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)

In the present study we compared, in vivo in rats, the hepatobiliary transport of monovalent (silver:Ag) and divalent metals (zinc:Zn; cadmium:Cd) with that of copper (Cu). Cu can have two oxidation states in vivo, i.e. Cu(I) and Cu(II). Studies were performed in normal Wistar (NW) rats and mutant GY Wistar rats. The latter express defective canalicular ATP-dependent glutathione-conjugate transport (cMOAT); reduced glutathione (GSH) is virtually absent in bile of these mutants. Cd (400 nmol/100g body wt, i.v.) was rapidly secreted into bile in NW rats concommitant with a 4-fold increase in biliary GSH secretion. In contrast, biliary Cd concentrations remained below detection limits in GY rats. Injection of Zn (1500 nmol/100g body wt) did not affect Zn secretion in GY rats and resulted only in a very small increase in NW rats (recovery < 2%). The biliary secretion pattern of Ag (800 nmol/100g body wt, i.v.) was highly similar to that of Cu (260 nmol/100g body wt). A biphasic pattern composed of a rapid and slow phase was observed in NW rats for both metals with a recovery of 48.5 +/- 10.6% and 44.9 +/- 8.4% of the dose for Ag and Cu, respectively. In GY rats, the rapid phase of both Ag and Cu secretion was absent and recoveries were 23.2 +/- 3.6% and 19.7 +/- 3.2%, respectively. When Ag and Cu were administered simultaneously, the recoveries of Ag and Cu were decreased in NW and GY rats when compared to single administration. Our data indicate that divalent and monovalent metals are secreted into bile via different transport systems in the rat. The absence of Cd and Zn secretion into bile of GY rats after their i.v. administration suggest a role of cMOAT in their biliary elimination. Cu and Ag probably share common transport systems for hepatobiliary removal, being in part dependent on the presence of either GSH in bile or cMOAT activity or on both. The GSH-independent portion of transport, i.e. the slow phase, may be mediated by the newly identified Cu transporting P-type ATPase (cCOP).
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PMID:Bile secretion of cadmium, silver, zinc and copper in the rat. Involvement of various transport systems. 884 10

The aim of this study was to estimate the anticataract action of vitamin E using an in vitro methylprednisolone (MP)-induced cataract model. The same severity of early cortical cataract was induced in lenses isolated from male Wistar rats aged 6 weeks by incubation with MP (1.5 mg/ml) in TC-199 medium. The cataractous lenses showed slight increases in lipid peroxide (LPO) content and Na+/K+ ratio and slight decreases in reduced glutathione (GSH) content and glyceraldehyde-3-phosphate dehydrogenase (GAP-DH), a sensitive index of oxidative stress, and Na+,K(+)-ATPase activities. When the cataractous lenses were further incubated in TC-199 medium with and without vitamin E (250 micrograms/ml) for 48 h, the progression of cataract was prevented in the vitamin E-treated lenses, but not in the vitamin E-untreated lenses. The vitamin E-untreated lenses showed a decrease in vitamin E content and an increase in water content in addition to further increases in LPO content and Na+/K+ ratio and further decreases in GSH content and GAP-DH and Na+,K(+)-ATPase activities. In contrast, the changes of these components and enzymes except for GSH were attenuated in the vitamin E-treated lenses. From these results, it can be estimated that vitamin E prevents in vitro cataractogenesis in rat lenses treated with MP by protecting the lenses against oxidative damage and loss of membrane function.
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PMID:Anticataract action of vitamin E: its estimation using an in vitro steroid cataract model. 888 85

