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PubMed1993

Mosaic tetrasomy 8p: molecular cytogenetic confirmation and measurement of glutathione reductase and tissue plasminogen activator levels.

We report the case of a 5-year-old girl with severe developmental disabilities, skeletal anomalies, hypotonia, rectal atresia, malrotation of the intestine, horseshoe kidney, vesicoureteric reflux, and minor facial anomalies. Conventional cytogenetic techniques suggested that she had a mosaic 46,XX/47,XX,+i(8p) constitution, and the identity of the isochromosome was confirmed by in situ hybridization and chromosome painting. Polymorphic DNA markers are consistent with the i(8p) having arisen as the result of a segregation error and centromere misdivision at the second maternal meiotic division. The i(8p) was seen in 17/25 (68%) lymphocytes at the age of one month but had declined to 31/100 (31%) cells by the age of 5 years. At this time the i(8p) was seen in 30/68 (44%) cultured skin fibroblasts. The proposita had an approximately twofold increase in red cell glutathione reductase activity but a normal level of tissue-plasminogen activator. These enzyme results are consistent with the known localisation of the glutathione reductase gene on the short arm of chromosome 8 but suggest that the tissue-plasminogen activator gene may map outside this region.

Abnormalities, Multiple↗
PubMed1988

Antioxidant enzymes of larvae of the cabbage looper moth, Trichoplusia ni: subcellular distribution and activities of superoxide dismutase, catalase and glutathione reductase.

In the mid-fifth instar larvae of the cabbage looper moth, Trichoplusia ni, the subcellular distribution of total superoxide dismutase was as follows: 3.05 units (70.0%), 0.97 units (22.3%), and 0.33 units (7.6%) mg-1 protein in the mitochondrial, cytosolic and nuclear fractions, respectively. No superoxide dismutase activity was detected in the microsomal fraction. Catalase activity was unusually high and as follows: 283.4 units (47.3%), 150.1 units (25.1%), 142.3 units (23.8%), and 22.9 units (3.8%) mg-1 protein in the mitochondrial, cytosolic, microsomal (containing peroxisomes), and nuclear fractions. No glutathione peroxidase activity was found, but appreciable glutathione reductase activity was detected with broad subcellular distribution as follows: 3.86 units (36.1%), 3.68 units (34.0%), 2.46 units (23.0%), and 0.70 units (6.5%) mg-1 protein in the nuclear, mitochondrial, and cytosolic fractions, respectively. The unusually wide intracellular distribution of catalase in this phytophagous insect is apparently an evolutionary adaptation to the absence of glutathione peroxidase; hence, lack of a glutathione peroxidase-glutathione reductase role in alleviating stress from lipid peroxidation. Catalase working sequentially to superoxide dismutase, may nearly completely prevent the formation of the lipid peroxidizing .OH radical from all intracellular compartments by the destruction of H2O2 which together with O2- is a precursor of .OH.

Animals↗
PubMedDate not supplied

[Activity of glutathione reductase in the adrenal glands and the liver of dogs after administration O,P-DDD, perthane and ACTH].

A study was made of the inhibitors of the adrenal gland function and ACTH on the activity of NADP-specific glutathionreductase in the adrenal glands and the liver of dogs. After a 10-day feeding to dogs of o,p'-dichlordiphenyldichlorethane (o,p'-DDD) and p,p'-diethyldiphenyl dichlorethane (p,p'-pertane) in a dose of 50 mg/kg there was observed a marked activation of glutathion reductase in the adrenal glands. Elevation of the activity of the enzyme was revealed as soon as 24 hours after the administration of o,p'-DDD. The inhibitors under study failed to influence the activity of the enzyme in the liver of dogs, this indicating a specific action of o,p'-DDD and pertane on the adrenal gland cortex. Stimulation of glucocorticoid biosynthesis under the effect of ACTH administered once in a dose of 25 Units/kg was not accompanied by the changes in the activity of glutathione reductase in the adrenal glands and the liver of dogs. Prolonged ACTH administration (4 Units/kg) caused a significant reduction of the enzyme activity calculated as per 1 mg of protein in the adrenal gland homogenate.

Adrenal Cortex↗
PubMed2004

[The intriguing influence of albendazole on glutathione reductase activity in the muscles from Trichinella spiralis infected mice].

