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PubMed1988

Glutathione concentrations in rat lung bronchoalveolar lavage fluid: effects of hyperoxia.

Glutathione concentrations were measured in rat bronchoalveolar lavage fluid (BALF) obtained from normal rats and rats exposed to a fraction of inspired oxygen (FiO2) of 0.8 for up to 5 days. We also perturbed rat lung glutathione concentrations by administering the compound diisopropylidene acetone (phorone) to a separate group of animals and correlated changes in BALF glutathione with changes in lung tissue glutathione. We found that reduced glutathione is present in normal rat BALF but glutathione disulfide is extremely low. Increases in lung tissue glutathione concentration and in BALF glutathione concentration occurred after 5 days of exposure to hyperoxia. Animals treated with phorone exhibited decreases in lung glutathione concentration two hours after dosing and increases in lung glutathione concentration 24 hours after dosing. Rat BALF obtained from phorone-treated animals at 2 or 24 hours after administration revealed that changes in BALF glutathione concentrations reflected changes in lung tissue glutathione concentration. The presence of glutathione in lung lavage fluid suggests that the compound could be playing an extracellular role in the lung, either as an antioxidant or as a coenzyme for other glutathione-related enzymatic reactions.

Animals↗
PubMed1979

New aspects of glutathione metabolism and translocation in mammals.

An appreciable fraction of the sulphur present in the mammal occurs in the form of glutathione, whose concentration in various tissues ranges from about 0.8 to about 8 mM; the extracellular concentration of glutatione (largely present as the disulphide) is in the micromolecular range. The synthesis of glutathione and its utilization take place by the reactions of the gamma-glutamyl cycle, which include those catalysed by gamma-glutamylcysteine and glutathione synthetases, gamma-glutamyl transpeptidase, cysteinylglycinase, gamma-glutamyl cyclotransferease, and 5-oxoprolinase. gamma-Glutamyl transpeptidase catalyses transpeptidation (with amino acids and dipeptides) and hydrolysis reactions with both blutathione and its disulphide. The transpeptidase is membrane-boudn, apparently to the outer surface of the cell, and is found in certain epithelial cells in anatomical sites that are involved in transport and secretory activities (e.g., renal tubule, jejunal villi, choroid plexus, ciliary body). Evidence that the reactions of the gamma-glutamyl cycle take place in vivo has come from studies with labelled metabolites and selective enzyme inhibitors, and on inborn errors of metabolism associated with specific enzyme deficiencies. Inhibition in vivo of gamma-glutamyl cyclotransferase and 5-oxoprolinase leads, respectively, to decreased and increased renal levels of 5-oxoproline. Administration of a specific inhibitor of gamma-glutamylcysteine synthetase, such as buthionine sulphoximine, leads to a rapid decline in the glutamylcysteine synthetase, such as buthionine sulphoximine, leads to a rapid decline in the glutathione level of the kidney and other tissues, reflecting the appreciable rate of glutathione utilization. When gamma-glutamyl transpeptidase is inhibited in vivo by injection of L- or D-gamma-glutamyl-(o-carboxy)phenylhydrazide, there is extensive glutathionuria and the blood plasma level of glutathione increases. Studies in which inhibitors of glutathione synthesis and transpeptidation were given to mice showed that transport of intracellular glutathione to membrane-bound transpeptidase is a discrete step in the gamma-glutamyl cycle, and that the level of plasma glutatione reflects (a) synthesis of glutathione and its export by liver, muscle, and other tissues and (b) utilization of glutatione by kidney and other tissues. Studies on several lymphoid cell lines show that these cells also actively translocate glutathione out of the cell. A summary scheme is given for the metabolism of glutathione in which glutathione is translocated to the cell membrane where it may be utilized as such or oxidized to glutathione disulphide. Oxidation is inhibited, and transpeptidation is promoted by the presence of amino acids that are substrates of the transpeptidase. Glutathione exported from cells that have membrane-bound transpeptidase may be recovered by the cell transport of gamma-glutamyl amino acids and free amino acids...

