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PubMed1997

Molecular characterization and expression of Onchocerca volvulus glutathione reductase.

Glutathione metabolism represents a potential target for anti-parasite drug design. The central role of glutathione reductase (GR) in maintenance of the thiol redox state and in anti-oxidative defence has to be evaluated in more detail in order to establish the essential function of this enzyme for the survival of the filarial parasite Onchocerca volvulus. The O. volvulus GR (OvGR) gene was cloned and sequenced. The gene is composed of 13 exons and 12 introns and spans 4065 bp. The first intron is located within the 5'-untranslated region of the gene, 16 nucleotides upstream of the translation initiation codon. Southern-blot analysis and structural characterization of the genomic sequence indicate that OvGR is encoded by a single-copy gene. Isolation of various cDNA clones revealed a polymorphism of polyadenylation initiation with no consensus polyadenylation sites in any of the cDNAs analysed. The entire cDNA is 1977 bp long and carries the nematode-specific spliced leader sequence SL1 at its 5' end, 236 nucleotides upstream of the first in-frame methionine. The cDNA codes for a polypeptide of 462 amino acids with 53.5% sequence identity with human GR (HsGR). A total of 18 out of 19 residues contributing to glutathione binding are identical in OvGR and HsGR. However, one of the arginine residues (Arg-224 in HsGR) involved in discrimination between NADPH and NADH in all known GRs is substituted by tryptophan (Trp-207 in OvGR). The coding region of OvGR was expressed in Escherichia coli as a histidine-fusion protein, and it was established that the parasite protein still favours the binding of NADPH (Km 10.9 microM) over NADH (Km 108 microM). The histidine-fusion protein has a subunit size of 54 kDa and is active as a homodimer of 110 kDa.

Amino Acid Sequence↗
PubMed1990

Effect of ischaemia-reperfusion on glutathione peroxidase, glutathione reductase and glutathione transferase activities in human heart protected by hypothermic cardioplegia.

The activities of glutathione peroxidase (GSH-px), glutathione reductase (GSSG-rx) and glutathione transferase (GST) were measured in myocardial specimens obtained from right atria of patients subjected to different period of ischaemic arrest (aortic clamping ranging from 10 min to 90 min) followed by 60 min. of reperfusion, during open heart surgery 41-90 min. period of aortic clamping induced a significant increase of GSH-px activity with both H2O2 (p less than 0.05) and cumene hydroperoxide (p less than 0.025) as substrates when compared with baseline levels. Aortic clamping and reperfusion, however did not significantly change the myocardial activities of glutathione transferase and glutathione reductase. It is suggested that the increase of GSH-px in ischaemic-reperfused human hearts may render the myocardium less susceptible to oxidative attack particularly during the reoxygenation period when the level of active oxygen species is greatly elevated.

Female↗
PubMed1986

The distribution and comparison of glutathione, glutathione reductase and glutathione S-transferase in various camel tissues.

Extracts prepared from liver, kidney, lung and brain of camel contain glutathione, glutathione S-transferase and glutathione reductase. Liver had the highest level of glutathione (218.7 mumol/g wet weight) whereas brain had the lowest level (66.4 mumol/g wet weight). The highest activity for glutathione reductase was found in the kidney (2.6 mumol/min/mg protein) while the lowest activity was found in the lung (0.9 mumol/min/mg protein). Glutathione S-transferase activity was the highest in liver (4.2 mumol/min/mg protein) and the lowest in brain (1 mumol/min/mg protein). Purified glutathione S-transferases from lung, kidney, brain and liver were similar in their molecular size, subunit composition as well as immuno-reactivity and showed some differences in their response to heat and inhibitors.

Animals↗
PubMedDate not supplied

[Effect of chloditan on the changes of activity of glutathione transferase, glutathione reductase and glutathione content in the adrenal glands and liver in rats].

The chloditan (o.p-DDD, mitotane), which causes the destruction of the human and dog adrenal cortex, on the most essential system of xenobiotic metabolism: glutathione-S-transferase--glutathione has been studied. The effect of o,p-DDD on GSH level and activity of glutathione-S-transferase and glutathione reductase which maintain the level of reduced glutathione was analyzed in the adrenal and liver tissue of rats. This species is resistant to adrenocorticolytic action of o,p-DDD. It was shown that feeding of rats weighting 200-240 g with oil solution of o,p-DDD (75 mg daily) for 3 days causes the decrease in activity of glutathione-S-transferase and content of oxidazed glutathione in the adrenals with simultaneous increase of the content of reduced glutathione. The glutathione-S-transferase and glutathione reductase activity in the liver rises under the effect of o,p-DDD, the decrease of the GSH level being observed. The revealed changes may explain the species sensitivity of animals to o,p-DDD.

