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)

The effect of acrylonitrile (VCN) on erythrocyte lipid metabolism was investigated in vitro in metabolically active red cells from male Sprague-Dawley rats containing three types of hemoglobins: oxyhemoglobin, methemoglobin, and carbon monoxyhemoglobin. VCN at the concentration of 10 mM rapidly depleted erythrocyte glutathione (GSH) (75% of control) and induced lipid peroxidation (274% of control). Degradation of oxy- and methemoglobin was directly proportional to the extent of lipid peroxidation (r = 0.89). Addition of glucose to the incubation medium decreased hemoglobin degradation while it slightly increased VCN-induced lipid peroxidation. The highest amount of lipid peroxidation occurred in erythrocytes containing carbon monoxyhemoglobin and glucose. In the isolated red cell membranes incubated with 10 mM VCN, the lipid peroxidation was 400% of controls. VCN (25 mM) noncompetitively inhibited erythrocyte membrane Na+/K(+)-ATPase activity and the degree of inhibition was inversely proportional to the reaction temperature (r = -0.88). These findings indicate that the VCN induced hemoglobin degradation and lipid peroxidation are two extremes of a spectrum of oxidative damage in red cells leading to a change in physical state of membrane structure causing inhibition of adenosine triphosphate (ATPase) activity.
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PMID:Hemoglobin degradation, lipid peroxidation, and inhibition of Na+/K(+)-ATPase in rat erythrocytes exposed to acrylonitrile. 196 27

The effect of gamma-irradiation on human erythrocytes in the presence of nitroimidazoles in aerobic conditions was investigated. It was found that both 1-(2-nitroimidazole-1-y1)-3-methoxy-2-propanol (misonidazole, MISO) and 1-(2-methyl-4,5-dinitroimidazoyle)-3-chloro-2-hydroxypropane (4,5-NO2) inhibited membrane-bound ATPase activity without irradiation. Treatment with 4,5-NO2 enhanced the radiation-induced decrease in the activity, whereas irradiation after treatment of membranes with MISO had a variable, concentration-dependent effect. Irradiation of cells in the presence of MISO concentrations less than 34 micrograms/ml decreased reduced glutathione (GSH) levels and increased malondialdehyde (MDA) formation. With the same concentrations a marked oxidative effect of 4,5-NO2 was observed. Significant correlations between 4,5-NO2 concentrations, GSH levels and lipid peroxidation, and also between GSH and MDA levels, were observed. Increasing radiation doses decreased erythrocyte membrane sensitivity to the stabilizing effect of unsaturated fatty acids. This effect for oleic acid was elevated by 4,5-NO2 and suppressed by GSH and BHT. Therefore, it is concluded that in aerobic conditions the red blood cell membrane is a target to radiation and to hypoxic cell radiosensitizers.
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PMID:The evaluation of erythrocyte membrane response to combined treatment of radiation and nitroimidazoles. 197 78

Reactive O2 species appear to be generated both during hypoxia and at reoxygenation, but it has not been established whether these species interact with heart tissue and cause injury. Oxidative changes were evaluated in isolated rat heart perfused with Krebs-Henseleit medium containing 10 mM glucose and 2.5 mM calcium. After 5-10 min hypoxia, tissue glutathione (GSH) decreased while glutathione disulfide (GSSG), protein carbonyls, and thiobarbituric acid reactive substances (TBARS) increased compared with controls. Similarly, sarcolemmal and sarcoplasmic reticular Ca-ATPase activity (an enzyme susceptible to oxidative inactivation) decreased in response to 10 min hypoxia. These changes were more pronounced after 60 min of hypoxia when protein-GSH mixed disulfides were also increased. There were no further oxidative changes after 4 min reoxygenation when the release of lactate dehydrogenase (LDH) was maximal. Myocardial protein thiol and alpha-tocopherol contents were not significantly changed by either hypoxia or reoxygenation. Mitochondria also exhibited oxidative changes but with more pronounced increases in GSSG and mixed disulfides. There was no change in GSH or GSSG efflux into the coronary effluent during hypoxia, although, in parallel with LDH release, both increased after reoxygenation. Diamide (200 microM), t-butylhydroperoxide (20 microM), or purine (2.3 mM) + xanthine oxidase (0.01 U/ml) were infused for 10 min. Except for large diamide-induced changes in protein thiols and mixed disulfides, the magnitude of the changes produced by these oxidants was similar to those produced by hypoxia. These data show that changes consistent with oxidative processes occur in whole heart and mitochondria in response to hypoxia. The absence of marked signs of oxidation at reoxygenation suggest that enzyme release at this time is unrelated to oxidative stress.
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PMID:Oxidative changes in hypoxic rat heart tissue. 203 61

