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PubMed1995

Kinetic analysis of glutathione in anchored cells with monochlorobimane.

A method for the measurement of intracellular glutathione content and glutathione S-transferase activity with monochlorobimane in adherent cells is described. The method involves the kinetic analysis of monochlorobimane conjugation to glutathione over a relatively short period of time. This permits extrapolation over time for determination of equilibrium fluorescence intensity (relative glutathione level) from scan intensity data that follows first-order kinetics, minimizing problems commonly associated with the use of monochlorobimane. By using measured fluorescence intensity values from glutathione standards, a suspension calibration curve was generated and, subsequently, was used to determine the photomultiplier tube saturation rate. A theoretical intracellular calibration curve was then generated to quantify glutathione content in cells. This method was also applied to study the changes in glutathione in a variety of rodent and human cell lines and in selected cocultures of cells exhibiting similar or different glutathione levels. Comparison of the glutathione levels obtained with monochlorobimane and a standard colorimetric method (GSH-400) indicated good correlation between the two methods. These studies support the use of laser cytometry for measuring intracellular glutathione with monochlorobimane as well as changes in glutathione occurring in cells that establish physical contacts with other cells. Laser cytometric analysis of glutathione in anchored cells also provides opportunities to monitor individual cellular responses to a variety of experimental manipulations, such as responses to various toxic insults or the protective effects of gap junction-mediated intercellular communication.

Animals↗
PubMed1991

Evidence for stimulated glutathione synthesis by phenobarbital pretreatment during an oxidative challenge in isolated hepatocytes.

Hepatocytes isolated from phenobarbital-pretreated and naive male Sprague-Dawley rats were preincubated with 80 microM N, N-bis (2-chloroethyl)-N-nitrosourea and subsequently exposed to varying concentrations of menadione. We observed that the reduced glutathione levels of the hepatocytes isolated from the sodium phenobarbital(PB)-pretreated, but not the naive rats, recovered to near-control levels after exposure to 200 microM menadione. Since this recovery occurred in the presence of N, N-bis (2-chloroethyl)-N-nitrosourea (an inhibitor of glutathione reductase), we hypothesized that this represented a PB-mediated increase in de novo synthesis of glutathione. To test this hypothesis and to further assess the possible contribution of glutathione reductase in the recovery of the glutathione levels, we preincubated hepatocytes isolated from PB-pretreated and naive rats with 2 mM buthionine sulfoximine, with or without N, N-bis (2-chloroethyl)-N-nitrosourea. Following exposure to menadione, samples were periodically removed for glutathione assessment. Consistent with our hypothesis, the addition of buthionine sulfoximine abrogated the ability of the PB-pretreated hepatocytes to restore glutathione levels following a menadione challenge. Buthionine sulfoximine in combination with N, N-bis (2-chloroethyl)-N-nitrosourea completely abolished hepatocellular glutathione homeostasis for all of the concentrations of menadione employed. The findings from this investigation underscore the importance of phenobarbital-mediated increases in glutathione synthesis, as well as the enhanced levels of glutathione reductase, in maintaining the pool of reduced glutathione and ultimately mitigating the consequences of oxidative stress. In addition, these findings suggest that PB pretreatment increases the reserve capacity of the hepatocyte for glutathione synthesis via a hitherto undescribed hormetic mechanism, a reserve expressed fully only on an oxidative stress of sufficient magnitude.

Animals↗
PubMed1984

Differential changes of glutathione S-transferase activity by dietary selenium.

Dietary selenium deficiency produced increased activity of the glutathione S-transferases in the liver, kidney and duodenal mucosa. In these tissues, the residual activity of total glutathione peroxidase that included selenium-independent activity was considerably higher than that of selenium-dependent glutathione peroxidase. The enhanced activity of glutathione S-transferases was restored to control level 48 hr after an injection of selenite equivalent to the amount of daily selenium intake. Under the same conditions, selenium-dependent glutathione peroxidase activity increased with time and reached 11.9, 11.6 and 46.2% of the activity in the liver, kidney and duodenal mucosa of selenium-supplemented rats, respectively, 48 hr after selenite injection, whereas total glutathione peroxidase activity was not altered except in the kidney. These differential changes of glutathione S-transferase activity were intimately related to those of selenium-dependent glutathione peroxidase activity produced by selenium depletion and repletion, suggesting that the glutathione S-transferase activity was regulated by dietary selenium. Present findings support the idea that glutathione S-transferases having selenium-independent glutathione peroxidase activity function as a substitute for selenium-dependent glutathione peroxidase in selenium-deficient rats.