Animals↗
PubMed1998

Glutathione conjugation of perchloroethene in subcellular fractions from rodent and human liver and kidney.

Perchloroethene (Per) is a widely used industrial solvent and common environmental contaminant. In rats, long-term inhalation of Per is known to cause a small increase in the incidence of renal tubule cell tumors in males only; renal toxicity is seen in female rats and in both sexes of mice after prolonged Per exposure. The renal toxicity of Per is likely mediated by a glutathione-dependent bioactivation reaction. Glutathione S-transferase mediated formation of S-(1,2,2-trichlorovinyl)glutathione is the first step in a sequence of reactions finally resulting in the formation of reactive intermediates in the kidney. In this study, we compared the enzymatic rates of formation of S-(1,2,2-trichlorovinyl)glutathione in liver and kidney subcellular fractions from rats, mice, and from both sexes of humans (n = 11). In microsomal fractions from the liver and kidney of all three species, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione from Per could not be observed. S-(1,2,2-Trichlorovinyl)glutathione formation (the structure was confirmed by electrospray mass spectrometry) was observed in liver cytosol from both male and female rats and mice. However, the rates of S-(1,2,2-trichlorovinyl)glutathione formation in liver cytosol from male rats (84.5+/-12 pmol/mg per min) were approximately four times higher than from female rats (19.5+/-8 pmol/mg per min) and from both sexes of mice (27.9+/-6 and 26.0+/-4 pmol/mg per min). Low rates of S-(1,2,2-trichlorovinyl)glutathione formation were also seen in kidney cytosol from mice (12+/-6 pmol/mg per min), but not from rats. In human liver subcellular fractions, enzymatic formation of S-(1,2,2-trichlorovinyl)glutathione could not be detected. The human liver cytosolic fractions, however, exhibited glutathione S-transferase activity (as determined using 1-chloro-2,4-dinitrobenzene and hexachlorobutadiene as marker substrates) in the same order of magnitude as rat and mouse liver cytosol. In contrast to other marker activities for glutathione S-transferases, the ability of all human liver cytosol samples to catalyze the glutathione conjugation of 1,2-dichloro-4-nitrobenzene was three orders of magnitude lower compared to rat and mouse liver cytosol. 1,2-Dichloro-4-nitrobenzene conjugation was also four times higher in liver cytosol from male rats compared to female rats. The results suggest that the ability of the human liver to catalyze the formation of S-(1,2,2-trichlorovinyl)glutathione from Per is at least two orders of magnitude lower than that of rat liver, and that sex-specific differences in the extent of hepatic conjugation of Per with glutathione, which may be relevant for nephrotoxicity, occur in rats.

Animals↗
PubMed1999

Potentiation of excitotoxic injury by high concentrations of extracellular reduced glutathione.

Glutathione is present in the central nervous system in millimolar concentrations, and is a predominant intracellular antioxidant and detoxicant. In addition, glutathione is released into the extracellular space via a depolarization-enhanced process. Although the role of extracellular glutathione has not been precisely defined, a growing body of experimental evidence suggests that it has multifaceted electrophysiological effects. At low micromolar concentrations, glutathione depolarizes neurons by binding to its own receptors and modulates glutamatergic excitatory neurotransmission by displacing glutamate from its ionotropic receptors. At higher concentrations, reduced glutathione may increase N-methyl-D-aspartate receptor responses by interacting with its redox sites. In this study, the effect of extracellular glutathione on excitotoxic neuronal injury was quantitatively assessed in murine cortical cell cultures. Neuronal death due to 20-25 h exposure to 6-9 microM N-methyl-D-aspartate was not altered by 10-100 microM reduced glutathione but was markedly enhanced by 300-1000 microM reduced glutathione; kainate neurotoxicity was unaffected. Two related compounds that lack a sulfhydryl group, oxidized glutathione and S-hexylglutathione, had no significant effect on N-methyl-D-aspartate neurotoxicity alone but completely blocked the effect of reduced glutathione. Mercaptoethanol, a sulfhydryl reducing agent that increases N-methyl-D-aspartate receptor responses by interacting with redox sites, increased N-methyl-D-aspartate neurotoxicity to a degree comparable to that of reduced glutathione; this effect was also blocked by equimolar S-hexylglutathione or oxidized glutathione. Addition of reduced glutathione to mercaptoethanol did not further increase N- methyl-D-aspartate-induced neuronal death. These results suggest that release of reduced glutathione from central nervous system cells that are subjected to traumatic or ischemic insults may enhance excitotoxic neuronal loss. Although multiple mechanisms may account for this phenomenon, the high concentrations required suggest that it is at least partly mediated by reduction of N-methyl-D-aspartate receptor redox sites.