The hepatotoxicity of CCl4 is mediated through its initial reduction by cytochrome P-450 to the CCl3.radical. This radical then damages important metabolic systems such as the ATP-dependent microsomal Ca2+ pump. Previous studies from our laboratory on isolated microsomes have shown that NADPH in the absence of toxic agents inhibits this pump. We have now found in in vitro incubations that CCl4 (0.5-2.5 mM) enhanced the NADPH-dependent inhibition of Ca2+ uptake from 28% without CCl4 to a maximum of 68%. These concentrations are in the range found in the livers and blood of lethally intoxicated animals (Dambrauskas, T., and Cornish, H. H. (1970) Toxicol. Appl. Pharmacol. 17, 83-97; Long, R.M., and Moore, L. (1988) Toxicol. Appl. Pharmacol. 92, 295-306) and are toxic to cultured hepatocytes (Long, R. M., and Moore, L. (1988) Toxicol. Appl. Pharmacol. 92, 295-306). The inhibition of Ca2+ uptake was due both to a decrease in the Ca2(+)-dependent ATPase and to an enhanced release of Ca2+ from the microsomes. The NADPH-dependent CCl4 inhibition was greater under N2 and was totally prevented by CO. GSH (1-10 mM) added during the incubation with CCl4 prevented the inhibition. This protection was also seen when the incubations were performed under nitrogen. When samples were preincubated with CCl4, the CCl4 metabolism was stopped, and then the Ca2+ uptake was determined; GSH reversed the CCl4 inhibition of Ca2+ uptake. This reversal showed saturation kinetics for GSH with two Km values of 0.315 and 93 microM when both the preincubation and the Ca2+ uptake were performed under air, and 0.512 and 31 microM when both were performed under nitrogen. Cysteine did not prevent the NADPH-dependent CCl4 inhibition of Ca2+ uptake. CCl4 increased lipid peroxidation in air, but no lipid peroxidation was seen under nitrogen. Lipid peroxidation was only modestly reversed by GSH. GSH did not remove 14C bound to samples preincubated with the 14CCl4. Although EDTA (100 microM) decreased the CCl4 inhibition, the metal-complexing agents deferoxamine (100 microM) and diethyldithiocarbamate (100 microM) had no effect on the inhibition of the pump. Similarly, the reactive oxygen scavengers catalase (65 micrograms/ml), superoxide dismutase (15 micrograms/ml), mannitol (10 mM), and dimethyl sulfoxide (50 mM) also had no effect. Our results suggest that the initial toxicity of CCl4 for the Ca2+ pump results from the metabolism of CCl4 to the CCl3. radical. This radical then directly oxidizes the Ca2+ pump, leading to decreased Ca2+ uptake.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The in vitro NADPH-dependent inhibition by CCl4 of the ATP-dependent calcium uptake of hepatic microsomes from male rats. Studies on the mechanism of the inactivation of the hepatic microsomal calcium pump by the CCl3.radical. 214 Mar 58

An ATP-dependent transport process for S-(2,4-dinitrophenyl) glutathione (Dnp-SG) mediated by a novel ATPase designated as Dnp-SG ATPase has been demonstrated in human erythrocytes (LaBelle et al., FEBS Lett. 228, 53-51, 1988). In order to investigate whether the Dnp-SG ATPase system represents a generalized mechanism for the transport of xenobiotic conjugates of glutathione (GSH), stimulation of this ATPase by different GSH conjugates was studied in membrane vesicles prepared from human erythrocytes. Kinetic parameters for several GSH conjugates including S-(methyl)glutathione, S-(n-propyl)glutathione, S-(n-pentyl)glutathione, S-(n-decyl)glutathione, S-(p-chlorophenacyl)glutathione, S-(p-nitrobenzyl)glutathione, and the GSH conjugate of 9,10-epoxystearic acid were determined in order to evaluate their affinity for Dnp-SG ATPase. These studies reveal that all these conjugates stimulated Dnp-SG ATPase of human erythrocyte membrane. The apparent Km values of Dnp-SG ATPase for different conjugates were found to be in the range of 0.26-0.66 mM with Vmax values ranging from 0.55 to 4.44 nmol/min/mg protein. The results of these studies indicate that erythrocyte membrane Dnp-SG ATPase represents a generalized mechanism for the transport of GSH conjugates formed with xenobiotics as well as with the endogenously generated electrophilic compounds such as epoxystearic acid. It is suggested that Dnp-SG ATPase in conjunction with GSH and GSH S-transferase may play an important role in the protection of erythrocytes from exogenous as well as endogenous electrophilic toxicants.
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PMID:Stimulation of a human erythrocyte membrane ATPase by glutathione conjugates. 214 5