Animals↗
PubMed1988

Glutathione depletion by naphthalene in isolated hepatocytes and by naphthalene oxide in vivo.

Previous studies have shown that naphthalene oxide and reactive naphthalene metabolites diffuse from intact, isolated hepatocytes. The amount of naphthalene oxide diffusing from the cells as a percentage of the total formed remained constant over a wide range of substrate concentrations, thus suggesting that depletion of glutathione might not be required prior to significant naphthalene oxide efflux. However, the relative intracellular versus extracellular covalent binding of reactive metabolites increased with increasing naphthalene concentrations, thereby suggesting that glutathione might be involved in modulating the extent of intracellular covalent binding. To examine this question in detail, intracellular glutathione levels were monitored in mouse hepatocytes incubated in the presence of various concentrations of naphthalene. Naphthalene produced a concentration- and time-dependent decrease in intracellular glutathione levels and, at higher concentrations, a marked decrease in the rate of glutathione efflux from hepatocytes. This decrease in hepatocellular glutathione levels correlated well with the shift in binding from predominantly extracellular to intracellular. Inclusion of glutathione and glutathione transferases in the cell incubation medium partially blocked the depletion of intracellular glutathione by naphthalene, thus suggesting that naphthalene oxide diffusing into the cell medium was partially responsible for intracellular glutathione depletion. Finally, in vivo administration of naphthalene oxide to mice produced a dose-dependent depletion of pulmonary but not hepatic or renal glutathione but only at doses that were greater than 75 mg/kg. These studies support the view that there is not a glutathione threshold for the efflux of naphthalene oxide from intact hepatocytes and suggest that naphthalene oxide is capable of diffusing into as well as out of isolated hepatocytes.

Animals↗
PubMed1975

Acid-volatile selenium formation catalyzed by glutathione reductase.

The production of acid-volatile selenide (apparently H2Se) was catalyzed by glutathione reductase in an anaerobic system containing 20 mM glutathione, 0.05 mM sodium selenite, a TPNH-generating system, and microgram quantities of highly purified yeast glutathione reductase. H2Se production in this system was proportional to glutathione reductase concentration and was maximal at pH 7. Significant nonenzymic H2Se production occurred in the system lacking glutathione reductase and TNPH. A concentration of arsenite (0.1 mM) which does not inhibit glutathione reductase inhibited selenide volatilization, as did bovine serum albumin (1.67 mg/ml). Both appear to inhibit Se volatilization by reacting with the selenide product(s). The selenotrisulfide derivative of glutathione (GSSeSG) was readily converted to H2Se by glutathione reductase and TPNH without the addition of glutathione. These results suggest that GSSeSG formed nonenzymically from glutathione and selenic undergoes stepwise reduction by glutathione reductase (or excess GSH) to GSSeH and finally to H2Se. The same pathway operates when glutathione is used as the reducing agent but to a lesser extent.

Animals↗
PubMed2004

Dehydroascorbate influences the plant cell cycle through a glutathione-independent reduction mechanism.

Glutathione is generally accepted as the principal electron donor for dehydroascorbate (DHA) reduction. Moreover, both glutathione and DHA affect cell cycle progression in plant cells. But other mechanisms for DHA reduction have been proposed. To investigate the connection between DHA and glutathione, we have evaluated cellular ascorbate and glutathione concentrations and their redox status after addition of dehydroascorbate to medium of tobacco (Nicotiana tabacum) L. cv Bright Yellow-2 (BY-2) cells. Addition of 1 mm DHA did not change the endogenous glutathione concentration. Total glutathione depletion of BY-2 cells was achieved after 24-h incubation with 1 mm of the glutathione biosynthesis inhibitor l-buthionine sulfoximine. Even in these cells devoid of glutathione, complete uptake and internal reduction of 1 mm DHA was observed within 6 h, although the initial reduction rate was slower. Addition of DHA to a synchronized BY-2 culture, or depleting its glutathione content, had a synergistic effect on cell cycle progression. Moreover, increased intracellular glutathione concentrations did not prevent exogenous DHA from inducing a cell cycle shift. It is therefore concluded that, together with a glutathione-driven DHA reduction, a glutathione-independent pathway for DHA reduction exists in vivo, and that both compounds act independently in growth control.