Animals↗
PubMed1998

Interference of S-alkyl derivatives of glutathione with brain ionotropic glutamate receptors.

The effects of glutathione, glutathione sulfonate and S-alkyl derivatives of glutathione on the binding of glutamate and selective ligands of ionotropic N-methyl-D-aspartate (NMDA) and non-NMDA receptors were studied with mouse synaptic membranes. The effects of glutathione and its analogues on 45Ca2+ influx were also estimated in cultured rat cerebellar granule cells. Reduced and oxidized glutathione, glutathione sulfonate, S-methyl-, -ethyl-, -propyl-, -butyl- and -pentylglutathione inhibited the Na+-independent binding of L-[3H]glutamate. They strongly inhibited also the binding of (S)-2-amino-3-hydroxy-5-[3H]methyl-4-isoxazolepropionate [3H]AMPA (IC50 values: 0.8-15.9 microM). S-Alkylation of glutathione rendered the derivatives unable to inhibit [3H]kainate binding. The NMDA-sensitive binding of L-[3H]glutamate and the binding of 3-[(R)-2-carboxypiperazin-4-yl][1,2-(3)H]propyl-1-phosphonate ([3H]CPP, a competitive antagonist at NMDA sites) were inhibited by the peptides at micromolar concentrations. The strychnine-insensitive binding of the NMDA coagonist [3H]glycine was attenuated only by oxidized glutathione and glutathione sulfonate. All peptides slightly enhanced the use-dependent binding of [3H]dizocilpine (MK-801) to the NMDA-gated ionophores. This effect was additive with the effect of glycine but not with that of saturating concentrations of glutamate or glutamate plus glycine. The glutamate- and NMDA-evoked influx of 45Ca2+ into cerebellar granule cells was inhibited by the S-alkyl derivatives of glutathione. We conclude that besides glutathione the endogenous S-methylglutathione and glutathione sulfonate and the synthetic S-alkyl derivatives of glutathione act as ligands of the AMPA and NMDA receptors. In the NMDA receptor-ionophore these glutathione analogues bind preferably to the glutamate recognition site via their gamma-glutamyl moieties.

Animals↗
PubMed1996

Glutathione-dependent protection against lipid peroxidation in sheep liver microsomes.

In the present studies we have described a glutathione-dependent system in sheep liver microsomes that protects against membrane lipid peroxidation initiated by either Fe+2/NADPH or Fe+2/ascorbate. Glutathione protected against lipid peroxidation in microsomes containing a wide range of alpha-tocopherol levels (0.02-0.11 microgram/mg protein). The addition of glutathione disulfide alone had no effect on microsomal lipid peroxidation, however, it prolonged the protection afforded by glutathione, particularly in assays containing Fe+2/NADPH. Whereas the glutathione-dependent protection was very labile, with loss of activity demonstrated in microsomes stored at 4 degrees C for 24 hours, the combined effect of glutathione and glutathione disulfide was not affected by storage. The glutathione S-transferase inhibitors, bromosulphothalein and S-hexylglutathione, reversed the protection observed with glutathione, indicating a possible role for microsomal glutathione S-transferases in this protection, but not that observed by the combination of glutathione and glutathione disulfide. In general, our findings support previous results observed with rat liver microsomes and suggest that microsomal glutathione S-transferases may be involved in the glutathione-dependent protection in sheep liver microsomes.