The half maximal inhibitory concentrations (IC50) of substituted benzimidazoles for the H+, K(+)-ATPase in hog gastric vesicles were measured by using the pyruvate kinase-lactate dehydrogenase-linked system in which hydrolysis of ATP was coupled with the oxidation of NADH. The vesicles were incubated in a solution containing a high concentration of KCl, valinomycin and Mg-ATP, and the intravesicular medium was acidified. The inhibitor was activated in the acidic medium and reacted with SH groups on the luminal (intravesicular) side of the ATPase. The active compound formed in the extravesicular medium (pH 6.11) was quenched by GSH. Under these conditions, IC50 of new compound E3810, 2[(4-(3-methoxypropoxy)-3-methylpyridine-2-yl)methyl-sulfinyl]-1H- benzimidazole sodium salt, was 0.072 microM and that of omeprazole was 0.47 microM at 25 degrees. On the other hand, the rates of formation of active compounds, tetracyclic sulfenamide derivatives, from original substituted benzimidazoles in 0.1 N HCl (k) were determined by measuring optical density at the characteristic wavelengths of the active compounds. There was a good correlation between IC50 and k for various substituted benzimidazoles including E3810, methoxy derivative of E3810, omeprazole, Ro 18-5364, H compound, picoprazole and timoprazole. This fact suggest that the rate of the formation of the acid-activated compound is a main factor determining the potency of the inhibitor.
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PMID:The potency of substituted benzimidazoles such as E3810, omeprazole, Ro 18-5364 to inhibit gastric H+, K(+)-ATPase is correlatedwith the rate of acid-activation of the inhibitor. 215 89

Incubation of rabbit heart microsomes with Adriamycin and NADPH resulted in the oxidation of approximately 25% of protein thiols and 66% inhibition of Ca-ATPase activity. Thiol oxidation and Ca-ATPase inactivation were iron-dependent and could be catalysed by ferritin. Removal of contaminating catalase revealed that both processes required H2O2 which could be supplied by O2 under aerobic conditions. However, O2- was not involved. Butylated hydroxytoluene (BHT), alpha-tocopherol and beta-carotene inhibited lipid peroxidation of microsomes, but did not inhibit thiol oxidation or the inactivation of Ca-ATPase. Likewise, the hydroxyl radical scavengers benzoate, formate and mannitol were not inhibitory. Glutathione (GSH), however, prevented inactivation of Ca-ATPase. It is concluded that Adriamycin-enhanced redox reactions involving iron and H2O2 are responsible for oxidizing microsomal thiol groups and inhibition of Ca-ATPase. Disruption of Ca transport within the myocyte by this process could contribute to the cardiotoxicity of Adriamycin.
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PMID:Thiol oxidation and inhibition of Ca-ATPase by adriamycin in rabbit heart microsomes. 215 95