Adrenal Glands↗
PubMed1992

Effects of phenol compounds, glutathione analogues and a diuretic drug on glutathione S-transferase, glutathione reductase and glutathione peroxidase from canine erythrocytes.

1. Phenol compounds (ellagic acid, quercetin and purpurogallin), glutathione analogues (S-hexylglutathione and S-octylglutathione) and a diuretic drug (ethacrynic acid) were compared for their inhibitory effects on glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidase (GSH-Px) in the canine erythrocytes. 2. All these compounds inhibited GST activity; quercetin was found to be the most potent inhibitor. 3. Ellagic acid, purpurogallin, quercetin and ethacrynic acid inhibited GR activity; S-hexylglutathione and S-octylglutathione had no effect on GR and GSH-Px activities. 4. Quercetin and purpurogallin inhibited GST non-competitively toward glutathione, whereas ellagic acid showed a competitive inhibition. Ellagic acid and purpurogallin inhibited GR non-competitively toward oxidized glutathione.

Animals↗
PubMed1984

Glutathione, glutathione reductase and glutathione S-transferase activities in erythrocytes and lymphocytes in chronic renal disease.

Erythrocyte and lymphocyte reduced glutathione (GSH) levels, and glutathione reductase (GR) and glutathione S-transferase (GST) activities have been investigated in uremic patients pre- and post-dialysis and normal subjects of the same age span. GSH levels and GST activities in erythrocytes and lymphocytes and GR activity in lymphocytes from uremic patients were higher as compared to the corresponding controls. Dialysis resulted in a 17% decrease in GSH levels in erythrocytes. Hemodialysis did not significantly alter erythrocyte GST and GR activities. Hemodialysis produced a 50% decrease in lymphocyte GST activity and a 32% decrease in lymphocyte GR activity. Elevated levels of GSH and increased activities of GST and GR in blood cells of uremic patients may be associated with a compensatory protective mechanism against accumulating toxic wastes in uremic plasma.

Adult↗
PubMed2000

Overexpression of Mn-superoxide dismutase in maize leaves leads to increased monodehydroascorbate reductase, dehydroascorbate reductase and glutathione reductase activities.

The effect of increased Mn-superoxide dismutase (SOD) on antioxidant enzymes and metabolites was studied using transformed maize, TG1+ and TG2+. The progeny of the backcross of each of the primary transformants with the parental line generated two populations denoted M6884 and M6885. These were grown at optimal (25 degrees C) and sub-optimal (18, 14 and 10 degrees C) temperatures to assess the impact of elevated SOD activity on cold tolerance and the antioxidant defences in maize. The plants of the M6885 population had similar foliar SOD activities to the untransformed maize plants. Within the segregating M6884 population 50% of the plants had elevated SOD activity (up to four times the activity of the untransformed controls) and 50% of the plants contained the product of the transgene. In untransformed plants grown at 25 degrees C and 18 degrees C, SOD activity was not detectable in mesophyll extracts. Similarly, increased foliar SOD activity in the M6884 transformed maize did not lead to detectable mesophyll SOD activity. Increased foliar KCN-insensitive SOD activities were accompanied by enhancement of monodehydroascorbate reductase, dehydroascorbate reductase and glutathione reductase activities; enzymes which are localized exclusively in the leaf mesophyll tissues. Increased foliar SOD activity had no effect on the hydrogen peroxide, glutathione or ascorbate contents of the leaves. This suggests that increased recycling of reduced ascorbate was required to compensate for enhanced hydrogen peroxide production in transformed plants.

Antioxidants↗
PubMed1985

Glutathione S-sulfonate, a sulfur dioxide metabolite, as a competitive inhibitor of glutathione S-transferase, and its reduction by glutathione reductase.

Glutathione S-sulfonate (GSSO3H) is a reaction product of glutathione disulfide (GSSG) and sulfite, the hydrated form of sulfur dioxide. In the present study, GSSO3H was found to be a potent competitive inhibitor of the glutathione S-transferases (GST) in the rat liver (Ki = 14 microM) and lung (Ki = 9 microM), and in human lung tumor-derived A549 cells (Ki = 4 microM). GSSO3H was also reduced by a cytosolic enzyme in the rat liver (Km = 313 microM) and lung (Km = 200 microM), and human lung A549 cells (Km = 400 microM). These results suggest that SO2 may affect the detoxification of xenobiotic compounds by inhibiting, via formation of GSSO3H, the enzymatic conjugation of glutathione (GSH) and reactive electrophiles. Although GSSO3H can be enzymatically degraded, the high substrate Km value suggests that this compound may not be readily reduced at low concentrations.

Animals↗
PubMed1977

Chloroplast glutathione reductase.

