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PubMed1975

Effect of o,p'-dichlorodiphenyldichloroethane on glutathione reductase activity and content of SH groups in the dog adrenals.

The effect of o, p'-dichlorodiphenyldichloroethane (DDD), a compound inducing atrophy of the adrenal cortex and blocking steroid production, on glutathione reductase activity was studied. As a result of feeding dogs with DDD in a dose of 50 mg/kg body weight for 14 days activation of glutathione reducatase took place in the homogenate, cytoplasmic fraction, and disintergrated mitochondria of the adrenals. On the additon of DDD in vitro the activity of the enzyme was unchanged. The content of SH groups expressed per 100 mg tissue was reduced in the homogenate and in all subcellular fractions. If expressed per 100 mg protein in the level of SH groups was lowered only in the microsomes and the disintergrated mitochondria.

Adrenal Glands↗
PubMed1995

Glutathione peroxidase and glutathione reductase activities in cancerous and non-cancerous human kidney tissues.

Selenium-dependent (Se-GSH-Px), selenium-independent (non-Se-GSH-Px) glutathione peroxidase and glutathione reductase (GSSG-Rx) activities have been determined in cancerous and non-cancerous human adult kidney. Large inter-individual variation in the activities of all enzymes tested were found in both tumour and non-tumour specimens. In general a significant decrease in the activities of the three enzymes was found in tumours. When a comparison was made between cancerous and non-cancerous tissues of the same individual, Se-GSH-Px activity was found to be lower in tumour in 17 cases out of 29, and the non-Se-GSH-Px activity in 20. In 20 cases out of 29 GSSG-Rx was found to be lower in tumour. It was concluded that changes in the factors involved in the anti-oxidative protection actually occur in human kidney tumour.

Adult↗
PubMed1984

Changes in superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities and thiobarbituric acid-reactive products levels in early stages of development in dystrophic chickens.

Cu-Zn superoxide dismutase, Mn superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activities and thiobarbituric acid-reactive products were assayed in the superficial pectoral muscles of genetically dystrophic chickens (line 413) and their controls (line 412) 1, 2, and 4 weeks, and 4 months after hatching. In control chickens, all these enzyme activities declined as they grew older. In dystrophic chickens, all these enzyme activities were significantly elevated at all stages of development studied, and their developmental time courses were quite different from those in the controls. Thiobarbituric acid-reactive products were also significantly elevated in dystrophic chickens after 2 weeks of age. Invasion of macrophages and lipid cells were not manifest until 4 weeks after hatching in the dystrophic chickens studied. Therefore, observed abnormalities were considered to represent biochemical pathologies within muscle cells. Increased activities of the enzymes which are responsible for the regulation of active oxygen species and the elevated thiobarbituric acid-reactive products would indicate the presence of increased turnover of those active oxygen species. These findings indicated that active oxygen species were playing a significant role in the pathogenesis of muscular dystrophies. The possible mechanisms of cellular damage by active oxygen species are discussed.

Animals↗
PubMed1992

Inhibition of glutathione reductase by flavonoids. A structure-activity study.

A structure-activity study of fourteen chemically related flavonoids was conducted to evaluate their abilities to inhibit glutathione reductase (GR). By comparing the I50 values of flavonoids from different classes possessing an identical hydroxyl configuration, we determined the following order of potency for inhibition of GR: anthocyanidin > dihydroflavonol = chalcone > flavonol > catechin. Enzyme inhibition by delphinidin chloride and myricetin was partially prevented in a N2 atmosphere which implicates a role for oxygen in the mechanism of inhibition. To determine the role of oxygen species in enzyme inhibition, GR was preincubated with either mannitol, diethylenetriaminepenta-acetic acid (DETAPAC), superoxide dismutase (SOD), catalase (CAT), or SOD and CAT prior to assays for enzyme inhibition by flavonoids. Enzyme inhibition by delphinidin chloride and myricetin was suppressed by the addition of SOD, suggesting that superoxide (O2-.) is involved. However, inhibition by quercetin and morin was not sensitive to antioxidants. To further investigate the role of O2-. in GR inhibition, a superoxide generating system was utilized in the presence and absence of flavonoid. The O2-. generating system failed to inhibit GR in the absence of flavonoid but enhanced the inhibition by myricetin, indicating that the O2-. did not directly inhibit GR but reacted directly with certain flavonoids to form a reactive intermediate which, in turn, inhibited GR. These findings suggest that the mechanism of inhibition of GR by flavonoids is complex and may have oxygen-dependent and oxygen-independent components.