Animals↗
PubMedDate not supplied

Glutathione derivatives enhance adriamycin cytotoxicity in a human lung adenocarcinoma cell line.

We evaluated the effects of a panel of glutathione derivative (S-butyl, S-decyl, S-ethyl, S-heptyl, S-hexyl; S-methyl, S-nonyl, S-octyl, S-propyl and S-pentyl glutathiones) on glutathione-S-transferase activity in the cell lysates of a human lung cancer, PC-9. Glutathione derivatives inhibited glutathione-S-transferase activity in PC-9 cell lysates by up to 67%. When PC-9 cells were incubated with the IC50 concentration of adriamycin (200 nM) and with nontoxic concentrations (1 microM) of the glutathione derivatives, cytotoxicity ranged from -20% to +55% of the control levels. Enhancement of adriamycin toxicity by glutathione derivatives was significantly correlated with the inhibition of glutathione-S-transferase activity. S-decyl-glutathione, which was one of the most potent inhibitors of glutathione-S-transferase activity, significantly enhanced the adriamycin-induced antitumor effect in vivo. Findings suggest that some glutathione derivatives, including the S-decyl, S-octyl, and S-hexyl glutathiones, enhance adriamycin-induced cytotoxicity in part by inhibiting glutathione-S-transferase and that these agents may be useful as chemosensitizers for adriamycin therapy. In conclusion, the present results showed that some glutathione derivatives enhanced sensitivity of tumor cells to ADR by inhibiting GST activity. The use of BSO and EA as sensitizers to chemotherapy is currently being evaluated in clinical trials. The present data suggest that the use of GSH derivatives to modulate GST activity may improve the response to ADR.

Adenocarcinoma↗
PubMed1989

Impairment of glutathione metabolism in erythrocytes from patients with diabetes mellitus.

The metabolism of glutathione and activities of its related enzymes were studied in erythrocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM). A decrease in the levels of the reduced form of glutathione and an increase in the levels of glutathione disulfide were found in erythrocytes of diabetics. To elucidate these changes in the levels of glutathione, synthetic and degradative processes were studied. The activity of gamma-glutamylcysteine synthetase was significantly lower in diabetics than in normal controls. The activity of glutathione synthetase of each group was the same. The rate of outward transport of glutathione disulfide in diabetics decreased to approximately 70% of that of normal controls. The activity of glutathione reductase decreased in diabetics. These data suggest that the decrease in the levels of reduced form of glutathione in erythrocytes of diabetics is brought about by impaired glutathione synthesis and that the increase in the levels of glutathione disulfide is brought about by the decreased transport activity of glutathione disulfide through the erythrocyte membrane together with a decrease in the activity of glutathione reductase. These data also suggest that the impairment of glutathione metabolism weakens the defense mechanism against oxidative stress in erythrocytes of diabetics.

Adult↗
PubMed2006

Direct measurement of the rate of glutathione synthesis in 1-chloro-2,4-dinitrobenzene treated human erythrocytes.