Apoptosis↗
PubMed1991

Roles of catalase and the glutathione redox cycle in the regulation of anterior-chamber hydrogen peroxide.

The effects of inhibition of both glutathione synthesis and of glutathione reductase and catalase activities have been determined in the regulation of hydrogen peroxide (H2O2) in the anterior chamber of pigmented rabbits. Glutathione reductase inhibition using intravitreal 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) did not significantly alter either total glutathione or the percent oxidized glutathione fraction in the iris-ciliary body. Intravitreal buthionine sulfoximine (BSO) significantly reduced the total glutathione content of iris-ciliary body and corneal endothelium, while not altering the oxidized fraction. BCNU increased the oxidized fraction of glutathione in the aqueous humor from 22 to 63% without significantly altering total glutathione levels. BSO, however, reduced total glutathione by 70% in the aqueous humor, and the oxidized fraction doubled. Decreases in the reduced glutathione concentration caused by BSO correlate with increases in the normally stable ratio of H2O2 to ascorbate concentrations in the aqueous humor, strongly suggesting that glutathione metabolism is correlated with H2O2 regulation at endogenous levels of this oxidant. Both BSO and 3-aminotriazole (3AT) separately increased the half-time for the loss of exogenously added H2O2 from the anterior chamber. BSO increased the half-time by 77% after 10 microliters of 10 mM H2O2 was injected intracamerally, while suppression of catalase activity with 3AT increased it by only 40%. With intracameral injections of 10 microliters of either 25 or 50 mM H2O2, however, 3AT had a greater effect than BSO. The half-time values after 3AT pretreatment were 61 and 135% greater than control values at the concentrations of 25 and 50 mM H2O2, respectively; those after BSO pretreatment were at 14 and 78%. From these data we conclude that the glutathione redox system protects the anterior segment tissues from hydrogen peroxide at low concentrations of this oxidant, while catalase assumes a greater role at higher concentrations of hydrogen peroxide.

Amitrole↗
PubMed2003

Inhibition of glutathione synthesis reverses Bcl-2-mediated cisplatin resistance.

Cisplatin is a potent cytotoxic agent that functions as a bivalent electrophile, forming both interstrand and intrastrand DNA cross-links. Cisplatin-mediated DNA damage results in cell cycle arrest and initiation of apoptotic cell death. Increased cellular glutathione concentrations have been closely correlated with cisplatin resistance but do not reduce the extent of cisplatin-DNA adduct formation. One hypothesis to explain the ability of glutathione to inhibit cisplatin cytotoxicity is that glutathione, through its antioxidant function, plays a role in apoptotic regulatory pathways. We tested this hypothesis using MCF-7 breast cancer cells transfected with the apoptotic inhibitor Bcl-2. Bcl-2 overexpression in MCF-7 cells was associated with a nearly 3-fold increase in cellular glutathione levels and with increased resistance to cell death after cisplatin exposure. Treatment of MCF-7 lines with buthionine sulfoximine, an inhibitor of glutathione synthesis, normalized glutathione levels in Bcl-2 and control transfectants and completely abrogated Bcl-2-mediated cisplatin resistance without affecting Bcl-2 expression. Bcl-2 overexpression and up-regulation of glutathione were not associated with a change in either cisplatin-DNA adduct formation or repair over time. These results suggest that Bcl-2-mediated cisplatin resistance in MCF-7 cells is dependent on up-regulation of glutathione production, which contributes to cell survival by mechanisms independent of cisplatin inactivation or inhibition of DNA adduct formation. A similar dependence on glutathione for Bcl-2-mediated inhibition of cisplatin toxicity was confirmed in a second cell line, the lymphocytic precursor FL5.12. Taken together, these data suggest that apoptotic signaling after genotoxic exposure can be inhibited by the antioxidant activity of glutathione. Inhibition of glutathione synthesis or modulation of glutathione stores in tumors that overexpress Bcl-2 may comprise a novel anticancer strategy.