A clear stimulation of the activity of glutathione reductase (RG, EC 1.6.4.2), one of the major enzymes participating in glutathione metabolism, was observed in the skeletal muscles from Trichinella spiralis infected mice. The maximal, almost two-fold increase in RG activity was observed in week 5 post-infection. Administration of albendazole, an anthelmintic widely used in trichinellosis treatment, resulted in an additional, about 40% stimulation of RG activity (small, but statistically significant) on week 2 post-infection. In weeks 6 and 7 post-infection, when no stimulation of RG activity in infected mice caused by drug was observed, the drug modified the structure of that allosteric enzyme, affecting the kinetics of its substrate saturation in this way that the shape of the substrate saturation curve changed from "double sigmoidal", typical of this enzyme kinetics in the muscles from infected mice, to hyperbolic, typical of this enzyme kinetics in the control, uninfected animals.

Albendazole↗
PubMed1993

Influence of o-phenanthroline on DNA single-strand breaks, alkali-labile sites, glutathione reductase, and formation of chromium(V) in Chinese hamster V-79 cells treated with sodium chromate (VI).

The effect of the cell-permeable metal chelator o-phenanthroline (OP) on the formation of chromium(V), DNA breaks, alkali-labile sites, and enzyme inhibition of chromium(VI) was studied using Chinese hamster V-79 cells. Alkaline elution assays demonstrated that treatment with OP (100-500 microM) resulted in a dose-dependent decrease in cellular levels of either alkali-labile sites or the combination of alkali-labile sites plus DNA single-strand breaks caused by Na2CrO4. Cellular treatment with OP also attenuated the inhibition of glutathione reductase attributed to Na2CrO4. Under the same experimental conditions, the cellular uptake of chromate was not affected by OP. ESR studies revealed that cellular treatment with OP (100-500 microM) resulted in a concentration-dependent decrease in the level of chromium(V) intermediate in cells treated with Na2CrO4. Furthermore, OP inhibited the chromium(V) complex that formed during the reaction of Na2CrO4 with glutathione in vitro, resulting in the decrease of chromium(V)-mediated hydroxyl radical formation while neither the reduction of chromium(VI) nor the formation of the chromium(VI)-glutathione complex was affected, indicating that OP may react with chromium(V) but not with chromium(VI). These results suggest that the metal chelator OP decreases chromate-induced alkali-labile sites or the combination of alkali-labile sites plus DNA strand breaks, as well as chromium inhibition of glutathione reductase, possibly through its ability to directly decrease chromium(V) complex in cells.

Animals↗
PubMed1991

Inhibition of glutathione disulfide reductase by glutathione.

Rat-liver glutathione disulfide reductase is significantly inhibited by physiological concentrations of the product, glutathione. GSH is a noncompetitive inhibitor against GSSG and an uncompetitive inhibitor against NADPH at saturating concentrations of the fixed substrate. In both cases, the inhibition by GSH is parabolic, consistent with the requirement for 2 eq. of GSH in the reverse reaction. The inhibition of GSSG reduction by physiological levels of the product, GSH, would result in a significantly more oxidizing intracellular environment than would be realized in the absence of inhibition. Considering inhibition by the high intracellular concentration of GSH, the steady-state concentration of GSSG required to maintain a basal glutathione peroxidase flux of 300 nmol/min/g in rat liver is estimated at 8-9 microM, about 1000-fold higher than the concentration of GSSG predicted from the equilibrium constant for glutathione reductase. The kinetic properties of glutathione reductase also provide a rationale for the increased glutathione (GSSG) efflux observed when cells are exposed to oxidative stress. The resulting decrease in intracellular GSH relieves the noncompetitive inhibition of glutathione reductase and results in an increased capacity (Vmax) and decreased Km for GSSG.

Animals↗
PubMed1984

Erythrocyte glutathione reductase activity and acquired trisomy #8 in various hematologic disorders.

The gene for erythrocyte glutathione reductase (E-GR) activity has been assigned to chromosome #8. In the present series, we examined the E-GR activity in 14 cases with chronic myelodysplastic syndrome (CMS, preleukemia), atypical acute myelogenous leukemia (AML), or chronic myelogenous leukemia (CML), with and without acquired trisomy #8. No difference in the incidence of high levels of this enzyme was found between two groups, i.e., those with and without trisomy #8 suggesting the existence of a complex regulatory system in addition to chromosome #8.

Chromosomes, Human, 6-12 and X↗
PubMed1977

Erythrocytic glutathione reductase deficiency in a hospital population in the United States.