Cell glutathione scavenges free radicals, degrades peroxides, removes damaging electrophiles and maintains the redox state. The aim of this study was to develop an effective and efficient method to measure the rate of glutathione synthesis from its constituent amino acids in whole erythrocytes (RBCs). RBCs (10% haematocrit) were exposed to 0.3 mM 1-chloro-2,4-dinitrobenzene (CDNB) to lower their total glutathione content by 70% and then incubated with glucose, and N-acetylcysteine as a cysteine source. Over 3 h, glutathione levels increased at a constant rate of 1.2 micromol (L RBC)(-1)min(-1), almost 5 times faster than the rate of glutathione synthesis in RBCs with normal glutathione levels. Glutathione at concentrations normally found in RBCs is known to inhibit glutamate cysteine ligase (the major rate controlling enzyme for glutathione synthesis). The rate of glutathione recovery was substantially reduced in RBCs treated with buthionine sulfoximine, a specific inhibitor of glutamate cysteine ligase. Our results indicate that the measurement of glutathione recovery rate after CDNB treatment can be used to estimate de novo synthesis of glutathione. Application of this direct method for measuring glutathione synthesis will increase understanding of the interactions of effectors that determine glutathione levels in RBCs under various physiological and pathological conditions.

Acetylcysteine↗
PubMed1994

Role of gamma-glutamyltranspeptidase-mediated glutathione transport on the radiosensitivity of B16 melanoma variant cell lines.

PURPOSE: To elucidate the role of gamma-glutamyltranspeptidase-mediated glutathione transport on the radiosensitivity of B16 melanoma variant cell lines. METHODS AND MATERIALS: B16 melanoma variant cell lines were examined for their levels of gamma-glutamyltranspeptidase (GGTP; E.C. 2.3.2.2), a plasma membrane-associated ectoenzyme that is involved in the transport of extracellular glutathione, by flow cytometric and biochemical analysis. B16 cell lines were examined for rates of de novo glutathione synthesis from extracellular glutathione and for their sensitivity to gamma-irradiation and glutathione synthesis inhibition. The GGTP inhibitors were examined for their effect on the radiosensitivity of B16 melanoma cells. RESULTS: B16-F10-BL6 (BL6) melanoma cells were shown to express a 20-fold higher level of GGTP than the B16-F1 melanoma variant cells. Cultures of BL6 and B16-F1 cells depleted extracellular glutathione at rates of 2.4 and < 0.1 nmol glutathione/10(6) cells/h, respectively, and BL6 cells exported glutathione at a rate 7.2-fold higher than B16-F1 cells (710 and 98 pmol glutathione/10(6) cells/h, respectively). BL6 melanoma cells replenished exhausted intracellular glutathione levels from an extracellular glutathione source at a rate of 1.21 nmol glutathione/h (18% basal glutathione/h); however, B16-F1 cells lacked the capacity to replenish intracellular glutathione despite the presence of exogenous glutathione in the culture medium. BL6 melanoma cells were radioresistant compared to the B16-F1 cell line, exhibiting extrapolation numbers (ñ) of 14.9 and 1.0, respectively, and a lower surviving fraction to a wide range of radiation doses. The GGTP inhibitor combination of L-serine and sodium borate blocked the repletion of intracellular glutathione and in the presence or absence of buthionine sulfoximine-mediated depletion of glutathione reverses the radiation resistance in BL6 melanoma cells to near baseline levels observed with the B16-F1 parent clone. Serine-borate treatment of low-GGTP expressing B16-F1 cells had no effect on the ñ value or the surviving fraction of cells to a range of ionizing irradiation doses. CONCLUSIONS: These results suggest that GGTP plays an important role in the extracellular metabolism and transport of glutathione, which also provides radioresistance to BL6 melanoma cells in vitro.

Animals↗
PubMed2006

Identification and expression of a novel class of glutathione-S-transferase from amphioxus Branchiostoma belcheri with implications to the origin of vertebrate liver.