We have reported previously that 2-[[[3-methyl-4-(2,2,2-trifluorethoxy)-2-pyridyl]methyl] sulfinil]- 1H-benzimidazole (AG-1749) inhibits (H+ + K+)-adenosine triphosphatase after being transformed into its cyclic sulfenamide form (AG-2000) or disulfide form (AG-1812) under acidic conditions. In this study, mechanisms related to the inhibition of acid formation by AG-1749 were investigated in isolated canine parietal cells. AG-1749 suppressed the acid formation stimulated by histamine, carbachol or dibutyryl cyclic AMP with IC50 values of approximately 0.09 microM: AG-1749 being twice as potent as omeprazole. The inhibitory effect of AG-1749 was antagonized by dithiothreitol (1 mM). 2-Cyclo-hexen-1-one (3 mM) decreased cytosolic glutathione to less than 10% of control value, and caused a 3-fold increase in the inhibitory effect of AG-1749. Glutathione, however, when added exogenously, did not affect the action of AG-1749. The inhibition was reversed by removing AG-1749 from the medium or by adding dithiothreitol (1 mM). The reversal of inhibition by these two procedures was hardly affected by puromycin (100 microM) or cycloheximide (300 microM) but significantly prevented by 2-cyclo-hexen-1-one (1 mM). Exogenously added AG-2000 (10 microM) or AG-1812 (5 microM), active forms of AG-1749, did not inhibit acid formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible mechanism for the inhibition of acid formation by the proton pump inhibitor AG-1749 in isolated canine parietal cells. 215 97

Lead (Pb) inhibited K(+)-stimulated para-nitrophenyl phosphatase (K(+)-PNPPase) of rat brain P2 fraction in a concentration-dependent manner with IC50 3.5 microM. Altered pH versus activity demonstrated comparable inhibitions by Pb in buffered acidic, neutral and alkaline pH ranges. Inhibition of enzyme activity was higher at lower temperatures (17-27 degrees C) compared to 37 degrees C. Preincubation of enzyme with sulfhydryl (-SH) agents such as cysteine (Cyst) and dithiothreitol (DTT) but not glutathione (GSH) protected against Pb-inhibition. Uncompetitive type of inhibition with respect to the activation of K+ was indicated by a decrease in Vmax from 16.2 to 8.37 mumoles of para-nitrophenol (PNP)/mg protein/hr and Km from 18.99 to 12.39 mM. Kinetic studies on substrate (p-nitrophenyl phosphate) activation in the presence of Pb (3.5 microM) indicated a significant decrease in Vmax from 8.94 to 4.69 mumoles of PNP/mg protein/hr with no change in Km. Cyst (3 microM) and DTT (10 microM) reversed the Pb-inhibited Vmax from 4.69 to 8.38 and 7.24 mumoles of PNP/mg protein/hr respectively. These results suggest that the critical conformational property of K(+)-PNPPase is sensitive to Pb. The data also indicates that the Pb inhibits Na(+)-K+ ATPase system by interacting with dephosphorylation of the enzyme-phosphoryl complex, while Cyst and DTT protected against Pb-inhibition.
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PMID:Effects of lead on K(+)-para-nitrophenyl phosphatase activity and protection by thiol reagents. 216 61

When 7,12-dimethylbenz[a]anthracene (DMBA) and aflatoxin B1 (AFB1) were activated by hepatocytes from Fischer 344 rats fed a diet containing 2% butylated hydroxyanisole (BHA), frequencies of mutation to 6-thioguanine resistance (TGR) at the HGPRTase gene locus and to ouabain resistance (OuR) at the Na+,K(+)-ATPase gene locus in V79 cells were 30-70% less than those obtained with hepatocytes from untreated controls. A difference in the mutation frequency did not occur when dimethylnitrosamine (DMN) was activated by BHA induced- rather than control-hepatocytes. Analysis of hepatocytes from rats fed 2% BHA showed a small (1.5-fold), but significant, increase in glutathione levels over that in the controls but no change in activity of cytochrome P450. Cytosolic glutathione S-transferase (GST) activity was increased 2-3-fold in hepatocytes from rats fed the 2% BHA diet. These results suggest that mutagenic response to DMBA and AFB1 is reduced, at least in part, because of BHA-induction of hepatocyte GST activity; while activation of DMN can occur by pathway(s) unaffected by BHA-induction of these liver enzymes. In contrast to mutation frequencies, significant differences between BHA- and control-activation in the production of sister-chromatid exchange (SCE) and micronucleus formation (MN) were not detected with any of the genotoxins. It was concluded that the mechanism(s) by which SCE and MN occur are likely unrelated to the capacity of BHA to induced activity of hepatic enzymes, e.g. the GSH S-transferases, that directly or indirectly affect mutation end-points.
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PMID:Comparative genotoxicity of 3 procarcinogens in V79 cells as related to glutathione S-transferase activity of hepatocytes from untreated rats and those fed 2% butylated hydroxyanisole. 216 83


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