Antioxidants↗
PubMed1993

Molecular Responses to Photooxidative Stress in Pinus sylvestris (L.) (II. Differential Expression of CuZn-Superoxide Dismutases and Glutathione Reductase.

The influence of photooxidative stress on genes expressing superoxide dismutase (Sod) and glutathione reductase (Gor) was analyzed in needles of top and side shoots of 3-year-old Pinus sylvestris (L.) seedlings. The study was carried out in the field during spring recovery. From mid-April the top shoots of seedlings protruded above the snow and thus were exposed to sunlight, whereas the side shoots were covered with snow until May 4. Needles were sampled from top and side shoots on five different occasions. At the beginning of May the mRNA levels for cytosolic CuZn-Sod were significantly higher in top-shoot needles than in side-shoot needles. Similar results were obtained for chloroplastic CuZn-Sod mRNA. After May 6 we could not detect any significant differences between top- and side-shoot needles for either CuZn-Sod mRNA level. Transcript accumulation for the chloroplastic CuZn-Sod was up to 4-fold higher than for cytosolic CuZn-Sod in both types of shoots. On June 1 minimum transcript levels were observed for both CuZn-SOD isoforms. Protein activity analysis for CuZn-SOD isozymes did not reveal any significant differences between top- and side-shoot needles during the whole period of measurements. The mRNA level for chloroplastic Gor was similar in both types of shoots. However, the total GR activity was significantly higher in top-shoot needles than in side-shoot needles at the beginning of May. The analysis of mRNA accumulation for chloroplastic CuZn-Sod and Gor indicates that transcript levels were at least 5- to 20-fold higher for CuZn-Sod than for chloroplastic Gor. The differential expressions of Sod and Gor genes are discussed in relation to regulation of the enzymic scavenging system during photooxidative stress conditions.

Journal Article↗
PubMed1994

A designed mutant of the enzyme glutathione reductase shortens the crystallization time by a factor of forty.

The packing of glutathione reductase from Escherichia coli in crystal form T showed a place where two molecules are at a distance of only 6 A between the closest atoms, i.e. where a contact is almost made. In order to form this contact with hydrogen bonds, two amino-acid residues were exchanged. This mutation had no effect on molecular packing or the resolution limit of the X-ray diffraction, but facilitated crystal nucleation dramatically and possibly increased the crystal growth rate and shortened the crystallization time.

Journal Article↗
PubMed1983

Comparison of the three-dimensional protein and nucleotide structure of the FAD-binding domain of p-hydroxybenzoate hydroxylase with the FAD- as well as NADPH-binding domains of glutathione reductase.

The chain fold of the FAD-binding domain of p-hydroxybenzoate hydroxylase resembles the chain folds of the two nucleotide-binding domains of glutathione reductase. This fold consists of a four-stranded parallel beta-sheet sandwiched between a three-stranded antiparallel beta-sheet and alpha-helices. The nucleotides bind in similar positions relative to this chain fold. The best superposition of the folds has been established and geometrically quantified, giving rise to an equivalencing scheme for 110 residue positions, of which only four residues are identical in all three domains. It is discussed whether this chain fold is also present in a number of other FAD-binding proteins with known sequence. After the second strand of the parallel beta-sheet both FAD-binding domains contain long chain excursions, which make intimate contacts to rather distant parts of the respective molecules. In the environment of the isoalloxazine rings we observe interesting similarities. In both enzymes the si-face of this ring is covered by polypeptide, and only the re-face is accessible for the cofactor NADPH. Furthermore, there is a long alpha-helix in each enzyme, which points with its N-terminal start to the O-2 alpha region of isoalloxazine. These helices are spatially in the same position with respect to the isoalloxazine ring but are at quite different positions along the polypeptide chain. Since they can stabilize a negative charge around O-2 alpha, they may be important for the catalytic processes.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed1979

Catalase, superoxide dismutase, glutathione reductase and thiobarbituric acid-reactive products in normal and dystrophic human muscle.