Antineoplastic Agents↗
PubMed1996

Changes in glutathione metabolic enzymes during yeast-to-mycelium conversion of Candida albicans.

Candida albicans is a dimorphic yeast capable of producing alternate morphological forms (yeast or mycelium) in response to environmental changes. The intracellular level of glutathione, which helps to maintain the redox potential of the cell, is decreased significantly during the thermal induction of yeast-to-mycelium conversion. The reason for the decline of glutathione in the mycelial form is not understood. We have, therefore, investigated the levels of glutathione reductase, glutathione S-transferase, gamma-glutamyltranspeptidase, and glutathione peroxidase, four key enzymes involved in glutathione metabolism, in the yeast and mycelial forms. Yeast cells of C. albicans 3153A were induced in Lee's medium (pH 6.5) at 37 degrees C for 3 h to produce germ tubes. Cell lysates were prepared from yeast and mycelial cells, and glutathione reductase, glutathione S-transferase, gamma-glutamyltranspeptidase, and glutathione peroxidase were assayed spectrophotometrically. There was a 640% increase of the level of gamma-glutamyltranspeptidase in the germ tubes as compared with the yeast cells. No other significant alteration of the levels of enzymes was noted. This increased activity of gamma-glutamyltranspeptidase, which cleaves the glutamic acid residue of glutathione (Glu-Cys-Gly) appears to be, at least in part, responsible for the rapid decrease of the intracellular glutathione in C. albicans during the yeast-to-mycelium conversion.

Amino Acid Sequence↗
PubMedDate not supplied

Glutathione metabolism in heart and liver of the aging rat.

A comprehensive study on glutathione metabolism in rat heart and liver as a function of age was performed. In the heart, reduced glutathione, total glutathione, and the glutathione redox index showed a decrease during aging, while oxidized glutathione levels increased in 5-month-old rats with respect to the young animals and remained quite constant in 14- and 27-month-old rats. In the liver, the highest levels of reduced glutathione were found in the 2-month-old rats, while oxidized glutathione reached a peak at 5 months. Glutathione-associated enzymes showed age-related changes. Glutathione peroxidase, unaffected by aging in the heart, decreased in the liver of the 27-month-old rats. In the heart and the liver, the highest values of glutathione S-transferase were found at 5 months and 27 months, respectively. Glucose-6-phosphate dehydrogenase followed a similar trend in both heart and liver. Glutathione reductase also showed the same behaviour in heart and in liver, increasing in old rats with respect to the other age groups. A decrease in gamma-glutamylcysteine synthetase was found in the heart and liver of 27-month-old rats in comparison with the 2-month-old ones. In conclusion, a decreased antioxidant capability has been demonstrated in both heart and liver of old rats.

Aging↗
PubMed1992

Glutathione-related enzyme activities and lipoperoxide levels in human internal mammary artery and ascending aorta. Relations with serum lipids.

The relation among glutathione-related enzyme activities, thiobarbituric acid-reactive substances of the human aorta and internal mammary artery, and serum lipids was studied in 40 male patients undergoing coronary revascularization. Glutathione peroxidase and glutathione reductase activities were significantly higher in the internal mammary artery, whereas glutathione transferase activity was elevated in the aortic wall. Moreover, non-selenium-dependent glutathione peroxidase activity was detectable only in the aorta. The levels of thiobarbituric acid-reactive substances were significantly higher in the aorta. A positive correlation was found among the activity of glutathione peroxidase, glutathione reductase, and thiobarbituric acid-reactive substances in the internal mammary artery and total cholesterol, low density lipoprotein cholesterol, and triglycerides. In the aortic wall, a positive correlation among the activity of glutathione peroxidase, glutathione transferase, thiobarbituric acid-reactive substances, and the previously mentioned serum lipids was evident. In contrast, high density lipoprotein cholesterol was inversely related to enzymatic activities and thiobarbituric acid-reactive substances in both the internal mammary artery and aorta. In conclusion, significant differences in the levels of glutathione-related enzyme activities and thiobarbituric acid-reactive substances in the internal mammary artery and aorta were found, suggesting a different ability of the two tissues to counteract oxidative stress: the glutathione-related antioxidant properties and the level of lipid peroxidation in the arterial tissue seem to be specifically influenced by serum lipids.

