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PubMed1985

Survival curves of glutathione synthetase deficient human fibroblasts: correlation between radiosensitivity in hypoxia and glutathione synthetase activity.

The role of intracellular non-protein bound sulphydryl compounds (NPSH), and in particular that of glutathione (GSH), in the response of cells to ionizing radiation under different O2 concentrations has been assessed using cell strains deficient in glutathione synthetase and exhibiting different NPSH levels. The cell strains used originated from patients with 5-oxoprolinuria and from their relatives (heterozygotes and proficient homozygotes). No correlation has been found between NPSH and GSH concentrations and radiosensitivity under oxic, aerobic and hypoxic conditions. However, a highly significant correlation has been observed between radiosensitivity under hypoxic conditions (and therefore the oxygen enhancement ratio) and the glutathione synthetase activity, suggesting that synthesis of GSH is required after irradiation. In order to explain our results we postulated, beside radical processes, the existence of a GSH-dependent enzymatic repair mechanism for N2 type damage. Hypoxic radio-sensitivity measured with survival curves would result from the interaction of both competition and biochemical repair processes.

Cell Survival↗
PubMed2007

Glutathione, glutathione peroxidase, and selenium status in HIV-positive and HIV-negative adolescents and young adults.

BACKGROUND: Antioxidant nutrient deficiencies may hasten the progression of HIV disease by impairing antioxidant defenses. OBJECTIVE: The objective of the study was to determine whether HIV infection is associated with poor selenium status and low antioxidant protection by glutathione and glutathione peroxidase (GPX). DESIGN: In a cross-sectional study of 365 HIV-positive and HIV-negative adolescents and young adults, we examined the relation of plasma selenium, whole-blood glutathione, and whole-blood GPX to HIV status, disease severity, immune activation, and oxidative damage. RESULTS: Selenium deficiency (plasma selenium < 0.070 microg/mL) was not seen in any subjects, and plasma selenium in 244 HIV-positive subjects (0.120 +/- 0.0013 microg/mL) did not differ significantly (P = 0.071) from that in 121 HIV-negative subjects (0.125 +/- 0.0020 microg/mL) . However, multiple regression analysis after adjustment for covariates showed a significant (P = 0.002) negative association between HIV-associated immune activation (plasma neopterin) and plasma selenium concentrations. GPX activity was highest in HIV-positive subjects taking antiretroviral therapy (median: 14.2; 25th, 75th percentiles: 11.1, 18.7 U/mL; n = 130), intermediate in HIV-positive subjects not taking antiretroviral therapy (11.8; 9.4, 15.1 U/mL; n = 114), and lowest in HIV-negative subjects (10.6; 8.6, 12.7 U/mL; n = 121; P < 0.05 for all comparisons). GPX was also positively associated with malondialdehyde, a marker of oxidative damage. CONCLUSIONS: Subjects had adequate selenium status, although HIV-related immune activation was associated with lower plasma selenium concentrations. GPX activity appears to have been induced by the oxidative stress associated with HIV infection and use of antiretroviral therapy. Thus, young, well-nourished subjects can mount a compensatory antioxidant response to HIV infection.

Adolescent↗
PubMed1988

Glutathione S-transferase isoenzymes and glutathione peroxidase activity in normal and tumour samples from human lung.