The level of thiobarbituric acid-reactive products and the specific activities of catalase and glutathione reductase were significantly higher in muscles from patients with major forms of muscular dystrophies over those of control subjects. Superoxide dismutase activity was not altered in dystrophic muscles. These findings indicate the occurrence in human dystrophic muscles of an increased level of lipid peroxidation and the possible activation of certain enzymes that could conceivably inhibit lipid peroxidation in vivo.

Catalase↗
PubMed1984

Oxidised glutathione reductase activity in mouse epidermis: TPA induced change and its modulation by vitamin A.

Single cutaneous application of 12-O-tetradecanoyl-phorbol-13-acetate (TPA) increased epidermal oxidised glutathione reductase activity in adult mouse by almost 100%. Pretreatment of animals with vitamin A for a week resulted in 75% inhibition of TPA induced change in the enzyme activity which remained unaffected in skin treated with vitamin A alone. This biochemical change in skin induced by TPA and modulated by vitamin A has been discussed in relation to epidermal hyperplasia.

Animals↗
PubMedDate not supplied

[Glutathione peroxidase and glutathione reductase activity in the rat liver after the administration of sodium selenite].

Sodium selenite 24h after its single administration to rats causes an increase in the activity of glutathione peroxidase and glutathione reductase in the liver tissue. 6 h after the selenium administration the enzymes activity does not differ from the control. Doses of 0.15, 0.3, 0.5 and 1 mg of selenium per 1 kg of the animal weight were investigated. 0.3 mg proved to be the least effective dose. An increase in the enzyme activity after administering 0.5 mg of selenium is retained for 6 days and 14 days after it does not differ from the control. The liver relative weight 24 h after administration of 0.5 mg of selenium per 1 kg of animal weight proved to be higher but three days later it did not differ from the control. After administering selenium in a dose of 1 mg/kg the liver relative weight was higher for 6 days. Actinomycin D administered in a dose of 0.5 mg/kg simultaneously with selenite prevents the rise in the enzyme activity and relative weight of the liver caused only by a single injection of selenium in the same dose.

Animals↗
PubMed1977

Severe generalized glutathione reductase deficiency after antitumor chemotherapy with BCNU" [1,3-bis(chloroethyl)-1-nitrosourea].

Patients receiving BCNU [1,3-bis(2 chloroethyl)-1-nitrosourea] acquire a profound deficiency of erythrocytic oxidized glutathione reductase (GSSG-R) within minutes after the first intravenous injection of a single therapeutic dose (75 mg/M.2) of the drug. This effect is not accompanied by changes in the activites of 19 additional erythrocytic enzymes tested, is reproducible in vitro in a dose-related manner, and is not caused by the antitumor agents administered concurrently with the nitrosourea. The inactivation of erythrocytic GSSG-R results in decreased levels of reduced glutathione (GSH), marked GSH instability and disturbed hydrogen peroxide removal with a positibe ascorbate cyanide test and leads to increased susceptibility to oxidative hemolysis, particularly in glucose-6-phosphate dehydrogenase (G-6-D)-deficient patients. BCNU inhibits GSSG-R irreversibly, probably through alkylation rather than carbamylation, and the reappearance of enzyme activity in vivo after each chemotherapy pulse depends on the capacity of the marrow to release erythrocytes with normal activity formed during the drug-free interval. BCNU inhibits GSSG-R not only in erythrocytes but also in human leukocytes and platelets, as well as in yeast, monkey erythrocytes, and all the organs tested in the mouse. This generalized, severe, and specific GSSG-R deficiency caused by therapeutic doses of BCNU may enhance or mediate the toxic and antitumor effects of the nitrosourea and provides a simple yet sensitive biochemical means of monitoring bone marrow reserve in patients receiving multiple courses of chemotherapy with this agent.

Animals↗
PubMed1987

The role of glutathione reductase in maintaining human granulocyte function and sensitivity to exogenous H2O2.