Glutathione reductase (EC 1.6.4.2) activity is present in spinach (Spinacia oleracea L.) chloroplasts. The pH dependence and substrate concentration for half-maximal rate are reported and a possible role in chloroplasts is proposed.

Journal Article↗
PubMed2003

Regeneration of the antioxidant ubiquinol by lipoamide dehydrogenase, thioredoxin reductase and glutathione reductase.

Ubiquinol is a powerful antioxidant, which is oxidized in action and needs to be replaced or regenerated to be capable of a sustained effort. This article summarises current knowledge of extramitochondrial reduction of ubiquinone by three flavoenzymes, i.e. lipoamide dehydrogenase, glutathione reductase and thioredoxin reductase, belonging to the same pyridine nucleotide-disulfide oxidoreductase family. These three enzymes are the most efficient extramitochondrial ubiquinone reductases so far described. The reduction of ubiquinone by lipoamide dehydrogenase and glutathione reductase is potently stimulated by zinc and the highest rate of reduction is achieved at acidic pH and the rates are equal with either NADPH or NADH as co-factors. The most efficient ubiquinone reductases are mammalian cytosolic thioredoxin reductases, which are selenoenzymes with a number of biological functions. Reduction of ubiquinone by thioredoxin reductase is in contrast to the other two enzymes investigated, inhibited by zinc and shows a sharp physiological pH optimum at pH 7.5. Furthermore, the reaction is selenium dependent as revealed from experiments using truncated and mutant forms of the enzyme and also in a cellular context by selenium treatment of transfected thioredoxin reductase overexpressing stable cell lines. The reduction of ubiquinone by the three enzymes offers a multifunctional system for extramitochondrial regeneration of an important antioxidant.

Animals↗
PubMed1999

Levels of glutathione reductase and glutathione peroxidase of human platelets in unstable angina and myocardial infarction.

Levels of glutathione peroxidase and glutathione reductase were measured in the platelets of 30 patients, 10 of them affected by unstable angina, 10 of them reperfused after myocardial infarction and 10 matched healthy controls. The specific activities of both the enzymes were lowered in both group of patients. Glutathione reductase activity resulted markedly lowered.

Angina, Unstable↗
PubMed1991

Age-related changes of glutathione content, glutathione reductase and glutathione peroxidase activity of human erythrocytes.

1. In order to investigate the effect of aging on the erythrocyte glutathione system, total glutathione (GSH), glutathione reductase (GSH-red) and glutathione peroxidase (GSH-px) levels were measured in erythrocytes from 33 young (mean age = 30.5 +/- 9.7 years) and 28 aged (mean age = 68.9 +/- 11.4 years) healthy individuals. 2. GSH was 3.5 +/- 1.8 microM/g Hb for the young group, a value significantly greater (P less than 0.01) than 2.3 +/- 0.9 microM/g Hb found for the aged group. Similarly, GSH-red activity, 5.5 +/- 1.8 IU/g Hb, was higher (P less than 0.05) for the young group than 3.4 +/- 0.9 IU/g Hb found for the aged group. The GSH-px activity levels for the young group, 21.1 +/- 5.9 IU/g Hb, were significantly greater (P less than 0.01) than 12.0 +/- 3.3 IU/g Hb for the aged group. The lower activity detected in the aged group for all of these parameters of the glutathione redox system was not related to low levels of hematocrit or hemoglobin. 3. There was no statistical difference in the activation coefficient (AC) of reductase (+FAD/-FAD) between groups, which seems to indicate that the lower activity of glutathione reductase observed in the aged group was not due to riboflavin deficiency. 4. Additional information is required to determine the mechanisms controlling the glutathione redox system and its role in the aging process.

Aged↗
PubMed2002

Docking and molecular dynamics studies at trypanothione reductase and glutathione reductase active sites.

A theoretical docking study on the active sites of trypanothione reductase (TR) and glutathione reductase (GR) with the corresponding natural substrates, trypanothione disulfide (T[S]2) and glutathione disulfide (GSSG), is reported. Molecular dynamics simulations were carried out in order to check the robustness of the docking results. The energetic results are in agreement with previous experimental findings and show the crossed complexes have lower stabilization energies than the natural ones. To test DOCK3.5, four nitro furanic compounds, previously designed as potentially active anti-chagasic molecules, were docked at the GR and TR active sites with the DOCK3.5 procedure. A good correlation was found between differential inhibitory activity and relative interaction energy (affinity). The results provide a validation test for the use of DOCK3.5 in connection with the design of anti-chagasic drugs.

Binding Sites↗
PubMed2004

Cell-free production of active E. coli thioredoxin reductase and glutathione reductase.