An increasing body of evidence suggests that glutathione-dependent enzymes are an important factor in determining the sensitivity of tumours to cytotoxic drugs. Ten randomized normal and tumour samples from individuals with lung cancer were analysed for glutathione S-transferase isoenzyme (GST) content and glutathione peroxidase (Gpx) activity. The normal tissue samples exhibited a 5.1- and 7.0-fold variation in GST and Gpx activity respectively. High levels of the pi class, acidic Yf, GST subunit were found in all the samples, with little variation between individuals. The concentration of alpha and mu class subunits was 5- to 10-fold lower and were subject to significant individual variability. The mu class subunit identified had a faster mobility on SDS-PAGE than the hepatic GST mu standard and did not appear subject to the genetic polymorphism associated with certain members of this gene family. This suggests the presence of a novel pulmonary protein which may correspond to the rat Yn Yn protein. The normal to tumour ratio for GST activity varied significantly between the samples and tended to follow the relative expression of the mu class subunit, and to a lesser extent the alpha class GST subunit. The pi subunit was present in the normal and tumour cells in very similar concentration. The expression of the mu class GST appeared to follow the differences in GST enzymic activity and although the numbers were small appeared to segregate according to tumour type. Gpx activity was also elevated in certain tumours. Of particular interest were the two adenocarcinomas which had a 20- to 30-fold higher tumour Gpx activity.

Enzyme Induction↗
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↗
PubMed2002

Induction of glutathione synthesis and glutathione reductase activity by abiotic stresses in maize and wheat.

The effect of different abiotic stresses (extreme temperatures and osmotic stress) on the synthesis of glutathione and hydroxymethylglutathione, on the ratio of the reduced to oxidised forms of these thiols (GSH/GSSG, hmGSH/hmGSSG), and on the glutathione reductase (GR) activity was studied in maize and wheat genotypes having different sensitivity to low temperature stress. Cold treatment induced a greater increase in total glutathione (TG) content and in GR activity in tolerant genotypes of both species than in sensitive ones. The GSH/GSSG and hmGSH/hmGSSG ratios were increased by this treatment only in the frost-tolerant wheat variety. High-temperature stress increased the TG content and the GSH/GSSG ratio only in the chilling-sensitive maize genotype, but GR activity was greater after this treatment in both maize genotypes. Osmotic stress resulted in a great increase in the TG content in wheat and the GR activity in maize. The amount of total hydroxymethylglutathione increased following all stress treatments. These results indicate the involvement of these antioxidants in the stress responses of wheat and maize.

Cold Temperature↗
PubMed2000

Glutathione and a UV light-induced glutathione S-transferase are involved in signaling to chalcone synthase in cell cultures.

UV irradiation stimulates expression of the gene encoding the key enzyme chalcone synthase (CHS), which leads to the generation of protective flavonoids in parsley cell cultures. CHS transcripts increase after 3 to 4 hr, and early genes are involved in the signal transduction to the CHS promoter. By using the fluorescent differential display technique in a large-scale screening, several early UV light-induced genes were isolated. Of these, a novel glutathione S-transferase (PcGST1) is induced within 2 hr and precedes CHS expression. Overexpression of PcGST1 in transformed cell lines containing a CHS promoter/luciferase reporter (CHS-LUC) affected the onset of LUC transcription. Supplementing these cell lines with glutathione immediately stimulated CHS-LUC expression within 2 hr in dark-incubated cells and resulted in a biphasic induction profile in UV-irradiated cells. Our data indicate the involvement of glutathione and PcGST1 in early events of a UV light-dependent signal transduction pathway to CHS. In this context, the oxidative status of a cell acts as a central regulating element.

Acyltransferases↗
PubMed2001

Eradication of Helicobacter pylori restores glutathione S-transferase activity and glutathione levels in antral mucosa.