Adult↗
PubMed2002

New model of glutathione deficit during development: Effect on lipid peroxidation in the rat brain.

Glutathione is a major regulator of the redox equilibrium, so its deficit weakens tissue resistance to oxidants. The nervous system is particularly susceptible to oxidative insults and is therefore very dependent on its glutathione content, especially during development, when brain metabolism and growth are maximal. In addition, various pathologies affecting the nervous system involve oxidative stress, possibly associated with a diminution of glutathione concentrations. To study the involvement of glutathione in brain redox homeostasis, we set up an experimental model of chronic glutathione deficit. Developing rats were treated daily with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and their brain levels of glutathione and lipid peroxidation products (TBARS) were measured. BSO induced a 40-50% glutathione deficit in the cortex, diencephalon, and pons/medulla. Despite the glutathione deficit induced by BSO, we did not observe any signs of oxidative stress. Because it is known that rats compensate for a glutathione deficit by enhancing their synthesis and tissue levels of ascorbic acid (AA), we performed the same experiment in osteogenic-disorder Shionogi (ODS) rats, a mutant strain that cannot synthetize AA. Although BSO induced a glutathione deficit of comparable intensity in the two strains of rats, it elevated TBARS levels in the diencephalon and pons/medulla only in ODS and not in nonmutant rats. These results suggest that ODS rats, which closely mimic the human redox regulation, will allow study of the long-term consequences of chronic glutathione deficit observed in various clinical situations.

Animals↗
PubMed1985

Effect of selenium deficiency on the disposition of plasma glutathione.

Selenium deficiency causes increased hepatic synthesis and release of GSH into the blood. The purpose of this study was to examine the effect of selenium deficiency on the disposition of plasma glutathione. Plasma glutathione concentration was 40 +/- 3.4 nmol GSH equivalents/ml in selenium-deficient rats and 17 +/- 5.4 nmol GSH equivalents/ml in control rats. The half-life and systemic clearance of plasma glutathione were found to be the same in selenium-deficient and control rats (t1/2 = 3.4 +/- 0.7 min). Because selenium-deficient plasma glutathione concentration was twice that of control, the determination that selenium deficiency did not affect glutathione plasma systemic clearance indicated that the flux of glutathione through the plasma was doubled by selenium deficiency. It has been proposed that the kidney is responsible for the removal of a major fraction of plasma glutathione. In these studies, renal clearance accounted for 24% of plasma systemic glutathione clearance in controls and 44% in selenium-deficient rats. This indicates that a significant amount of glutathione is metabolized at extrarenal sites, especially in control animals. More than half of the increased plasma glutathione produced in selenium deficiency was removed by the kidney. Thus, selenium deficiency results in a doubling of cysteine transport in the form of glutathione from the liver to the periphery as well as a doubling of plasma glutathione concentration.

Animals↗
PubMed1992

Studies on the activation of rat liver microsomal glutathione transferase in isolated hepatocytes.

