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PubMed1991

[Effects of emoxipine on lipid peroxidation in patients with chronic heart failure].

Lipid peroxidation (LPO) was studied in 90 patients with chronic heart failure (CHF) in relation to the disease stage. The patients with various CHF showed increased LPO and decreased antioxidative function. Impaired LPO was more pronounced in patients with Stage II CHF. To correct LPO processes, emoxipine, a new synthetic antioxidant, was used in 48 patients. The agent in a dose of 40 mg/day was ascertained to have a regulatory effect on the oxidative-antioxidative system in patients with heart failure. A more profound effect was observed in patients with Stage I patients. The main mechanism of the antioxidative action of emoxipine in CHF was to enhance glutathione reductase and glutathione peroxidase and to lower the level on dienic conjugates in patients with Stage IIB CHF.

Adult↗

PubMed1991

Anomalous relationship between cisplatin sensitivity and the formation and removal of platinum-DNA adducts in two human ovarian carcinoma cell lines in vitro.

Two human ovarian tumor cell lines (SK-OV-3 and TR175), established from patients previously treated with alkylating agents, but not with cisplatin, expressed greater than 23-fold differences in cisplatin sensitivities in vitro. Cisplatin resistance in SK-OV-3 cells appeared to be associated with increased levels of glutathione and activities of glutathione reductase and glutathione peroxidase, with reduced catalase activity. No significant modification of drug uptake was noted and there was only marginally lower (16%) total platination of DNA, measured immunochemically, in these cells compared with the more sensitive TR175 cell line. SK-OV-3 cells, however, showed a significantly lower overall ability to remove drug-induced DNA damage, with an apparent inability to remove either the major DNA-DNA intrastrand cross-links in the sequence pGpG or the adducts cis-Pt(NH3)2d(GMP)2, although by alkaline elution repair of DNA-DNA interstrand cross-links was demonstrated. Significantly more of these interstrand cross-links were induced in these resistant cells. These data provide evidence for the involvement of altered glutathione metabolism and increased tolerance of certain types of drug-induced DNA damage as factors associated with the resistance phenotype of SK-OV-3 cells. Paradoxically, however, although the highly cisplatin-sensitive TR175 cells had lower glutathione levels this was not reflected in significantly higher total platination of DNA, and these cells appeared to be proficient in removing all the major platinum-DNA adducts quantitated in this study. Mechanisms responsible for this relative sensitivity to cisplatin remain to be identified.

Buthionine Sulfoximine↗

PubMed1989

Tissue and biliary glutathione disulfide in the perfused vitamin E-deficient rat liver.

Vitamin E and glutathione protect against oxidative damage in vivo. In this study the relationship between these two defenses has been examined in the isolated perfused rat liver. The activities of glutathione reductase and glutathione S-transferase were unaffected by vitamin E deficiency, while glutathione peroxidase activity was decreased slightly. The glutathione redox status of vitamin E-deficient and control livers was assessed. GSSG was slightly higher in vitamin E-deficient livers (70 +/- 5 nmol GSH equivalents/g liver) than in controls (56 +/- 3 nmol GSH equivalents/g liver) under basal conditions. However, biliary GSSG release was 41% lower in vitamin E-deficient livers (0.46 +/- 0.08 nmol GSH equivalents/g liver.min) than in controls (0.78 +/- 0.23 nmol GSH equivalents/g liver.min). Inhibition of GSSG reduction by BCNU raised liver and biliary GSSG by a similar amount in vitamin E-deficient and control livers. Thus biliary GSSG efflux, a frequently used index of oxidant stress, is not increased in vitamin E-deficient perfused livers compared with control. Therefore, in the perfused rat liver model, no evidence was obtained that vitamin E deficiency activates the hepatic glutathione system.

Animals↗

PubMed1987

Glutathione metabolism in isolated rat hepatocytes: acinar heterogeneity of detoxifying enzymes and effects of ethanol.