Glutathione S-transferases (GST) and glutathione peroxidases (GPO) are important in detoxification. GST activity in the mucosa of the gastrointestinal tract is inversely correlated with the development of gastrointestinal cancer. Helicobacter pylori (H. pylori) infection has been associated with gastric cancer. We studied GST activity and the substrate glutathione (GSH) in patients with H. pylori-associated gastritis. GST activity and isoenzyme levels, GPO activity and GSH levels were studied in antral biopsies of 38 H. pylori-positive patients, before and after eradication treatment. In 31 patients in whom H. pylori was successfully eradicated, antral GST enzyme activity before therapy was 532 (465 - 598) nmol / mg protein. min (mean and 95% confidence interval) and that after therapy was 759 (682 - 836) nmol / mg protein. min (P < 0.0001). Correspondingly, levels of GST alpha and GST-P1 were higher after eradication (P < 0.001). GSH concentration significantly increased: 21.2 (16.2 - 26.2) nmol / mg protein before and 27.1 (23.6 - 30.6) nmol / mg protein after therapy (P < 0.05). In 7 patients in whom H. pylori was not eradicated, GST activity was 671 (520 - 823) nmol / mg protein. min and 599 (348 - 850) nmol / mg protein before and after treatment respectively (P = 0.32). GSH levels were 17.4 (9.0 - 25.7) nmol / mg protein and 18.2 (9.1 - 27.3) nmol / mg protein, respectively (P = 0.84). No differences in antral GPO enzyme activity, both of selenium (Se)-dependent and total GPO, before and after successful treatment were found. Eradication of H. pylori infection increases GST activity and GSH levels in antral mucosa. Low GST activity and GSH concentration due to H. pylori infection might play a role in gastric carcinogenesis.

Adult↗
PubMed1983

Detoxification of xenobiotics by glutathione S-transferases in erythrocytes: the transport of the conjugate of glutathione and 1-chloro-2,4-dinitrobenzene.

The incubation of human erythrocytes with 1-chloro-2,4-dinitrobenzene (CDNB) results in almost quantitative conjugation of glutathione (GSH) to form S-(2,4-dinitrophenyl) glutathione. The reaction is catalysed by erythrocyte glutathione S-transferase. During the present studies we have identified the conjugate in the incubation medium of CDNB-treated erythrocytes, indicating that the conjugate of GSH and CDNB is transported out by the erythrocytes. Quantitation of the conjugate in the incubation medium by amino acid analysis and thin layer chromatography indicates that the erythrocytes transport the conjugate at an approximate rate of 140 nmol/h/ml erythrocytes. The transport of the conjugate is inhibited by sodium fluoride. Exhaustion of ATP from the erythrocytes results in a significant decrease in the rate of transport which is restored with the regeneration of ATP by incubating the erythrocytes with adenine and inosine. This indicates that the transport of conjugate is an energy dependent process.

Adenosine Triphosphate↗
PubMed1993

Electrostatic evidence for the activation of the glutathione thiol by Tyr7 in pi-class glutathione transferases.

A number of spectrophotometric studies [Graminski, G.F., Kubo, Y. & Armstrong, R.N. (1989) Biochemistry 28, 3562-3568; Liu, S., Zhang, P., Ji, X., Johnson, W.W., Gilliland, G.L. & Armstrong, R.N. (1992) J. Biol. Chem. 267, 4296-4299] have recently shown that the glutathione (GSH) thiol is deprotonated when it is in complex with glutathione S-transferase. Different models have been proposed for the activation of the glutathione S gamma, all pointing out the key role of active-site residue Tyr7. It remains unclear, however, how Tyr7 is actually involved in this process. In this paper we present an analysis of the electrostatic potential in the region of the active site of a pi-class GSH transferase. This analysis provides evidence that the titration behaviour of the absorption band of the E.GSH complex with a pK between 6 and 7 [Liu, S., Zhang, P., Ji, X., Johnson, W.W., Gilliland, G.L. & Armstrong, R.N. (1992) J. Biol. Chem. 267, 4296-4299] should rather be explained by the protonation/deprotonation equilibrium of Tyr7 than by the protonation/deprotonation equilibrium of the GSH thiol group itself. On the basis of this conclusion, a mechanism for activation of GSH is proposed: the Tyr7 OH group is deprotonated by the influence of the protein charge constellation and the peptide dipoles. Thus it acts as a general base, promotes proton abstraction from the GSH thiol and creates a thiolate anion with high nucleophilic reactivity.

Animals↗
PubMed1997

The malaria parasite supplies glutathione to its host cell--investigation of glutathione transport and metabolism in human erythrocytes infected with Plasmodium falciparum.

