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 (MDR), caused by overexpression of either P-glycoprotein (Pgp) or the multidrug-resistance associated protein (MRP), is characterised by a decreased cellular drug accumulation. One form of MDR is the sequestration of the drug inside cytoplasmic vesicles followed by an a exocytotic and/or efflux process. In some studies, increased intracellular glutathione (GSH) has been associated with MDR. In this study, we examined the effects of 7-chloro-4-nitrobenz-2-oxa-1,3-diazole or NBD (a H(+)-ATPase pump inhibitor) and buthionine sulphoximine or BSO (an inhibitor of GSH biosynthesis) on the subcellular distribution of daunorubicin or DNR in two leukemic homoharringtonine-resistant K562 cell lines, overexpressing MRP (K-H30) and Pgp (K-H300). DNR nuclear accumulation was carried out using microspectrofluorometry. Our results show that DNR nuclear accumulation and sensitivity of K-H30 cells were increased by NBD and BSO whereas in K-H300 cells, NBD and BSO were unable to increase the DNR nuclear accumulation and sensitivity of these cells. This study demonstrates clearly that even if vesicular sequestration can happen in cells overexpressing MRP and Pgp proteins, only the MRP protein is able to extrude the drug through intracellular vesicles and efflux. In addition, GSH plays an important part in the pathway of drug transport in cells overexpressing MRP. Data entrain also the notion of functional discrimination between the MDR and MRP phenotype.
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PMID:Evidence for functional discrimination between leukemic cells overexpressing multidrug-resistance associated protein and P-glycoprotein. 1050 Jul 90

The concentrations of sodium, potassium, reduced glutathione (GSH) and free amino acids and Na-K-ATPase activity in erythrocytes were examined in 35 purebred Jindo dogs in Korea. The incidence of Jindo dogs with a high potassium concentration and high activity of Na-K-ATPase in erythrocytes (HK phenotype) was 25.7%. The erythrocyte GSH concentration in HK Jindo dogs varied widely, from 2.45 to 12.38 mmol/l of RBCs, and was positively correlated with the erythrocyte glutamate concentration. These results indicate that HK Jindo dogs have normal to very high levels of erythrocyte GSH, which might result from the varying quantity of Na-dependent glutamate influx in the erythrocytes.
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PMID:Relation between erythrocyte reduced glutathione and glutamate concentrations in Korean Jindo dogs with erythrocytes possessing hereditary high activity of Na-K-ATPase and a high concentration of potassium. 1056 1

Amino acids (AA) which were proposed as an alternative osmotically active agents in dialysates are toxic to human peritoneal mesothelial cells (HPMC) due to disturbance of the antioxidant-oxidant balance in cells by reducing level of glutathione. We assessed if the addition intracellular glutathione precursors: N-acetyl-cysteine (NAC), tioproline (TP), L--2-oxo--4-thiazolidine acid (PC), and glutathione (GSH) could reduce the cytotoxicity of AA, as measured by inhibition of cells proliferation and disorders of intracellular 86Rb transport. HPMC were obtained from omentum from nonuremic donors and cultured in in vitro conditions. The HPMC proliferation capacity was assessed indirectly by the 3H-methyl-thymidine incorporation assay. The injury to HPMC membrane integrity was assessed by the release of radioisotope molecules of 86Rb from the prelabelled cells. We have found that AA diminished the intracellular potassium (86Rb) influx. Supplementation of AA mixture with NAC enhanced the total 86Rb influx into HMC. Other precursors of intracellular glutathione (TP,PC,GSH) tested in the presence of AA significantly stimulated intracellular transport of 86Rb via Na,K-ATPase dependent channel, but the total intracellular transport of 86Rb was still lower than in control. HMC proliferation was significantly inhibited by AA what was measured by incorporation of H-metyl-tymidine. In the presence of NAC inhibition of HMC proliferation caused by AA was weaker. Our results suggest that some of intracellular glutathione precursors may reduce the disturbances of the HMC function caused by AA.
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PMID:In vitro effect of glutathione precursors on cytotoxicity of amino acids to human mesothelial cells. 1057 75