Human granulocytes (polymorphonuclear leukocytes, PMN) produce H2O2 and other reactive oxygen species while undergoing phagocytosis. To examine the role of the glutathione cycle in metabolizing H2O2, we incubated PMN with 1,3-bis (2-chloroethyl) nitrosourea (BCNU). Incubation of PMN with BCNU results in a dose-dependent inhibition of PMN glutathione reductase (GRED), with 50% inhibition occurring at approximately 2 micrograms/mL BCNU. PMN hexose monophosphate shunt activity stimulated with an exogenous H2O2-generating system was inhibited only when the GRED activity was reduced to less than 30% of control. BCNU-treated cells contained lower levels of reduced sulfhydryls and reduced glutathione, which decreased even more in the presence of an exogenous H2O2-generating system. The effect of BCNU and exogenous H2O2 on various aspects of phagocytosis were examined. Exposure of BCNU-treated PMN to an H2O2-generating system resulted in an inhibition of chemotactic peptide-induced shape changes and degranulation. The ability of BCNU-treated cells to produce O2- was diminished only when the PMN were incubated with an H2O2-generating system in the presence of cyanide. Ingestion of opsonized bacteria by BCNU-treated PMN was unaffected by incubation in an H2O2-generating system even in the presence of cyanide. We conclude that PMN GRED is inhibited by BCNU, the ability of PMN to metabolize H2O2 is affected only when GRED is reduced more than 70%, this inhibition affects the glutathione content of these cells, and some, but not all of the phagocytic functions of GRED-inhibited PMN are inhibited after exposure to an H2O2-generating system.

Carmustine↗
PubMed2003

Glutathione reductase of the malarial parasite Plasmodium falciparum: crystal structure and inhibitor development.

The malarial parasite Plasmodium falciparum is known to be sensitive to oxidative stress, and thus the antioxidant enzyme glutathione reductase (GR; NADPH+GSSG+H(+) <==> NADP(+)+2 GSH) has become an attractive drug target for antimalarial drug development. Here, we report the 2.6A resolution crystal structure of P.falciparum GR. The homodimeric flavoenzyme is compared to the related human GR with focus on structural aspects relevant for drug design. The most pronounced differences between the two enzymes concern the shape and electrostatics of a large (450A(3)) cavity at the dimer interface. This cavity binds numerous non-competitive inhibitors and is a target for selective drug design. A 34-residue insertion specific for the GRs of malarial parasites shows no density, implying that it is disordered. The precise location of this insertion along the sequence allows us to explain the deleterious effects of a mutant in this region and suggests new functional studies. To complement the structural comparisons, we report the relative susceptibility of human and plasmodial GRs to a series of tricyclic inhibitors as well as to peptides designed to interfere with protein folding and dimerization. Enzyme-kinetic studies on GRs from chloroquine-resistant and chloroquine-sensitive parasite strains were performed and indicate that the structure reported here represents GR of P.falciparum strains in general and thus is a highly relevant target for drug development.

Amino Acid Sequence↗
PubMed1996

Charge is the major discriminating factor for glutathione reductase versus trypanothione reductase inhibitors.

Benson et al. (Biochem. J. 1992, 286, 9) reported three novel competitive inhibitors of trypanothione reductase (TR), which were selected to complement a hydrophobic region identified on the TR structure which was not present on human glutathione reductase (hGR). Benson et al. also noted that chlorpromazine, a tricyclic antidepressant known to have trypanocidal activity, was an inhibitor of TR. Here we show that chlorpromazine is a competitive inhibitor of TRs from Crithidia fasciculata (Ki = 14 microM) and Trypanosoma cruzi (Ki = 10 microM), but the drug binds > 50-fold more weakly (Ki = 762 microM) to hGR. Analogues of chlorpromazine differing in the length of the side chain carrying the positively charged R-group are also selective TR inhibitors whereas, a tricyclic structure carrying a negatively charged side chain is a competitive inhibitor with selectivity for hGR (K(hGR)i = 165 microM vs. K(TR)i = 1400 microM). This finding suggests that simple charge characteristics, rather than differences in hydrophobicity, may account for a significant portion of the selectivity of this series of inhibitors for these two enzymes. Electrostatic analysis of the structures of TR and hGR thus provides a rationale for these results, and offers a new principle for inhibitor design. The principle gains further support from the observation that all known tricyclic competitive inhibitors of TR are positively charged. In order to investigate the in vivo relevance of our findings we have examined the effect of chlorpromazine and its negatively charged analogue on the growth of C. fasciculata parasites. Consistent with our kinetics, chlorpromazine (50 microM) inhibited the growth of parasites by 50%, while no measurable decrease in parasite growth rate was noted in the presence of the negatively charged inhibitor (400 microM). Furthermore, the highly similar inhibitory profiles of C. fasciculata TR and T. cruzi TR suggest that drug-design studies using the structurally better-studied C. fasciculata TR are also relevant to the human pathogen T. cruzi.