We have previously demonstrated that arsenite-resistant SA7 cells can extrude arsenite more effectively and completely than their parental Chinese hamster ovary cells. Our present results show that arsenite efflux from SA7 cells is inhibited by chemosensitizing agents to multidrug resistant-associated protein: verapamil and cyclosporin A and by glutathione-depleting agents: dinitrofluorobenzene and diethyl maleate. These results suggest that arsenite extrusion in SA7 cells may be mediated by a GSH-dependent and verapamil- and cyclosporin A-sensitive membrane transport system. Since arsenite extrusion was found dose-dependently inhibited by energy poison [potassium cyanide (KCN)] and an ATPase inhibitor (sodium vanadate), ATP is apparently required for arsenite extrusion in SA7 cells.
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PMID:Arsenite efflux is inhibited by verapamil, cyclosporin A, and GSH-depleting agents in arsenite-resistant Chinese hamster ovary cells. 891 71

A permanent increase in cytosolic Ca2+ levels seems to be associated with various pathological situations which may result in cell death. Hg2+ and CH3Hg+ are potent neurotoxic agents, but the precise molecular mechanism(s) underlying their effects are not sufficiently understood. In the present study we investigated the potential role of Ca(2+)-ATPase located in the endoplasmic reticulum as a molecular target for mercury. Hg2+ and CH3Hg+ inhibited Ca(2+)-ATPase and Ca2+ uptake by brain microsomes with similar potencies. However, the inhibitory potency of Hg2+ was higher than that of CH3Hg+, probably reflecting differences in the affinity for the sulfhydryl groups of these compounds. Passive or unidirectional Ca2+ efflux (measured in the absences of Ca(2+)-ATPase ligands) was increased significantly by CH3Hg+ and Hg2+. Again, the potency of Hg2+ was higher than that of CH3Hg+. Blockers of Ca2+ channels (ruthenium red, procaine, heparin) did not affect the increase in passive Ca2+ efflux induced by mercury compounds, possibly indicating that Ca2+ release occurs through Ca(2+)-ATPase. Addition of physiological concentrations of glutathione (GSH) simultaneously with mercury abolished the inhibitory effects of both forms of Hg on ca(2+)-transport. However, if the enzyme was first inhibited with Hg2+ or CH3Hg+ and subsequently treated with GSH, the reversal of inhibition was about 50%, suggesting that part of the cysteinyl residues involved in the inhibitory actions of mercury in Ca(2+)-transport bind to mercury with an extremely high affinity.
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PMID:Effects of Hg2+ and CH3Hg+ on Ca2+ fluxes in rat brain microsomes. 895 21

While oxidative stress can induce a heat shock response, the primary signals that initiate activation have not been identified. To identify such signals, HepG2 and V 79 cells were exposed to menadione, a compound that redox-cycles to generate superoxide. The oxidative stress generated by menadione resulted in oxidation of protein thiols in a dose-dependent manner. This was followed by protein destabilization and denaturation, as determined by differential scanning calorimetry of whole cells. To directly evaluate the effect of non-native disulfides on protein conformation, Ca2(+)-ATPase, isolated from rabbit sarcoplasmic reticulum, was chemically modified to contain non-native intermolecular or glutathione (GHS)-mixed disulfides. Differential scanning calorimetry profiles and 1-anilinonaphthalene-8-sulfonic acid fluorescence indicated that formation of non-native disulfides produced protein destabilization, denaturation, and exposure of hydrophobic domains. Cellular proteins shown to contain oxidized thiols formed detergent-insoluble aggregates. Cells treated with menadione exhibited activation of HSF-1, accumulated Hsp 70 mRNA, and increased synthesis of Hsp 70. This work demonstrates that formation of physiologically relevant, non-native intermolecular and GSH-mixed disulfides causes proteins to destabilize, unfold such that hydrophobic domains are exposed, and initiate a signal for induction of the heat shock response.
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PMID:Proteins containing non-native disulfide bonds generated by oxidative stress can act as signals for the induction of the heat shock response. 913 Apr 61