Studies have been carried out to examine in vitro drug transport in plasma membrane vesicles isolated from HL60/ADR cells that overexpress MRP. The results demonstrate that glutathione (GSH) enhances transport of daunomycin. A greater increase in transport activity occurs when the reaction is carried out in the presence of both GSH and sodium chloride. Sodium chloride alone has no effect on daunomycin transport. It has also been observed that GSH in the presence of sodium chloride induces a major increase in the transport level of LTC4. Thus far, no metal ion other than sodium chloride has been found to be active in the drug transport system. Kinetic analysis reveals that GSH in the presence of sodium chloride greatly reduces Km and increases Vmax, for daunomycin. Additional studies show that ATPase activity in isolated plasma membrane from HL60/ADR cells is greatly enhanced in the presence of both GSH and sodium chloride. These results suggest the possibility that GSH and sodium chloride stimulate MRP-mediated transport as a result of increased ATPase activity.
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PMID:Multidrug resistance-associated protein (MRP) mediated transport of daunomycin and leukotriene C4 (LTC4) in isolated plasma membrane vesicles. 1065 18

The effect of mild hypothermia on Na(+)-K+ ATPase and lipid peroxidation in canine brain tissue following a 18-minute cardiac arrest and resuscitation for 8 hours were studied. Mild hypothermia improved the restoration of the activity of Na(+)-K+ ATPase, LDH, protect the activity of SOD, decrease the loss of GSH, but not completely blocked the ischemia reperfusion induced lipid peroxidation.
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PMID:[Effects of mild hypothermia on Na(+)-K+ ATPase and lipid peroxidation in canine brain tissue following cardiac arrest and resuscitation]. 1068 82

The transport mechanism by which the multidrug resistance protein 1 (MRP1) effluxes cytotoxic agents out of cells is still not completely understood. However, the cellular antioxidant glutathione (GSH) has been shown to have an important role in MRP1-mediated drug transport. In this study we show that GSH stimulates the ATPase activity of MRP1 in a natural plasma membrane environment. This stimulation was dose-dependent up to 5 mM. The MRP1 substrates vincristine and daunorubicin do not induce MRP1 ATPase activity. In addition, the effect of GSH on the MRP1 ATPase activity is not increased by daunorubicin or by vincristine. In contrast, a GSH conjugate of daunorubicin (WP811) does induce the ATPase activity of MRP1. In the presence of GSH the effect of WP811 was not significantly increased. Finally, (iso)flavonoid-induced MRP1 ATPase activity is not synergistically increased by the presence of GSH. In conclusion, we show that GSH has no apparent influence on the ATPase reaction induced by several MRP1 substrates and/or modulators. The subclasses of molecules had different effects on the MRP1 ATPase activity, which supports the existence of different drug binding sites.
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PMID:The effect of glutathione on the ATPase activity of MRP1 in its natural membranes. 1070 54

The 56-kDa B1 subunit of the vacuolar H(+)ATPase has a C-terminal DTAL amino acid motif typical of PDZ-binding proteins that associate with the PDZ protein, NHE-RF (Na(+)/H(+) exchanger regulatory factor). This B1 isoform is amplified in renal intercalated cells, which play a role in distal urinary acid-base transport. In contrast, proximal tubules express the B2 isoform that lacks the C-terminal PDZ-binding motif. Both the B1 56-kDa subunit and the 31-kDa (E) subunit of the H(+)ATPase are pulled down by glutathione S-transferase NHE-RF bound to GSH-Sepharose beads. These subunits associate in vivo as part of the cytoplasmic V1 portion of the H(+)ATPase, and the E subunit was co-immunoprecipitated from rat kidney cytosol with NHE-RF antibodies. The interaction of H(+)ATPase subunits with NHE-RF was inhibited by a peptide derived from the C terminus of the B1 but not the B2 isoform. NHE-RF colocalized with H(+)ATPase in either the apical or the basolateral region of B-type intercalated cells, whereas NHE-RF staining was undetectable in A-intercalated cells. In proximal tubules, NHE-RF was located in the apical brush border. In contrast, H(+)ATPase was concentrated in a distinct membrane domain at the base of the brush border, from which NHE-RF was absent, consistent with the expression of the truncated B2 subunit isoform in this tubule segment. The colocalization of NHE-RF and H(+)ATPase in B- but not A-intercalated cells suggests a role in generating, maintaining, or modulating the variable H(+)ATPase polarity that characterizes the B-cell phenotype.
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PMID:The B1 subunit of the H+ATPase is a PDZ domain-binding protein. Colocalization with NHE-RF in renal B-intercalated cells. 1074 65