Periportal and perivenous hepatocytes were isolated by the digitonin-collagenase perfusion technique. The activity of the cytosolic glutathione S-transferase was higher in perivenous cells, but the cytosolic glutathione reductase and the microsomal glutathione S-transferase activities were evenly distributed. In contrast, both the Se-dependent and the microsomal Se-independent glutathione peroxidase activity and the glucose-6-phosphate dehydrogenase activity was much lower in perivenous hepatocytes, suggesting that these cells have a lowered detoxification capacity, which may contribute to their greater susceptibility to damage by xenobiotics. The mechanism of the ethanol-induced GSH depletion in vivo was studied by incubating conventionally isolated hepatocytes. In the absence of glutathione precursors, ethanol (80 mM) did not influence the GSH content, despite accumulation of acetaldehyde (10-100 MicroM). L-Methionine or L-cysteine stimulated GSH replenishment to in vivo rates. Ethanol oxidation resulted in acetaldehyde accumulation, but did not inhibit GSH replenishment from L-methionine and even stimulated that from L-cysteine. This seems to exclude conjugation of GSH with acetaldehyde as a mechanism by which ethanol suppresses GSH levels in vivo.

Animals↗

PubMed1986

[Activation of peroxisomal acyl-CoA oxidase and lipid peroxidation in the rat myocardium as affected by prolonged administration of ethanol].

The influence of chronic alcoholic intoxication on the activity of peroxisomal acyl-CoA oxidase and antioxidative defensive enzymes (catalase, glutathione reductase, glutathione-S-transferase, superoxide dismutase, glucose-6-phosphate dehydrogenase) was studied in the rat myocardium. The parameters of lipid peroxidation in cardiomyocytes (the level of spontaneous chemiluminescence, accumulation of thiobarbituric acid-reactive material), as well as reduced glutathione content were also examined. The data obtained suggest that ethanol-induced activation of lipid peroxidation in the myocardium may be due to the elevation of hydrogen peroxide-generating activity of peroxisomes.

Acyl-CoA Oxidase↗

PubMed1984

Monitoring metabolic reactions in erythrocytes using NMR spectroscopy.

The kinetics of several metabolic reactions in intact human erythrocytes and in lysates were studied using 1H spin-echo and 13C nuclear magnetic resonance spectroscopy (NMR). The reactions monitored involved the following enzymes: (1) arginase, (2) glutathione reductase, (3) glutathione synthetase, (4) gamma-glutamyl cyclotransferase, (5) di- and tripeptidase, and (6) NAD-glycohydrolase; the first six enzymes are cytosolic whilst the latter is membrane associated. Detailed kinetics of the arginase reaction are given together with the rate of arginine transport into the cells.

Arginase↗

PubMed1982

Secretion of oxygen intermediates: role in effector functions of activated macrophages.

The ability of macrophages to secrete reactive oxygen intermediates, such as superoxide or hydrogen peroxide, correlates closely with their capacity to kill trypanosoma, toxoplasma, leishmania, and candida. In this sense, secretion of oxygen intermediates is a biochemical marker of macrophage activation. The close correlation between oxidative metabolism and antimicrobial activity appears to stem from the direct involvement of oxygen intermediates in the killing of the same parasites by the macrophages. Similarly, there seem to be at least three experimental settings in which oxygen intermediates play a major role in nonphagocytic lysis of tumor cells by macrophages: in the presence of phorbol myristate acetate, of antitumor antibody, or of a peroxidase derived from eosinophils. These findings direct attention to antioxidant defenses in tumor cells and parasites. The oxidation-reduction cycle of glutathione is one major pathway used by tumor cells to limit oxidative injury by macrophages and granulocytes. Thus, cytotoxicity is augmented by inhibition of glutathione reductase or glutathione peroxidase, by interruption of glutathione synthesis, or by diversion of glutathione into another pathway. On the other hand, catalase appears to play a prominent role in limiting macrophage effector function against toxoplasma.

Animals↗

PubMed1984

Oxygen metabolism in cloned macrophage cell lines: glucose dependence of superoxide production, metabolic and spectral analysis.