Specific binding of Hg2+ to ouabain-sensitive Na(+)-K(+)-ATPase of rat liver plasma membrane was demonstrated with a Ka of 2.64 x 10(9) and Bmax of 1.6 nmole mg-1 protein. The binding of mercury to the enzyme also causes significant inhibition of the enzyme, which is greater than its ouabain sensitivity. In the cytosol Hg2+ binding to reduced glutathione (GSH) is stimulated by GSH-S-transferase (GST), the activity of which was found to be significantly enhanced by 15 mM Na+ and 10 mM Hg2+. It is proposed that the transport of Hg2+ inside the cell takes place by increased dissociation of Hg2+ from the membrane due to greater avidity of Hg2+ towards cytosolar GSH binding. The GSH-Hg complex enters the nucleus where it dissociates to bind the metal response element (MRE) of the metallothionein (MT) gene to induce MT transcription.
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PMID:Specific binding of inorganic mercury to Na(+)-K(+)-ATPase in rat liver plasma membrane and signal transduction. 924 94

Paraquat (PQ) induces lung, liver and kidney damage. Since PQ mainly is eliminated by the kidney, the kidney damage is of particular importance to the outcome of PQ poisoning. The exact toxic mechanism of PQ is still unclear but it is assumed to involve redox cycling and formation of reactive oxygen species. In this study, further investigations on the toxic mechanism and metabolic effects of PQ were performed using isolated renal proximal tubules from rabbits. Proximal tubules were isolated using a combined iron perfusion and collagenase method. Suspended tubules were incubated for varying periods and concentrations of PQ at 25 or 37 degrees C in Krebs-Ringer phosphate buffer or HCO3-/CO2 buffer. The cytotoxic effect of PQ was evaluated by (1) markers of oxidative stress: status of glutathione (GSH/GSSG) and formation of malondialdehyde (MDA); and (2) markers of tubular metabolism: oxygen consumption (QO2), transport of 14C-p-aminohippuric acid (PAH) and 14C-tetraethylammonium (TEA). Using 0.5 and 5 mM PQ, the GSH/GSSG ratio decreased whereas formation of MDA increased indicating oxidative stress. PQ reduced the accumulation of PAH and TEA, the basal QO2 and the ouabain sensitive QO2 indicating inhibition of the Na/K-ATPase. Nystatin-stimulated QO2 was reduced by PQ, excluding inhibition of Na+ entry as a possible cytotoxic mechanism and suggesting mitochondrial injury. This was confirmed by measuring FCCP-uncoupled QO2. Thus high concentrations of PQ appear to disrupt mitochondrial electron chain transfer resulting in reduction of metabolic functions.
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PMID:The cytotoxic effect of paraquat to isolated renal proximal tubular segments from rabbits. 927 8

The biliary pathway represents the major excretory route for copper (Cu). It has been suggested that glutathione (GSH) plays a role in this process. However, biliary secretion of endogenous Cu is unaffected in canalicular multispecific organic anion transporter (cmoat)/multi-drug resistance protein (mrp2)-deficient GY/TR- rats, which is a mutant rat strain expressing defective canalicular adenosine triphosphate (ATP)-dependent GSH-conjugate transport and which is unable to secrete GSH into bile. Secretion of Cu after iv Cu load is markedly impaired in GY/TR- rats when compared with normal Wistar (NW) rats. Administration, iv, of 65, 325, or 2300 nmol/100 g body wt CuSO4 dose-dependently increased Cu secretion in normal Wistar (NW) rats. Secretion rates in GY/TR rats were much lower and plateaued with higher loads at a level of about 35 nmol/h/100 g body wt. Clearance of an intravenous (iv) bolus of 64Cu (250 nmol/100 g body wt) was faster in GY/TR- rats than in controls, but secretion of 64Cu into bile was clearly reduced in the mutants. Specific activity of biliary Cu was similar in both groups. To investigate the removal of excess dietary Cu via bile, GY/TR and NW rats received water supplemented with Cu (CuSO4 8 mmol/L) for up to 12 weeks (Cu-fed) or tap water (controls). Cu feeding resulted in an increase of biliary Cu secretion from approximately 6 to approximately 30 nmol/h/100 g body wt within two weeks, both in NW and GY/TR- rats; Cu secretion also did not further increase during the course of the experiment. Hepatic Cu content was similar in NW and GY/TR- rats and progressively increased during Cu feeding. Our data indicate that biliary secretion of diet-derived Cu proceeds exclusively via a saturable Cu transporting system, which is distinct from cmoat/mrp2 and which is independent of biliary GSH. This transport may be mediated by the recently identified Cu-ATPase. In contrast, excess hepatic Cu after iv Cu load depends on cmoat/mrp2 activity for rapid removal. It is concluded that iv administered and dietary (endogenous) Cu is, in part, processed differently by rat liver, which might be related to differences in Cu redox state.
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PMID:Differences in hepatic processing of dietary and intravenously administered copper in rats. 932 20