The reducing compound glutathione (GSH) exists in an unusually high concentration in the lens where it functions as an essential antioxidant vital for maintenance of the tissue's transparency. In conjunction with an active glutathione redox cycle located in the lens epithelium and superficial cortex, GSH detoxifies potentially damaging oxidants such as H2O2 and dehydroascorbic acid. Recent studies have indicated an important hydroxyl radical-scavenging function for GSH in lens epithelial cells, independent of the cells' ability to detoxify H2O2. Depletion of GSH or inhibition of the redox cycle allows low levels of oxidant to damage lens epithelial targets such as Na/K-ATPase, certain cytoskeletal proteins and proteins associated with normal membrane permeability. The level of GSH in the nucleus of the lens is relatively low, particularly in the aging lens, and exactly how the compound travels from the epithelium to the central region of the organ is not known. Recently, a cortical/nuclear barrier to GSH migration in older human lenses was demonstrated by Sweeney et al. The relatively low ratio of GSH to protein -SH in the nucleus of the lens, combined with low activity of the glutathione redox cycle in this region, makes the nucleus especially vulnerable to oxidative stress, as has been demonstrated with use of in vivo experimental animal models such as hyperbaric oxygen, UVA light and the glutathione peroxidase knockout mouse. Effects observed in these models, which are currently being utilized to investigate the mechanism of formation of human senile nuclear cataract, include an increase in lens nuclear disulfide, damage to nuclear membranes and an increase in nuclear light scattering. A need exists for development of therapeutic agents to slow age-related loss of antioxidant activity in the nucleus of the human lens to delay the onset of cataract.
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PMID:Glutathione: a vital lens antioxidant. 1080 23

The aim of this study was to investigate whether the preincubation of brain homogenates with L-phenylalanine (Phe), L-cysteine (Cys) or reduced glutathione (GSH) could reverse the free radical effects on Na+,K+-ATPase activity. Two well established systems were used for the production of free radicals: 1) FeSO4 (84 microM) plus ascorbic acid (400 microM) and 2) FeSO4, ascorbic acid and H2O2 (1 mM) for 10 min at 37 degrees C in homogenates of adult rat whole brain. Changes in brain Na+,K+-ATPase activity and total antioxidant status (TAS) were studied in the presence of each system separately, with or without Phe, Cys or GSH. TAS value reflects the amount of free radicals and the capacity of the antioxidant enzymes to limit the free radicals in the homogenate. Na+,K+-ATPase was inhibited by 35-50% and TAS value was decreased by 50-60% by both systems of free radical production. The enzymatic inhibition was completely reversed and TAS value increased by 150-180% when brain homogenates were preincubated with 0.83 mM Cys or GSH. However, this Na+,K+-ATPase inhibition was not affected by 1.80 mM Phe, which produced a 45-50% increase in TAS value. It is suggested that the antioxidant action of Cys and GSH may be due to the binding of free radicals to sulfhydryl groups of the molecule, so that free radicals cannot induce Na+,K+-ATPase inhibition. Moreover, Cys and GSH could regulate towards normal values the neural excitability and metabolic energy production, which may be disturbed by free radical action on Na+,K+-ATPase.
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PMID:Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition induced by free radicals. 1081 19

We are attempting to supply a new insight on interaction between Na(+)/K(+)-ATPase and H(2)O(2). We demonstrate that in vitro the Na(+)/K(+)-ATPase, a non heme-protein, is able to disproportionate H(2)O(2) catalatically into dioxygen and water, as well as C(40) catalase. By polarography, we quantify O(2) production and by Raman spectroscopy H(2)O(2) consumption. A comparative analysis of kinetics parameters relative to O(2) production shows that for Na(+)/K(+)-ATPase the affinity of the catalytic site able to transform H(2)O(2) into O(2) is twice weaker than that for C(40) catalase. It also shows that the molar activity for O(2) production is 300-fold weaker for ATPase than for catalase. Inhibitors, pH and GSH studies highlight the differences between the heme- and nonheme-proteins. Indeed, for C(40), NaN(3) is strongly inhibiting, but much less for ATPase. The pH range for the catalatic activity of ATPase is wide (6.5 to 8.5), while it is not for C(40) catalase (optimum at pH 8). The Na(+)/K(+)-ATPase catalatic activity is reduced in presence of glutathione, while it is not the case with C(40) catalase.
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PMID:A possible role of the Na(+)/K(+)-ATPase for O(2) production from H(2)O(2). 1092 49


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