycoprotein (P-gp) is important for drug discovery but is also generally reliant on time-consuming in vitro and in vivo studies. As an alternative approach, the current study applied pharmacophore models and database screening to rapidly retrieve molecules that bind as substrates or inhibitors for P-gp from commercial databases and then confirmed their affinity as inhibitors in vitro. Seven molecules (acitretin, cholecalciferol, misoprostol, nafcillin, repaglinide, salmeterol, and telmisartan) with no published details for P-gp affinity, one positive control inhibitor (miconazole), and two negative control molecules (phenelzine and zonisamide) were selected for testing. The MDCK-MDR1 in vitro cell model was used to confirm their inhibitory effect on [3H]digoxin transport, and the ATPase assay was used as an additional in vitro tool to indicate P-gp activation. All seven test drugs were confirmed to have P-gp affinity. Additionally, our experimental results provided plausible explanations for the published pharmacokinetic profiles of the tested drugs and their classification according to the biopharmaceutics and drug disposition classification system. In this study, we showed the successful application of pharmacophore models to accurately predict P-gp binding, which holds promise to anticipate drug-drug interactions from screening drug databases and a priori prediction of novel P-gp inhibitors or substrates.
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PMID:Rapid identification of P-glycoprotein substrates and inhibitors. 1699 8

MDR1 (multidrug resistance 1)/P-glycoprotein is an ATP-driven transporter which excretes a wide variety of structurally unrelated hydrophobic compounds from cells. It is suggested that drugs bind to MDR1 directly from the lipid bilayer and that cholesterol in the bilayer also interacts with MDR1. However, the effects of cholesterol on drug-MDR1 interactions are still unclear. To examine these effects, human MDR1 was expressed in insect cells and purified. The purified MDR1 protein was reconstituted in proteoliposomes containing various concentrations of cholesterol and enzymatic parameters of drug-stimulated ATPase were compared. Cholesterol directly binds to purified MDR1 in a detergent soluble form and the effects of cholesterol on drug-stimulated ATPase activity differ from one drug to another. The effects of cholesterol on K(m) values of drug-stimulated ATPase activity were strongly correlated with the molecular mass of that drug. Cholesterol increases the binding affinity of small drugs (molecular mass <500 Da), but does not affect that of drugs with a molecular mass of between 800 and 900 Da, and suppresses that of valinomycin (molecular mass >1000 Da). V(max) values for rhodamine B and paclitaxel are also increased by cholesterol, suggesting that cholesterol affects turnover as well as drug binding. Paclitaxel-stimulated ATPase activity of MDR1 is enhanced in the presence of stigmasterol, sitosterol and campesterol, as well as cholesterol, but not ergosterol. These results suggest that the drug-binding site of MDR1 may best fit drugs with a molecular mass of between 800 and 900 Da, and that cholesterol may support the recognition of smaller drugs by adjusting the drug-binding site and play an important role in the function of MDR1.
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PMID:Modulation of drug-stimulated ATPase activity of human MDR1/P-glycoprotein by cholesterol. 1702 89

Human ABC transporter P-glycoprotein (P-gp/ABCB1) encoded by the multidrug resistance (MDR1) gene is recognized as one of the most important factors regulating pharmacokinetics of a number of clinically important drugs because of its function of extruding a wide range of structurally unrelated amphiphilic and hydrophobic drugs from the inside to the outside of cells in an ATP-driven mechanism. In the present study, we have evaluated the high-speed ATPase activity assay method by comparing with in vitro transport assay systems using MDR1-transfected MDR1-MDCK cells. Since substrate drugs were found to interfere with the photometric detection of inorganic phosphate (Pi) that was liberated according to the hydrolysis of ATP to ADP in ATPase activity assay, at first, a method in which the amount of Pi can be calculated correctly. Results demonstrate that the kinetic parameters obtained in ATPase activity assay are not necessarily correspond with those in in vitro transport assay, suggesting that these methods might detect the different processes of drug-P-gp interaction. The combining of the ATPase activity assay and in vitro transport technologies provides us the insight into mechanisms of the membrane transport of drugs by P-gp.
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PMID:Evaluation of human P-glycoprotein (MDR1/ABCB1) ATPase activity assay method by comparing with in vitro transport measurements: Michaelis-Menten kinetic analysis to estimate the affinity of P-glycoprotein to drugs. 1714 83