The requirements of a cloned macrophage-like cell line, J774.16, for oxygen metabolism, and the nature of the defect in oxidative metabolism in a variant clone derived from it, J774.C3C, were studied. Upon stimulation with phorbol myristate acetate (PMA), the parental clone produced approximately 1 nmol O2-/min/10(6) cells, whereas the variant clone produced no detectable O2- under the same conditions. Sustained O2- production by J774.16 was totally dependent on extracellular glucose; in glucose-free medium, the cells initiated O2- production but could not sustain it. When cells were stimulated with PMA, glucose-C-1 oxidation of J774.16 cells increased 20-fold while that of J774.C3C remained at resting levels. O2- production in J774.16 cells was inhibited by some agents known to block mitochondrial electron transport before coenzyme Q, such as rotenone and tetrathiafulvalene, whereas antimycin A enhanced O2- production. A dissociation between O2- production and glucose-C-1 oxidation was observed when J774.16 was treated with certain metabolic inhibitors. Quinacrine, 2,4-dinitrophenol, chlorpromazine, and trifluoperazine inhibited O2- production completely under conditions in which glucose-C-1 oxidation was reduced only by 30%. Rotenone inhibited O2- production with no effect on glucose-C-1 oxidation whereas antimycin A augmented O2- production 50% but inhibited glucose oxidation by 20%. Glucose transport studies, with 2-deoxy-D-glucose, showed that the Km for glucose transport of both clones was about 1 mM, indicating that cells could effectively transport glucose even at low concentrations. The Vmax for glucose transport in both J774.16 and variant J774.C3C cells doubled after PMA stimulation, indicating that the variant was effectively stimulated by PMA, even though O2- was not produced. Similarly, PMA induced protein phosphorylation in both clones. No differences between clones J774.16 and J774.C3C in hexokinase, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, glutathione reductase, or glutathione peroxidase activities could be found. When dithionite-reduced and -oxidized difference spectra of plasma membranes of these clones were compared, comparable levels of b-type cytochrome were found in both clones. However, CO difference spectra indicated that CO was bound to a b-type cytochrome (presumed to be b-245) in clone J774.16 but not in J774.C3C.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Effect of a mixture of 15 commonly used pesticides on DNA levels of 8-hydroxy-2-deoxyguanosine and xenobiotic metabolizing enzymes in rat liver.

The level of 8-OH-2-deoxyguanosine in rat liver DNA was measured as an index of oxidative damage after treating rats for 10 days at a dose ranging from 0.75 to 10 mg/kg with a mixture of 15 pesticides (dithiocarbamate, benomyl, thiabendazole, diphenylamine, chlorthalonil, procimidone, methidathion, chlorpyrifos-ethyl, fenarimol, parathion-methyl, chlorpropham, parathion, vinclozolin, chlorfenvinphos, pirimiphos-ethyl) commonly found in foods of central Italy. At the doses of 0.75 and 1 mg/kg DNA levels of 8-OH-2-deoxyguanosine were significantly increased relative to controls, whereas at higher doses (2.5, 5, 10 mg/kg) the levels returned to control values. The administration of the pesticide mixture dose dependently reduced benzo(a)pyrene hydroxylase, N-demethylase activities, glutathione peroxidase, glutathione reductase, glutathione-S-transferase and thiol transferase activities in the liver. The results show that the pesticide mixture induced free radical DNA damage at low doses. However, at higher doses it produced a depression of cellular metabolism, inhibiting a further expression of oxidative damage.

8-Hydroxy-2'-Deoxyguanosine↗

PubMedDate not supplied

[Activity of various enzymes of formed elements in the blood plasma during extracorporeal circulation].

The activity of the enzymes whose high activity is observed in blood cells, such as the glutathione metabolic enzymes glutathione reductase, glutathione-S-transferase, glutathione peroxidase in erythrocytes and monoaminooxidase in the platelets, was examined at different perfusion stages in the plasma of 30 patients undergone open heart surgery. The findings suggest that the enzymes release from the blood cells damaged during extracorporeal circulation into the plasma, which may be useful as a test for defining the degree of perfusion-induced damage of blood cells.

Blood Platelets↗

PubMedDate not supplied

[Effect of various perfusion temperature regimens in heart surgery with extracorporeal circulation on glutathione levels and activity of enzymes of glutathione metabolism in erythrocytes].

The level of glutathione and the activity of its exchange enzymes (glutathione reductase, glutathione-S-transferase, glutathione peroxidase), the content of malonic dialdehyde were studied in the red blood levels of 70 patients operated on under hypothermal perfusion for correction of acquired cardiac diseases. The plasma concentrations of myoglobin were also measured. There was a relationship of the time course of changes in the parameters in question to the depth of the body's cooling during surgical interventions. Shallow hypothermia (30-34 degrees C) caused a compensatory increase in the activity of glutathione peroxidase (by more than 30%) and in the concentration of glutathione (by more than 60%) at the cooling stage. Moderate hypothermia (26-29 degrees C) produced no impact on the level of glutathione and the activity of its exchange enzymes while deeper hypothermia (25 degrees C or below) induced decreases in the levels of glutathione (by more than 30 degrees C) and suppressed the activity of all the tested enzymes of its exchange. At the same time there are elevated concentrations of malonic dialdehyde at the warming-up stage and during early postperfusion. Myoglobin washing into plasma occurs under all temperature conditions of perfusion at the warming-up stages and in the early postperfusion period, but it is most profound in deeper hypothermia, which is caused by the toxic effect of oxygen whose plasma solubility increases with lowered temperatures.