In the USA, erythrocytic glutathione reductase (GSSG-R) deficiency is significantly more common, and can be considerably more pronounced in hospitalized patients (118/3198) than in outpatients (37/1639) or in apparently healthy persons (12/849). Retrospective analysis of illnesses found in 118 inpatients with erythrocytic GSSG-R deficiency revealed a striking and previously unsuspected association of the enzyme deficiency with a variety of chemotherapeutically treated hematological or nonhematological malignancies (51/118 patients, 43.2%, or 51/170 diagnoses, 30.0%). The prevalence of erythrocytic GSSG-R deficiency also increased in malnutrition, liver disease, and sepsis. Drugs of the nitrosourea class, particularly BCNU [1, 3-bis(2-chloroethyl)-1-nitrosourea] are causally implicated in the association of GSSG-R deficiency with malignancies. Severe of complete GSSG-R deficiency may handicap host response to infections.

Erythrocytes↗
PubMed1989

Switching kinetic mechanism and putative proton donor by directed mutagenesis of glutathione reductase.

By directed mutagenesis of the cloned Escherichia coli gor gene encoding the flavoprotein glutathione reductase, Tyr-177 (the residue corresponding to Tyr-197 in the NADPH-binding pocket of the homologous human enzyme) was changed to phenylalanine (Y177F), serine (Y177S), and glycine (Y177G). The catalytic activity of the Y177F mutant was very similar to that of the wild-type enzyme, but that of the Y177S and Y177G mutants was substantially diminished. However, all three mutants retained the ability to protect the reduced flavin from adventitious oxidation, indicating that Tyr-177 does not act as a simple "lid" on the NADPH-binding pocket and that the protection of the reduced enzyme must be due largely to burial of the isoalloxazine ring in the protein. The wild-type enzyme and Y177F mutant displayed ping-pong kinetics, but the Y177S and Y177G mutants appeared to have switched to an ordered sequential mechanism. This could be explained by supposing that the enzyme normally functions by a hybrid kinetic mechanism and that the Y177S and Y177G mutations diverted flux from the ping-pong loop favored by the wild-type enzyme to an ordered sequential loop. The necessary change in the partitioning of the common E-NADPH intermediate could be caused by a slowing of the formation of the EH2 intermediate on the ping-pong loop, or by the observed concomitant fall in the Km for glutathione favoring flux through the ordered sequential loop. In another experiment, His-439, thought to act as a proton donor/acceptor in the glutathione-binding pocket, was mutated to a glutamine residue.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1989

Mechanism of inhibition of erythrocyte glutathione reductase by mitomycin-C.

Mitomycin-C (MT-C) inhibits human erythrocyte glutathione reductase (EGR). We found that Km values of EGR for GSSG, NADPH, and FAD were 1.3 X 10(-4) mol/l, 2.3 X 10(-5) mol/l, and 3.9 X 10(-7) mol/l respectively, and that EGR was inhibited by MT-C non-competitively with respect to both the substrate GSSG (Ki = 4.8 X 10(-5) mol/l) and the cofactor NADPH (Ki = 2.2 X 10(-4) mol/l), and competitively with respect to FAD (Ki = 4.2 X 10(-5) mol/l). On the other hand, we demonstrated that FAD makes a complex with MT-C, the dissociation constant (K = 6.5 X 10(-5) mol/l) of which was obtained from fluorescence quenching of FAD with MT-C. It also became clear that spectra wf FAD at around 375 nm changes with increasing MT-C concentration. So, the data strongly suggest that the mechanism of inhibition of EGR by MT-C is mainly due to complex formation of the co-enzyme FAD with MT-C.

Erythrocytes↗
PubMed1994

Purification and characterization of glutathione reductase isozymes specific for the state of cold hardiness of red spruce.

Isozymes of glutathione reductase (GR) have been purified from red spruce (Picea rubens Sarg.) needles. Two isozymes could be separated by anion-exchange chromatography from both nonhardened or cold-hardened tissue. Based on chromatographic elution profiles, the isozymes were designated GR-1NH and GR-2NH in preparations from nonhardened needles, and GR-1H and GR-2H in preparations from hardened needles. N-terminal sequencing and immunological data with antisera obtained against GR-1H and GR-2H established that the isozymes from hardened needles are different gene products and show significant structural differences from each other. Chromatographic, electrophoretic, and immunological data revealed only minor differences between GR-2NH and GR-2H, and it is concluded that these isozymes are very similar or identical. Anion-exchange chromatography and native polyacrylamide gel electrophoresis also established that GR-1NH and GR-1H are different proteins. From these data we conclude that GR-1H is a distinct gene product, present only in hardened needles. Therefore, GR-1H can be considered to be a cold-hardiness-specific GR isozyme, and GR-1NH can be considered to be specific for nonhardened needles. It is proposed that GR-1H is a cold-acclimation protein.