The mechanism of activation of microsomal glutathione transferase in isolated liver cells by diisapropylidene acetone (phorone) was investigated. Phorone (1 mM) causes a time-dependent increase (up to 2.6-fold) in the glutathione transferase activity of microsomes isolated from treated hepatocytes. Since phorone reacts with sulfhydryl groups, the possibility that this compound activated microsomal glutathione transferase directly was studied. It was found that neither the activity of the purified enzyme nor that in isolated microsomes is affected by phorone. It has been suggested [Masukawa T and Iwata H, Biochem Pharmacol 35: 435-438, 1986] that activation of microsomal glutathione transferase by phorone in vivo is mediated through thiol-disulfide interchange involving oxidized glutathione (GSSG). It is shown here that the glutathione transferase activity of isolated microsomes, which was increased by the addition of 10 mM GSSG, can be decreased to the basal level with 0.1 M dithioerythritol. Dithioerythritol, on the other hand, only marginally decreases the glutathione transferase activity in microsomes isolated from phorone-treated hepatocytes. This finding argues against a role for thiol-disulfide interchange in the activation of the enzyme by phorone. Furthermore, the glutathione depletion caused by phorone does not seem to be responsible for activation per se, since other thiol depletors [e.g. diethylmaleate (DEM)] do not affect the activity of the enzyme. Immunoblot analysis of microsomes isolated from phorone-treated hepatocytes did not reveal any partial proteolysis which might have accounted for the activation. It is suggested that activation of microsomal glutathione transferase by phorone proceeds through a mechanism which might reflect an in vivo regulation of this enzyme. Additional compounds which have been shown to activate the microsomal glutathione transferase in vivo were also tested and significant activation was obtained with 1,2-dibromoethane (1.4-fold) but not with DEM or carbon tetrachloride. Activation was also obtained with 1-chloro-2,4-dinitrobenzene (CDNB) (1.6-fold) and to a small extent with t-butyl hydroperoxide (1.2-fold). The activation by 1,2-dibromoethane and CDNB is probably mediated through covalent binding, considering the known alkylating properties of these compounds. CDNB is the first substrate shown to activate the microsomal glutathione transferase implying that electrophilic compounds which are substrates can increase the rate of their own elimination by reacting with this enzyme. In addition, activation by t-butyl hydroperoxide indicates that oxidative stress can activate microsomal glutathione transferase.

Animals↗
PubMed1989

Glutathione depletion and cytotoxicity by naphthalene 1,2-oxide in isolated hepatocytes.

The ability of naphthalene 1,2-oxide to diffuse across intact cellular membranes, the subsequent biotransformation of this epoxide and its potential to produce losses in cellular viability have been examined in incubations of isolated hepatocytes. Addition of 1R,2S- or 1S,2R-naphthalene oxide enantiomers (15, 30 and 60 microM) to isolated hepatocytes resulted in a rapid depletion of intracellular glutathione. Depletion of glutathione was concentration dependent and maximal at 5-15 min. Addition of either of the enantiomeric oxides at 60 microM resulted in the loss of more than 20 nmol glutathione/10(6) cells (1 ml cells); thus more than a third of the added epoxide was available for conjugation with intracellular glutathione. The time course and concentration dependence of glutathione depletion corresponded to the rapid, concentration-dependent formation of naphthalene oxide glutathione conjugates. The levels of glutathione adduct were highest 1 min after addition of naphthalene oxide and declined to 25% of this level after 30 min. Loss of glutathione conjugates from incubations correlated with the formation of N-acetylcysteine adducts. In contrast, the levels of glutathione adducts added exogenously to hepatocytes were relatively stable over a 120-min incubation suggesting that although further metabolism of naphthalene oxide glutathione adducts formed intracellularly is possible, extracellular glutathione adducts cannot penetrate the hepatocellular membrane. Small amounts of radiolabel from [3H]naphthalene 1,2-oxide were bound covalently to macromolecules in hepatocytes; the rate of this binding slowed rapidly after the first minute of incubation. Severe blebbing of the surface of the hepatocytes was noted in cells incubated for 30 min with 480 microM naphthalene oxide. Many of the cells were vacuolated at 60 min and progressed to frank necrosis with pyknotic nuclei and inability to exclude trypan blue. Cells incubated with 1-naphthol responded in a qualitatively similar fashion to those cells incubated with epoxide; however, hepatocytes incubated with 1-naphthol progressed to frank cellular necrosis at a slower rate. In hepatocytes partially depleted of glutathione by pretreatment with buthionine sulfoximine, addition of 1S,2R-naphthalene oxide at a rate of 1 nmol/min/10(6) cells resulted in significant losses in cell viability. In contrast, no losses in cell viability were observed with the enantiomer, 1R,2S-naphthalene oxide. Both epoxides produced similar losses in cellular glutathione levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1992

Tissue distribution of monomeric glutathione peroxidase in broiler chicks.