Cardiac Surgical Procedures↗

PubMed1996

Vulnerability of multidrug-resistant tumor cells to the aromatic fatty acids phenylacetate and phenylbutyrate.

Cytotoxic chemotherapies often give rise to multidrug resistance, which remains a major problem in cancer management. In pursuit of alternative treatments for chemoresistant tumor cells, we tested the response of multidrug-resistant (MDR) tumor cell lines to the aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB), two differentiation inducers currently in clinical trials. Both compounds induced cytostasis and maturation of multidrug-resistant breast, ovarian, and colon carcinoma cells with no significant effect on cell viability. In contrast to their poor response to doxorubicin, the MDR cells were generally more sensitive to growth arrest by PA and PB than their parental counterparts. The aromatic fatty acids, like the differentiation-inducing aliphatic fatty acid butyrate, up-regulated mdr-1 gene expression. However, while butyrate increased multidrug resistance, PA and PB potentiated the cytotoxic activity of doxorubicin against MDR cells. The latter was associated with time-dependent declines in glutathione levels and in the activity of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and glutathione S-transferase, the antioxidant enzymes implicated in cell resistance to free radical-based therapies. Taken together, our in vitro data indicate that PA and PB, differentiation inducers of the aromatic fatty acid class, may provide an alternative approach to the treatment of MDR tumors.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1998

Oxidative stress induced by environmental tobacco smoke in the workplace is mitigated by antioxidant supplementation.

Environmental tobacco smoke (ETS) is a pervasive contaminant in the workplace. Previous studies by this laboratory have shown that exposure to workplace ETS results in increased oxidative stress and damage, as measured by increased levels of the antioxidant enzymes superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase. 8-Hydroxy-2-deoxyguanosine, a marker of oxidative DNA damage, was also 63% greater in the exposed group compared with controls. Subjects in the previous study who reported workplace exposure to ETS were given a 60-day supply of an over-the-counter antioxidant formulation consisting of 3000 microg of beta-carotene, 60 mg of vitamin C, 30 I.U. of alpha-tocopherol, 40 mg of zinc, 40 microg of selenium, and 2 mg of copper. After the 60-day supplementation period, blood samples were again drawn, and the results were compared with the presupplementation values. A 62% decrease in 8-hydroxy-2-deoxyguanosine was observed after supplementation. Lipid peroxidation levels were also decreased, as were the antioxidant enzyme activities. The biochemical evidence suggests that exposure to ETS in the workplace increases oxidative stress and that antioxidant supplementation may provide some protection.

Adult↗

PubMed1998

[The antioxidant action of taurine in acute hypoxic hypoxia].

It was found that preliminary treatment by amino acid taurine protected rats from lipid peroxidation intensification (expressed in terms of malondialdehyde and conjugated dienes contents) in the liver, brain and heart under acute severe normobaric hypoxic hypoxia. The mechanisms of the antioxidant action of taurine are connected to the prevention of lactate accumulation in tissues and cell membrane structure disorders (expressed in a decrease of membrane Na+, K(+)-ATPase activity). It was also shown that taurine reduced significantly a decrease of glutathione antioxidant system activity protecting tissues against reduced glutathione pool depletion and preventing a decrease of glutathione reductase and glutathione peroxidase activities in acute severe hypoxia.

Acute Disease↗

PubMed1993

Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions.

SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared. (1) SR 4233 did not affect hepatocyte viability (as determined by plasma membrane disruption) or glutathione levels under aerobic conditions. SR 4233 however induced cyanide-resistant respiration, an indicator of redox cycling mediated oxidative stress and became cytotoxic if hepatocyte catalase or glutathione reductase was inactivated. Glutathione oxidation occurred well before cytotoxicity ensued. Addition of ascorbate markedly enhanced SR 4233 cytotoxicity to these compromised hepatocytes. (2) In contrast, SR 4233 was highly toxic to hypoxic hepatocytes. Addition of ascorbate to enhance SR 4233 reduction also caused a marked increase in hepatocyte toxicity and an SR 4233 radical was detected with ESR spectroscopy. SR 4233 cellular reduction and toxicity was prevented with fructose or inhibitors of NADPH:cytochrome P-450 reductase. Inactivation of catalase or glutathione reductase had no effect on SR 4233 toxicity and hepatocyte GSH was not oxidised indicating oxidative stress did not occur during hypoxic SR 4233 hepatocyte toxicity. (3) The lack of SR 4233 cytotoxicity under aerobic conditions could probably be attributed to the detoxification of the SR 4233 radical by mitochondrial oxidation as SR 4233, but not its metabolite SR 4317 markedly increased state III and IV mitochondrial respiration in the presence of NADH. The increased respiration was inhibited by the respiratory inhibitors KCN and antimycin A but not by rotenone. Furthermore SR 4233 cytotoxicity under aerobic conditions was markedly increased by partially inhibiting hepatocytes respiration with cyanide but not rotenone.

Animals↗

PubMed1984

Changes in glutathione and glutathione metabolizing enzymes in erythrocytes and lymphocytes of mice as a function of age.

Changes in reduced glutathione levels in liver, lung and whole blood of female Swiss-Webster mice with age were determined. In addition, glutathione content, and glutathione S-transferase and glutathione reductase activities of erythrocytes and lymphocytes of mice as a function of age were examined. Reduced glutathione content increased in liver, lung, whole blood, erythrocytes and lymphocytes with age from 3 to 9 months, reached a maximum level at 9 months of age and decreased thereafter with advanced age in all tissues. Glutathione S-transferase and glutathione reductase activities in erythrocytes and lymphocytes increased with age from 3 to 9 months, reached maximum activities at 9 months and decreased thereafter with advanced age. The glutathione content of erythrocytes from animals 18 months of age decreased by 56% as compared to 9 month old mice, while the activities of glutathione S-transferase and glutathione reductase decreased by 56 and 48%, respectively, over the same age span.

Aging↗

PubMedDate not supplied

[Activity of glutathione-dependent enzymes and superoxide dismutase in peptic ulcer].

Activity of Cu, Zn-superoxide dismutase, glutathione-S-peroxidase, glutathione-S-transferase, glutathione reductase, glucoso-6-phosphate dehydrogenase and content of glutathione reduced in blood of patients with gastric and duodenal ulcer depending on the age and parallel lesion of the hepatobiliary system have been studied. Considerable inhibition of superoxide dismutase, glucoso-6-phosphate-dehydrogenase activity and decrease of the content of reduced glutathione, the most pronounced in patients with parallel lesion of the hepatobiliary system, have been revealed. Glutathione reductase activity is high in all the patients, except for aged and old people with parallel lesions of the liver and biliferous tracts. Glutathione peroxidase is essentially active in adult patients, especially in case of combined pathology. Glutathione peroxidase activity is lower in aged and old patients as compared to the age norm, while the level of glutathione-S-transferase activity is high; at the same time there are no considerable changes in the glutathione-S-transferase activity in adult patients. The mechanisms of compensation and decompensation of functioning of enzymatic antiradical and antioxidant system under the peptic ulcer depending on the age of patients and concomitant lesions of the hepatobiliary system are discussed.

Adult↗

PubMed1990

The effect of 1,3 bis-(2-chloroethyl)-1-nitrosourea on rat brain glutathione status under conditions of normoxia and hyperoxia.

The effect of inhibition of rat brain glutathione reductase, under conditions of normoxia and hyperoxia, on tissue ratios of reduced:oxidized glutathione was tested. Under conditions of normoxia, inhibition of brain glutathione reductase by approximately 50%, had no effect on reduced or oxidized glutathione in any of the three brain regions analyzed. After exposure of rats to 4 ATA 100% oxygen for one hour, in the presence of the same degree of enzyme inhibition, significant increases in oxidized glutathione in the cortical and subcortical areas of the brain were detected. Coupled with small, but nonsignificant decreases in reduced glutathione, a highly significant decrease in the ratio of reduced:oxidized glutathione was demonstrated in these two brain regions. These results indicate that under the conditions of an increased oxidizing environment, inhibition of brain glutathione reductase enhances the oxidative stress experienced by this organ.

Animals↗