Malaria-infected red blood cells are under a substantial oxidative stress. Glutathione metabolism may play an important role in antioxidant defense in these cells, as it does in other eukaryotes. In this work, we have determined the levels of reduced and oxidized glutathione (GSH and GSSG, respectively) and their distributions in the parasite, and in the host-cell compartments of human erythrocytes infected with the malaria parasite Plasmodium falciparum. In intact trophozoite-infected erythrocytes, [GSH] is low and [GSSG] is high, compared with the levels in normal erythrocytes. Normal erythrocytes and the parasite compartment display high GSH/GSSG ratios of 321.6 and 284.5, respectively, indicating adequate antioxidant defense. This ratio drops to 26.7 in the host-cell compartment, indicating a forceful oxidant challenge, the low ratios resulting from an increase in GSSG and a decline in GSH concentrations. On the other hand, the concentrations of GSH and GSSG in the parasite compartment remain physiological and comparable to their concentrations in normal red blood cells. This results from de novo glutathione synthesis and its recycling, assisted by the intensive activity of the hexose monophosphate shunt in the parasite. A large efflux of GSSG from infected cells has been observed, its rate being similar from free parasites and from intact infected cells. This result suggests that de novo synthesis by the parasite is the dominating process in infected cells. GSSG efflux from the intact infected cell is more than 60-fold higher than the rate observed in normal erythrocytes, and is mediated by permeability pathways that the parasite induces in the erythrocyte's membrane. The main route for GSSG efflux through the cytoplasmic membrane of the parasite seems to be due to a specific transport system and occurs against a concentration gradient. Gamma-glutamylcysteine [Glu(-Cys)] and GSH can penetrate through the pathways from the extracellular space into the host cytosol, but not into that of the parasite. This implies that the parasite membrane is impermeable to these peptides, and that the host cannot supply GSH to the parasite as suggested previously. Exogenous Glu(-Cys) is not converted into GSH in the host cell, arguing that GSH synthetase may not be functional. Compartment analysis of Mg2+ in infected erythrocytes revealed that the host compartment exhibits a low concentration of Mg2+ (0.5 mM) in comparison with the parasite compartment (4 mM) and the normal erythrocytes (1.5-3 mM). The drop in [Mg2+] results in cessation of Glu(-Cys) synthesis, and hence of GSH synthesis in the host-cell compartment. The decrease in [Mg2+] can affect other Mg2+-ATP-dependent functions, such as Na+ and Ca2+ active efflux. The present investigation confirms that the host-cell compartment is oxidatively distressed, whereas the parasite is efficiently equipped with anti-oxidant means that protect the parasite from the oxidative injury. The parasite has a huge capacity for de novo synthesis of GSH and for the reduction of GSSG. Part of the GSSG that is actively extruded from the parasite is reduced to GSH in the host cell whose own GSH synthesis is crippled.

Animals↗
PubMed1999

Increased glutathione and glutathione peroxidase in lungs of individuals with chronic beryllium disease.

Reactive oxygen species (ROS) are mediators of chronic tissue damage and fibrosis. Endogenous antioxidants may increase in response to oxidants and reduce tissue injury. We investigated the antioxidant response of the lungs to the chronic release of ROS, as occurs in the immune-specific granulomatous inflammation of chronic beryllium disease (CBD), and compared it with that in healthy controls and individuals exposed to cigarette smoke. The antioxidants superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione (GSH) were quantitated in lung epithelial lining fluid (ELF) and serum from control subjects (n = 10), cigarette smokers (n = 8), and individuals with CBD (n = 9). GPx activity and extracellular GPx (eGPx) protein were increased in the ELF of subjects with CBD in comparison with that of control subjects and smokers (eGPx in ELF: controls, 1.3 +/- 0.2 microgram/ml, smokers, 1.9 +/- 0.3 microgram/ml, CBD, 3.8 +/- 0.8 microgram/ml; p = 0.002; GPx U/ml ELF, controls 1.4 +/- 0.3, smokers 1.8 +/- 0.4, CBD, 4.5 +/- 1, p = 0.02). Smokers' ELF had higher levels of GSH than that of controls, but CBD patients' ELF contained much more GSH than that of either controls or smokers (p < 0.001). Increases in GSH were correlated with eGPx, indicating similar inducing mechanisms for these antioxidants. Thus, coordinate augmentation of the glutathione antioxidant system occurs in granulomatous lung inflammation.