It is known that there are two kinds of enzymes which show glutathione peroxidase activity, 'classical' glutathione peroxidase and glutathione S-transferase. Recently, a third enzyme was found, monomeric glutathione peroxidase, in broiler chick liver cytosolic fraction. To gain an insight into the possible physiological role of the monomeric glutathione peroxidase, the distribution of this enzyme in other broiler tissues was studied. The monomeric glutathione peroxidase was found in all tissues examined and in erythrocytes. The percentage of the total glutathione peroxidase activity accounted for by the monomeric enzyme ranged from 4 per cent in erythrocytes to 28 per cent in liver. Livers from three avian and two mammalian species contained the monomeric glutathione peroxidase. The contribution of the monomeric enzyme to total glutathione peroxidase activity with cumene hydroperoxide was high in poultry livers, while only trace monomeric glutathione peroxidase activity was found in mammalian livers. Chick monomeric glutathione peroxidase showed high activity toward phospholipid hydroperoxide. Thus, monomeric glutathione peroxidase might be an important enzyme in reducing membrane lipid hydroperoxides in birds.

Animals↗
PubMed1992

Glutathione: new candidate neuropeptide in the central nervous system.

The physiological significance of glutathione in the mammalian central nervous system is still uncertain, although some evidence indicates that it may be an important regulatory peptide. In the present study, the distribution and characteristics of glutathione binding sites in the brain have been studied. Biotinyl-glutathione was synthesized as a probe to detect glutathione binding sites in the CNS. Specific glutathione binding sites in the brain were largely localized to the white matter, suggesting the presence of glutathione receptors on neuroglial cells. The colloidal gold technique and immunofluorescence double staining allowed the visualization of the receptor at the cellular level and thus demonstrated that there are glutathione receptors on cultured astrocytes. Glutathione applied to cultured astrocytes elicited increased levels of intracellular inositol-1,4,5-trisphosphate, suggesting that glutathione receptors were coupled to phospholipase C. The localization of glutathione receptors on astrocytes and the activation of a second messenger system by glutathione suggest that glutathione may be a neuropeptide in the central nervous system.

Animals↗
PubMed1999

Tissue-specific regulation of glutathione homeostasis and the activator protein-1 (AP-1) response in the rat conceptus.

Oxidative stress in the conceptus is characterized by an increased oxidized to reduced glutathione (GSSG:GSH) ratio and the induction of fos and jun mRNAs, transcripts for components of the activator protein-1 (AP-1) transcription factor. We investigated the role of glutathione homeostasis in the rat conceptus in the regulation of: (1) AP-1 expression and activity, and (2) the activities of glutathione-dependent cytoprotective enzymes. Glutathione content was enhanced with the addition of l-2-oxothiazolidine-4-carboxylate (OTC), a precursor of cysteine, a rate-limiting substrate in glutathione biosynthesis. Day 10 rat conceptuses were cultured for 44 hr with 0, 5, 10, or 20 mM OTC. High concentrations (10 and 20 mM) of OTC were embryotoxic. Incubation of the conceptus in 5 mM OTC caused mild (not statistically significant) embryotoxicity, increased significantly the embryonic glutathione content, prevented culture-induced oxidative stress, and inhibited the induction of AP-1 transcripts and DNA binding activity in the embryo. In contrast, in the yolk sac, 5 mM OTC failed to increase glutathione content or to prevent oxidative stress or AP-1 induction. Thus, regulation of glutathione status in the conceptus is tissue-specific. Glutathione S-transferase and glutathione peroxidase activities were increased approximately 50% in cultured embryos and yolk sacs. OTC treatment (5 mM) prevented this induction in the embryo, but not in the yolk sac, suggesting a role for glutathione homeostasis in the regulation of these enzymes. Tissue-specific regulation of glutathione status and of cytoprotective enzymes in the conceptus during organogenesis may impact on the consequences of insult with oxidative stress.

Animals↗