Acclimatization↗
PubMed1996

Glutathione reductase activity, riboflavin status, and disease activity in rheumatoid arthritis.

OBJECTIVE: To measure erythrocyte glutathione reductase (EGR) activity and riboflavin status, and their relations to disease activity, in rheumatoid arthritis patients compared to healthy controls. METHODS: Patients with rheumatoid arthritis were classified as active if there were features of articular inflammation which required initiation or change of disease modifying therapy, and as inactive if they had little evidence of articular inflammation. EGR was measured in patients and healthy controls by a functional assay with or without the addition of flavin adenine dinucleotide (FAD). The ratio of stimulated EGR (with FAD added) to basal EGR (no added FAD), which measures riboflavin status, is known as the EGR activation coefficient (EGRAC). An EGRAC > or = 1.3 represents biochemical riboflavin deficiency. RESULTS: 91 patients with rheumatoid arthritis, including 57 with active disease, and 220 healthy controls were studied. Both basal and stimulated EGR were significantly higher in patients with rheumatoid arthritis (P = 0.0001) than in controls. Biochemical riboflavin deficiency was identified in 41% controls and 33% patients with active rheumatoid arthritis but was significantly less frequent (9%) in patients with inactive compared to active disease (P = 0.02) or healthy controls (P = 0.0006). Pain score, articular index, C reactive protein, and erythrocyte sedimentation rate were increased in patients with riboflavin deficiency (all P < 0.02). CONCLUSIONS: Higher basal and stimulated EGR might be expected in patients with rheumatoid arthritis in response to chronic oxidative stress due to synovial inflammation. The association of riboflavin deficiency with increased disease activity suggests that impaired EGR activity could facilitate continuing inflammation in these patients.

Adult↗
PubMed1991

Effect of ascorbic acid on DNA damage, cytotoxicity, glutathione reductase, and formation of paramagnetic chromium in Chinese hamster V-79 cells treated with sodium chromate(VI).

The effect of pretreatment with ascorbic acid (vitamin C) on chromate-induced DNA damage, cytotoxicity, and enzyme inhibition as well as on the cellular reduction of chromium(VI) was investigated using Chinese hamster V-79 cells. Cellular pretreatment with nontoxic levels of 1 mM ascorbic acid for 24 h prior to exposure resulted in a significant increase (1.7-fold) in cellular levels of this vitamin. Alkaline elution assays demonstrated that this pretreatment decreased cellular levels of Na2CrO4-induced alkali-labile sites while the numbers of DNA-protein crosslinks produced by chromate increased. In colony-forming assays, pretreatment with ascorbic acid enhanced the cytotoxicity of chromate. However, the inhibition of glutathione reductase attributed to Na2CrO4 was attenuated by this pretreatment. Under the same experimental condition, the uptake of chromate in pretreated cells was found to increase. ESR studies revealed that cellular pretreatment with ascorbic acid reduced the level of chromium(V) intermediate and increased the level of chromium(III) complex, indicating that cellular reduction of chromium(VI) to chromium(III) was accelerated by this vitamin. These results suggest that ascorbic acid decreases chromate-induced alkali-labile sites and chromium inhibition of glutathione reductase, but it enhances DNA-protein cross-links and cytotoxicity caused by this metal through its ability to directly reduce chromium(VI).

Animals↗
PubMed1997

Glutathione reductase turned into trypanothione reductase: structural analysis of an engineered change in substrate specificity.