Adolescent↗
PubMedDate not supplied

Beneficial effects of allopurinol on glutathione levels and glutathione peroxidase activity in rat ischaemic acute renal failure.

The protective effect of allopurinol, an inhibitor of the enzyme, xanthine oxidase, against the renal ischaemia-reperfusion of the rat was investigated. Rats were subjected to renal ischaemia by clamping of the left renal artery and vein for 45 min, and were then reperfused for 24 h; these animals were randomized to receive either saline (n = 10) or allopurinol (n = 10) at a dose of 50 mg/kg bolus intraperitoneally 5 min before reperfusion. The control group comprised seven healthy rats not exposed to ischaemia or reperfusion. The blood urea nitrogen and plasma creatinine levels were increased in the allopurinol group, but the increase was less than that in the placebo group, compared with the controls. The kidney glutathione level was significantly reduced in the placebo group but not in the allopurinol group compared with the controls. The glutathione peroxidase activity in the kidney tissues was reduced more than two-fold in the placebo group compared with the controls, but the reduction in glutathione peroxidase was considerably less in the allopurinol group. Renal tissue lactate dehydrogenase, aspartate amino-transferase, gamma-glutamyl transferase and alkaline phosphatase activities were reduced almost two-fold in the placebo group, but allopurinol treatment maintained these enzyme activities close to the control activities. These results provide evidence that allopurinol treatment may have beneficial effects on antioxidant defences against ischaemia-reperfusion injury of rat kidneys.

Acute Kidney Injury↗
PubMed2003

Multiple roles of glutathione binding-site residues of glutathione s-transferase.

This study was designed to characterize residues in the glutathione binding site of AdGSTD4-4 from the mosquito malaria vector Anopheles dirus. The data revealed that Leu33, His38 and His50 each play a role in enzyme catalysis and glutathione binding. The mutants of these three residues also displayed differences in hydrophobic substrate specificity, suggesting that changes in the active site conformation occurred. Differences in conformations was also suggested by protein stability changes. These results indicate that residues in the glutathione binding site are not only important in the catalytic function but also play a role in the structural integrity of the enzyme.

Animals↗
PubMed1980

Glutathione-peroxidase and glutathione-reductase activities of normal and pathologic human liver: relationship with age.

Liver glutathione-peroxidase (L-GSH-Px) and glutathione-reductase (GSSG-Red) activities were measured in supernatants of liver tissues obtained from a total of 36 subjects. Sixteen of these patients had a functionally normal liver (control group), whereas of the remaining 20 patients, 10 were cirrhotic and 10 had a liver disease other than cirrhosis. The mean value of L-GSH-Px of the control group was 33.12 +/- 12.66 U/g protein, a value similar to that found in patients with liver disease. The L-GSH-Px of the control group was positively correlated with the age of the subjects (r = 0.620; p less than 0.02). In contrast, in patients with liver disease an opposite behaviour of the two parameters was noted (r = -0.497; p less than 0.05). L-GSH-Px activity tended to be higher in males than in females, whereas the erythrocyte glutathione-peroxidase (E-GSH-Px) of the same patients was higher in females, albeit not significantly. L-GSH-Px and E-GSH-Px were not correlated either in normal or in liver disease. The mean GSSG-Red of the control group was 40.63 +/- 11.10 U/g protein, which is not different from that of the group of liver patients. GSSG-Red was not correlated with L-GSH-Px or with the age of patients. In two patients with hepatoma, the GSH-Px activity of the cancer tissue was low and the GSSG-Red activity high.