The preventive action of vitamin E (Vit. E)-containing liposomes on cataractogenesis was examined in male Wistar rats (five weeks old) fed a 25% galactose diet. Vit. E-containing liposomes prepared with dipalmitoylphosphatidylcholine were instilled into both eyes three times a day over a 45-day period. Cataract appeared at 18-day galactose feeding and developed gradually thereafter. Simultaneous Vit. E-containing liposome instillation delayed this cataractogenesis. Lenses of 18-day galactose-fed rats showed decreases in Vit. E and reduced glutathione (GSH) contents and Na+, K(+)-ATPase activity and increases in lipid peroxide (LPO), galactitol, and water contents. Lenses of 45-day galactose fed rats showed decreases in GSH content and Na+,K(+)-ATPase activity and increases in Vit. E, LPO, galactitol, and water contents. Serum Vit. E and cholesterol levels decreased in 18-day galactose-fed rats, while both levels increased in 45-day galactose-fed rats. Simultaneous Vit. E-containing liposome instillation prevented these changes except for the changes of lenticular galactitol and water contents and serum Vit. E and cholesterol levels. These results indicate that simultaneously instilled Vit. E-containing liposomes can delay cataractogenesis in young adult rats fed a 25% galactose diet mainly by the antioxidative action of Vit. E contained in the instilled liposomes.
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PMID:Preventive action of vitamin E-containing liposomes on cataractogenesis in young adult rats fed a 25% galactose diet. 943 57

The effects of Hg(II) on bioenergetic and oxidative status of rat renal cortex mitochondria were evaluated both in vitro, and in vivo 1 and 24 h after treatment of animals with 5 mg HgCl2/kg i.p. The parameters assessed were mitochondrial respiration, ATP synthesis and hydrolysis, glutathione content, lipid peroxidation, protein oxidation, and activity of antioxidant enzymes. At low concentration (5 microM) and during a short incubation time, Hg(II) uncoupled oxidative phosphorylation while at slightly higher concentration or longer incubation time the ion impaired the respiratory chain. The rate of ATP synthesis and the phosphorylation potential of mitochondria were depressed, although inhibition of ATP synthesis did not exceed 50%. In vivo, respiration and ATP synthesis were not affected 1 h post-treatment, but were markedly depressed 24 h later. ATP hydrolysis by submitochondrial particle FoF1-ATPase was inhibited (also by no more than 50%) both in vitro, and in vivo 1 and 24 h post-treatment. Hg(II) induced maximum ATPase inhibition at about 1 microM concentration but did not have a strong inhibitory effect in the presence of Triton X-100. Oxidative stress was not observed in mitochondria 1 h post-treatment. However, 24 h later Hg(II) reduced the GSH/GSSG ratio and increased mitochondrial lipid peroxidation and protein oxidation, as well as inhibited GSH-peroxidase and GSSG-reductase activities. These results suggest that the following sequence of events may be involved in Hg(II) toxicity in the kidney: (1) inhibition of FoF1-ATPase, (2) uncoupling of oxidative phosphorylation, (3) oxidative stress-associated impairment of the respiratory chain, and (4) inhibition of ATP synthesis.
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PMID:Hg(II)-induced renal cytotoxicity: in vitro and in vivo implications for the bioenergetic and oxidative status of mitochondria. 945 Jun 45


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