Escherichia coli thioredoxin reductase (TR) and glutathione reductase (GR) are dimeric proteins that require a flavin adenine dinucleotide (FAD) cofactor for activity. A cell-free protein synthesis (CFPS) reaction supplemented with FAD was used to produce TR at 760 microg/ml with 89% of the protein being soluble. GR accumulated to 521 microg/ml in a cell-free reaction with 71% solubility. The TR produced was fully active with a specific activity of 1390 min(-1). The GR had a specific activity of 139 U/mg, which is significantly more active than reported for GR purified from cells. The specific activity for both TR and GR decreased without FAD supplementation. This research demonstrates that CFPS can be used to produce enzymes that are multimeric and require a cofactor.

Cell-Free System↗
PubMed2003

Decreased enzyme activity of hepatic thioredoxin reductase and glutathione reductase in rabbits by prolonged exposure to inorganic arsenate.

Chronic exposure of humans to inorganic arsenic, mainly pentavalent arsenate (iAsV), results in drinking water-induced oxidative stress (Pi et al., 2002). Thioredoxin reductase (TR) and glutathione reductase (GR) are the two critical enzymes in the response to oxidative stress in vivo. In the present study we examined alterations in enzyme activities of hepatic TR and GR from prolonged exposure of male New Zealand white rabbits to iAsV. Exposure of rabbits to iAsV in drinking water (5 mg/L) for 18 weeks caused a significant suppression of hepatic TR and GR activities, of approximately 30% and 20%, respectively, below controls. In vitro experiments suggested that trivalent inorganic arsenic (iAsIII) but not pentavalent arsenicals including iAsV, monomethylarsonic acid (MMAsV), and dimethylarsinic acid (DMAsV) affected the hepatic TR activity of rabbit. So it was suggested that in the present study iAsV ingested via drinking water was metabolized to reactive trivalent arsenicals, such as iAsIII, which may play an important role in the decreased TR and GR activities from prolonged exposure to iAsV observed in vivo.

Administration, Oral↗
PubMed1993

Corneal aldehyde dehydrogenase, glutathione reductase, and glutathione S-transferase in pathologic corneas.

Previously we have reported that various pathologic corneas exhibited a "diseased" two-band corneal aldehyde dehydrogenase (ALDH) zymogram after native polyacrylamide gel electrophoresis as compared with the three bands in the normal human cornea. Experimentally, such a "diseased" zymogram pattern could be induced by addition of reduced glutathione (GSH) to the normal corneal epithelial extract. This finding suggests that in vivo the conformation of corneal ALDH may be related to changes in the GSH redox system during the process of corneal diseases. To investigate this hypothesis in keratoconus corneal epithelial extracts and a separate group comprising other corneal disorders, mainly herpes keratitis, we indirectly measured the GSH turnover by assaying the activity of glutathione reductase (GR) which is responsible in producing GSH and glutathione s-transferase (GST), which converts GSH into mercapturic acid. Our results indicate that there is a correlation between the activity of GR and GST in the normal and the separate group of corneal disorders. Because GST is the first enzyme in the mercapturic acid pathway, which detoxifies xenobiotic substrates including aldehydes, as by-products of membrane lipid peroxidation, an elevated GSH turnover might be necessary to counteract oxidative threats. However, no correlation was found between corneal ALDH level with either GR or GST. On the other hand, keratoconus samples demonstrated a distinct enzymatic behavior that was in concordance with our earlier result in the corneal ALDH zymogram after isoelectric focusing. Furthermore, analysis of our several studies tends to support the proposed structural function of ALDH in human cornea.

Aldehyde Dehydrogenase↗
PubMed1988

Micromethods in single muscle fibers. 2. Determination of glutathione reductase and glutathione peroxidase.

This paper extends the previous study for systems which control intracellular oxidative events in muscle and describes procedures suitable to assay glutathione peroxidase (GSHPx), glutathione reductase (GR), and total glutathione (GSH + GSSG) after fiber typing of individual muscle fibers. In human skeletal muscle, both GR and GSHPx activities were relatively low when compared to those of other tissue. No difference was found among fiber types (I, IIA, and IIB) with regard to GR activity, but in contrast GSHPx activity was significantly lower in type IIB fibers than in the other types. These results suggest that type IIB fibers may have a reduced ability to cope with hydroperoxides generated during oxidative stress, which, in turn, could lead to increased damage to membrane structures by lipid peroxidation or oxidation of sensitive intracellular thiol (-SH) enzymes by hydrogen peroxide. The Km of skeletal muscle GR for GSSG was 27 microM and for NADPH was 22 microM. If one assumes approximately 95% of total glutathione is present in the reduced state, then GSSG concentration would be of the order of 0.3 mmol/kg and under these conditions skeletal muscle GR would be efficient in all muscle fiber types.

Fluorescence↗