Glabridin is a major constituent of the root of Glycyrrhiza glabra, which is commonly used in the treatment of cardiovascular and central nervous system diseases. This study aimed to investigate the role of P-glycoprotein (PgP/MDR1) in the intestinal absorption of glabridin. The systemic bioavailability of glabridin was approximately 7.5% in rats, but increased when combined with verapamil. In single-pass perfused rat ileum with mesenteric vein cannulation, the permeability coefficient of glabridin based on drug disappearance in luminal perfusates (P(lumen)) was approximately 7-fold higher than that based on drug appearance in the blood (P(blood)). Glabridin was mainly metabolized by glucuronidation, and the metabolic capacity of intestine microsomes was 1/15 to 1/20 of that in liver microsomes. Polarized transport of glabridin was found in Caco-2 and MDCKII monolayers. Addition of verapamil in both apical (AP) and basolateral (BL) sides abolished the polarized transport of glabridin across Caco-2 cells. Incubation of verapamil significantly altered the intracellular accumulation and efflux of glabridin in Caco-2 cells. The transport of glabridin in the BL-AP direction was significantly higher in MDCKII cells overexpressing PgP/MDR1 than in the control cells. Glabridin inhibited PgP-mediated transport of digoxin with an IC(50) value of 2.56 microM, but stimulated PgP/MDR1 ATPase activity with a K(m) of 25.1 microM. The plasma AUC(0-24h) of glabridin in mdr1a(-/-) mice was 3.8-fold higher than that in wild-type mice. These findings indicate that glabridin is a substrate for PgP and that both PgP/MDR1-mediated efflux and first-pass metabolism contribute to the low oral bioavailability of glabridin.
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PMID:Role of P-glycoprotein in the intestinal absorption of glabridin, an active flavonoid from the root of Glycyrrhiza glabra. 1722 Feb 45

Baicalin and its aglycone, baicalein, being are strong antioxidants and have various pharmacological actions. Baicalein has shown a unique metabolic fate in rat intestine, being excreted into the intestinal lumen from mucosal (epithelial) cells following glucuronidation of baicalein absorbed after oral administration. The purpose of this study was to examine the absorption and excretion of baicalin and baicalein in a Caco-2 cell monolayer model to evaluate the disposition of baicalin and baicalein in the human intestine. When baicalein at 5 microM was loaded on the apical side of the Caco-2 cell monolayer, baicalein was not transferred to the basolateral side, but more baicalin was excreted onto the apical side than was being absorbed onto the basolateral side. The amount of baicalin recovered on both sides accounted for more than 90% of the baicalein absorbed from the apical surface. This was supported by the fact that Caco-2 cell microsomes showed UDP-glucuronate glucuronosyltransferase activity towards baicalein to form baicalin. On the other hand, when baicalein was loaded at higher concentrations, baicalin excretion became saturated, and then baicalein was transferred to the basolateral side. Furthermore, baicalin efflux was not inhibited by MDR1/P-glycoprotein substrates such as ciclosporin and vinblastine, but significantly inhibited by multidrug resistance-associated protein 2 (MRP2, ABCC2) substrates such as probenecid and genistein. MRP2 was also detected in Caco-2 cells by Western blotting using specific antibodies. In addition, baicalin, but not baicalein, enhanced dose-dependently the vanadate-sensitive ATPase activity of human MRP2. These results indicated that, in Caco-2 cells, any baicalein absorbed after loading at low concentrations of baicalein was not transferred to the basolateral side, but was first transformed into baicalin in the cells and excreted through the action of MRP2, mainly to the apical side.
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PMID:Efflux of baicalin, a flavone glucuronide of Scutellariae Radix, on Caco-2 cells through multidrug resistance-associated protein 2. 1722 25

Recently, we have introduced [tris(1,10-phenanthroline)lanthanum(III)] trithiocyanate (KP772, FFC24) as a new lanthanum compound which has promising anticancer properties in vivo and in vitro. Aim of this study was to investigate the impact of ABC transporter-mediated multidrug resistance (MDR) on the anticancer activity of KP772. Here, we demonstrate that all MDR cell models investigated, overexpressing ABCB1 (P-glycoprotein), ABCC1 (multidrug resistance protein 1), or ABCG2 (breast cancer resistance protein) either due to drug selection or gene transfection, were significantly hypersensitive against KP772. Using ABCB1-overexpressing KBC-1 cells as MDR model, KP772 hypersensitivity was demonstrated to be based on stronger apoptosis induction and/or cell cycle arrest at unaltered cellular drug accumulation. KP772 did neither stimulate ABCB1 ATPase activity nor alter rhodamine 123 accumulation arguing against a direct interaction with ABCB1. Accordingly, several drug resistance modulators did not sensitize but rather protect MDR cells against KP772-induced cytotoxicity. Moreover, long-term KP772 treatment of KBC-1 cells at subtoxic concentrations led within 20 passages to a complete loss of drug resistance based on blocked MDR1 gene expression. When exposing parental KB-3-1 cells to subtoxic, stepwise increasing KP772 concentrations, we observed, in contrast to several other metallo-drugs, no acquisition of KP772 resistance. Summarizing, our data demonstrate that KP772 is hyperactive in MDR cells and might have chemosensitizing properties by blocking ABCB1 expression. Together with the disability of tumor cells to acquire KP772 resistance, our data suggest that KP772 should be especially active against notoriously drug-resistant tumor types and as second line treatment after standard chemotherapy failure.
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PMID:Multidrug-resistant cancer cells are preferential targets of the new antineoplastic lanthanum compound KP772 (FFC24). 1744 75


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