Trypanosoma and Leishmania, pathogens responsible for diseases such as African sleeping sickness, Chagas' heart disease, or Oriental sore, are two of the very few genera that do not use the ubiquitous glutathione/glutathione reductase system to keep a stable cellular redox balance. Instead, they rely on trypanothione and trypanothione reductase to protect them from oxidative stress. Trypanothione reductase (TR) and the corresponding host enzyme, human red blood cell glutathione reductase (GR), belong to the same flavoprotein family. Despite their closely related three-dimensional structures and although their natural substrates share the common structural glutathione core, the two enzymes are mutually exclusive with respect to their disulfide substrates. This makes the parasite enzyme a potential target for antitrypanosomal drug design. While a large body of structural data on GR complexes is available, information on TR-ligand interactions is very limited. When the two amino acid changes Ala34Glu and Arg37Trp are introduced into human GR, the resulting mutant enzyme (GRTR) prefers trypanothione 700-fold over its original substrate, effectively converting a GR into a TR [Bradley, M., Bücheler, U. S., & Walsh, C. T. (1991) Biochemistry 30, 6124-6127]. The crystal structure of GRTR has been determined at 2.3 A resolution and refined to a crystallographic R factor of 20.9%. We have taken advantage of the ease with which ligand complexes can be produced in GR crystals, a property that extends to the isomorphous GRTR crystals, and have produced and analyzed crystals of GRTR complexes with glutathione, trypanothione, glutathionylspermidine and of a true catalytic intermediate, the mixed disulfide between trypanothione and the enzyme. The corresponding molecular structures have been characterized at resolutions between 2.3 and 2.8 A with R factors ranging from 17.1 to 19.7%. The results indicate that the Ala34Glu mutation causes steric hindrance leading to a large displacement of the side chain of Arg347. This movement combined with the change in charge introduced by the mutations modifies the binding cavity, forcing glutathione to adopt a nonproductive binding mode and permitting trypanothione and to a certain degree also the weak substrate glutathionylspermidine to assume a productive mode.

Animals↗
PubMed1994

Effect of carbamate thioester derivatives of methyl- and 2-chloroethyl isocyanate on glutathione levels and glutathione reductase activity in isolated rat hepatocytes.

The present study examined the effects of S-(N-methylcarbamoyl)glutathione (SMG), S-(N-methylcarbamoyl)-L-cysteine (L-SMC) and some analogs of these S-linked conjugates of methyl isocyanate (MIC) on the activity of glutathione reductase (GR) in freshly isolated rat hepatocytes and on the levels of reduced and oxidized glutathione (GSH and GSSG) in exposed cells. Both SMG and its monoethyl ester (0.5 mM) were found to inhibit GR weakly, although L-SMC proved to be an effective inhibitor of the enzyme (60 +/- 4% activity remaining after a 4-hr incubation at 0.5 mM). The cysteine adduct (SCC) of 2-chloroethyl isocyanate (CEIC) was a strong inhibitor of GR (27 +/- 1% activity remaining after a 1-hr incubation at 0.1 mM) and was essentially equipotent with the antitumor agent N,N'-bis(2-chloroethyl)-N-nitrosourea (BCNU). L-SMC depleted intracellular GSH in a time- and concentration-dependent manner up to 2 hr of incubation, beyond which time GSH levels began to recover. Exposure of cells to the enantiomeric conjugate, D-SMC, led to a similar concentration- and time-dependent inhibition of GR and fall in intracellular GSH, but in this case the depletion of GSH was extensive and was sustained throughout the 5-hr incubation period. Only a small amount (less than 10%) of the GSH that was lost from cells exposed to SMC was recovered in the medium, indicating that SMC did not cause efflux of GSH (most of the free cysteine released during breakdown of SMC was recovered in the medium). Experiments with hepatocytes exposed for 5 hr to SCC (0.1 mM) demonstrated that GSSG levels were elevated by 32 +/- 5% relative to controls. Collectively, these results indicate that carbamate thioester conjugates of MIC and CEIC inhibit GR, probably via release of the free isocyanate at the cell surface, which then penetrates the hepatocyte. The inhibitory effects of the isocyanates on GR, coupled with their propensity to react spontaneously with GSH, combine to deplete significantly intracellular stores of GSH.

Animals↗
PubMed2002

Erythrocyte glutathione reductase activity and riboflavin nutritional status in early-weaned piglets.

The reliability of erythrocyte glutathione reductase activity (EGRAC) as an indicator of riboflavin (vitamin B2) status was determined in 36 piglets weaned at two weeks of age. Total B2 metabolites determined by high-performance liquid chromatography (HPLC) in plasma, red blood cells, and liver were used as reference values. There was no correlation between EGRAC values and total B2 metabolites either in circulation (r < 0.15, p > 0.08) or in liver (r < 0.01, p > 0.95). EGRAC does not appear to be a reliable biochemical indicator of vitamin B2 status in the pig.

Animals↗