Animals↗
PubMed2006

Glutathione reductase in leaves of cowpea: cloning of two cDNAs, expression and enzymatic activity under progressive drought stress, desiccation and abscisic acid treatment.

BACKGROUND AND AIMS: Reactive oxygen species are frequently produced when plants are exposed to abiotic stresses. Among the detoxication systems, two enzymes, ascorbate peroxidase and glutathione reductase (GR) play key roles. GR has also a central role in keeping the reduced glutathione pool during stress thus allowing the adjustments on the cellular redox reactions. The aim of this work was to study the variations in cytosolic and dual-targeted GR gene expression in the leaves of cowpea plants submitted to progressive drought, rapid desiccation and application of exogenous abscisic acid (ABA). METHODS: Two cowpea (Vigna unguiculata) cultivars, one drought-resistant ('EPACE-1'), the other drought-sensitive ('1183') were submitted to progressive drought stress by withholding irrigation. Cut-off leaves were air-dried or treated with exogenous ABA. Two GR cDNAs, one cytosolic, the other dual-targeted to chloroplasts and mitochondria were isolated by PCR and cloned in plasmid vectors. Reverse-transcription PCR was used to study the variations in GR gene expression. KEY RESULTS: Two new cDNAs encoding a putative dual-targeted and a cytosolic GR were cloned and sequenced from leaves of V. unguiculata. Drought stress induced an up-regulation of the expression of the cytosolic GR gene directly related to the intensity of the stress in both cultivars. The expression of dual-targeted GR was up-regulated by the drought treatment in the susceptible cultivar only. Under a fast desiccation, the '1183' cultivar responded later than the 'EPACE-1', although in 'EPACE-1' it was the cytosolic isoform which responded and in '1183' the dual-targeted one. Exogenous ABA enhanced significantly the activity and expression levels of GR in both cultivars after treatment for 24 h. CONCLUSIONS: These results demonstrate a noticeable activation in both cultivars of the antioxidant metabolism under a progressive water stress, which involves both GR genes in the case of the susceptible cultivar. Under a fast desiccation, the susceptible cultivar responded later than the resistant one, suggesting a weaker capacity of response versus the resistant one. Exogenous ABA probably acts on GR gene expression via a mediated signal transduction pathway.

Abscisic Acid↗
PubMed1984

A simple assay for monoamine oxidase using glutathione peroxidase and glutathione reductase.

A new fluorometric assay for the determination of monoamine oxidase activity that is applicable to any substrates including dopamine and serotonin is described. Hydrogen peroxide formed during the monoamine oxidase reaction was reduced in the presence of glutathione and glutathione peroxidase, and the oxidized glutathione was measured fluorometrically as NADP+ via oxidation of NADPH by glutathione reductase. This method was applied for inhibitor studies using clorgyline and deprenyl.

Animals↗
PubMed1987

[Lactate dehydrogenase, glucosephosphate dehydrogenase, glutathione reductase and adenosine triphosphatase activities in the erythrocytes of patients with acute viral hepatitis].

Some indices of erythrocyte metabolism (EM): activity of lactate dehydrogenase (LDH), glucose-6-phosphate dehydrogenase (G-6-PD), glutathione reductase (GR) and common adenosinetriphosphatase (ATPase) activity were studied in 102 patients with acute viral hepatitis (AVH). The suppression of erythrocyte enzymatic activity (EE) was revealed. It was most noticeable at the peak of average and severe AVH. In a decrease of jaundice and during reconvalescence G-6-PD, GR and ATPase activity reduced up to the control level. The suppression of LDH activity was more noticeable, maintained at discharge and was of prognostic value in investigation at early periods of disease in cases of prolonged reconvalescence. Changes in EE activity showed correlation with indices of liver function (levels of certain bilirubin fractions and transaminase activity). In cases of developing deficiency of erythrocyte G-6-PD activity there was a high correlation between a degree of cytolysis and the suppression of erythrocyte LDH activity. The importance of erythrocyte metabolic derangements revealed in AVH pathogenesis was discussed.

Acute Disease↗