Adult↗
PubMed1993

Significance of an unusually low Km for glutathione in glutathione transferases of the alpha, mu and pi classes.

1. Interactions of glutathione transferases (GST) of the alpha, mu and pi classes with glutathione (GSH) and glutathione conjugates (GS-X) are in contrast with those of a GST of the theta class (GST5-5). 2. GST 5-5 has a Km for GSH of approx. 5 mM. Thus Km/ambient [GSH] is approx. 1, within the range of Km/ambient [s] of glycolytic enzymes. GSTs of the alpha, mu and pi classes yield much lower values of Km for GSH (approx. 0.1 mM) hence Km/ambient [s] is significantly lower than those of most (non-GST) enzymes (p < 0.025). 3. GSTs of the alpha, mu and pi classes are sensitive to inhibition by GS-X (i.e. product) and GS-X analogues. GST 5-5 is not. 4. Rate enhancements up to 10(10), similar to an average enzyme (10(8)-10(12)), are seen in catalysis by GST 5-5, but not in catalysis by GSTs of alpha, mu and pi classes (> 10(7)). 5. Comparisons of primary structure indicate that theta class GSTs may have a decreased binding of the glu-alpha-amino- and gly-COO(-)-groups of GSH compared with GSTs of the other classes. 6. It is concluded that GSTs of alpha, mu and pi classes have evolved towards increased product binding at the expense of catalytic efficiency. Thus GSH is uniquely utilized both as a nucleophile and a 'tag' which can be used to bind and sequester product particularly during GSH-depletion. This interpretation unifies the catalytic and binding properties of these GSTs and alters their perceived role in detoxication.

Adaptation, Physiological↗
PubMed1993

Ethacrynic acid and its glutathione conjugate as inhibitors of glutathione S-transferases.

1. The diuretic drug ethacrynic acid (EA) is a potent reversible inhibitor of rat and human glutathione S-transferases (GST), with I50-values (microM) of 4.6-6.0, 0.3-1.9 and 3.3-4.8 for alpha, mu and pi-class, respectively. 2. The reversible inhibition by the glutathione conjugate of EA is even stronger for alpha and mu-class, with I50-values (microM) of 0.8-2.8 and < 0.1-1.2, respectively, while the I50 for the pi-class is 11. 3. Inhibition of rat and human pi-class GST also occurs by covalent binding of ethacrynic acid. 14C-ethacrynic acid, 0.8 nmol EA per nmol pi-class GST could be incorporated, resulting in 65-93% inhibition of the catalytic activity. 4. Owing to the chemical nature of the covalent binding (Michael addition), this reaction should be reversible. Indeed, full restoration of the catalytic activity of GST P1-1 inactivated by covalently-bound EA was reached in about 125 h by incubation with an excess of glutathione. 5. EA has been used to inhibit GST in biological systems. The reversible covalent binding may very well play a role in the observed inhibition of GST by EA in vivo.

Animals↗
PubMed1990

Increased reduced glutathione and glutathione S-transferase activity in chronic cephaloridine nephrotoxicity studies in the rat.

The effect of repeated cephaloridine treatment on renal glutathione and related enzymes has been investigated in young adult male and female Sprague-Dawley rats. Animals were given intraperitoneally daily doses of either 750 mg/kg for two weeks or 500 or 750 mg/kg for three months. Measurement of blood and urinary parameters (electrolytes, urea, creatinine) did not reveal any renal function impairment and histological examination confirmed the absence of renal damage. By contrast, an increase in reduced glutathione (2 to 3-fold) and glutathione S-transferase activity (1.5 to 2-fold) was observed. These results are consistent with the development of an adaptative phenomenon to cephaloridine subchronic treatment in the rat, leading to a tolerance to high repeated doses.

Acetylglucosaminidase↗