Glutathione-S-transferases have been identified in all the living species examined so far, yet little is known to date about them in amphioxus, a model organism for insights into the origin and evolution of vertebrates. We have isolated a cDNA encoding an amphioxus (Branchiostoma belcheri) glutathione-S-transferase with a predicted molecular mass of approximately 26 kDa, from the gut cDNA library. The glutathione-S-transferase had 43.7-51.8% identity to most glutathione-S-transferases identified from aquatic organisms including fish and green alga, but it was much less identical (<27%) to other cytosolic glutathione-S-transferase classes. The phylogenetic analysis revealed that the glutathione-S-transferase was grouped together with most piscine and algal glutathione-S-transferases, separating from other cytosolic glutathione-S-transferase classes. Moreover, the glutathione-S-transferase had an exon-intron organization typical of zebrafish putative GST, red sea bream GSTR1 and plaice GSTA1 genes. The recombinant glutathione-S-transferase has been successfully expressed and purified, which showed a relatively high catalytic activity (3.37+/-0.1 unit/mg) toward 1-chloro-2, 4-dinitrobenzene and a moderate activity toward ethacrynic acid (0.41+/-0.01 unit/mg), although it had no detectable activity toward 1, 2-dichloro-4-nitrobenzene, 4-hydroxynonenal, 4-nitrobenzyl chloride and cumene hydroperoxide. In addition, we have revealed a tissue-specific expression pattern of the glutathione-S-transferase gene in B. belcheri, with the most abundant expression in the hepatic caecum. All these indicate that the amphioxus glutathione-S-transferase belongs to a novel rho-class of glutathione-S-transferases with a tissue-specific expression pattern. The relation between the glutathione-S-transferase expression in amphioxus hepatic caecum and the origin of vertebrate liver is also discussed.

Amino Acid Sequence↗
PubMed2005

Synaptic plasticity impairment and hypofunction of NMDA receptors induced by glutathione deficit: relevance to schizophrenia.

Increasing evidence suggests that the metabolism of glutathione, an endogenous redox regulator, is abnormal in schizophrenia. Patients show a deficit in glutathione levels in the cerebrospinal fluid and prefrontal cortex and a reduction in gene expression of the glutathione synthesizing enzymes. We investigated whether such glutathione deficit altered synaptic transmission and plasticity in slices of rat hippocampus, with particular emphasis on NMDA receptor function. An approximately 40% decrease in brain glutathione levels was induced by s.c. administration of L-buthionine-(S,R)-sulfoximine, an inhibitor of glutathione synthesis. Such glutathione deficit did not affect the basal synaptic transmission, but produced several NMDA receptor-dependent and -independent effects. Glutathione deficit caused an increase in excitability of CA1 pyramidal cells. The paired-pulse facilitation was diminished in glutathione-depleted slices, in a manner that was independent of NMDA receptor activity. This suggests that lowering glutathione levels altered presynaptic mechanisms involved in neurotransmitter release. NMDA receptor-dependent long-term potentiation induced by high-frequency stimulation was impaired in glutathione-depleted slices. Pharmacologically isolated NMDA receptor-mediated field excitatory postsynaptic potentials were significantly smaller in L-buthionine-(S,R)-sulfoximine-treated than in control slices. Hypofunction of NMDA receptors under glutathione deficit was explained at least in part by an excessive oxidation of the extracellular redox-sensitive sites of the NMDA receptors. These results indicate that a glutathione deficit, like that observed in schizophrenics, alters short- and long-term synaptic plasticity and affects NMDA receptor function. Thus, glutathione deficit could be one causal factor for the hypofunction of NMDA receptors in schizophrenia.

Animals↗
PubMed2001

Verapamil-stimulated glutathione transport by the multidrug resistance-associated protein (MRP1) in leukaemia cells.

Multidrug resistance mediated by the multidrug resistance-associated protein MRP1 is associated with decreased drug accumulation, which is in turn dependent on cellular glutathione. We have reported that verapamil, an inhibitor of drug transport, caused a decrease in cellular glutathione in CCRF-CEM/E1000 MRP1-overexpressing leukaemia cells (Biochem Pharmacol 55;1283--9, 1998). We now demonstrate that other inhibitors of MRP1-mediated drug transport (e.g. MK571, indomethacin, genistein, and nifedipine) deplete cellular glutathione in these leukaemia cells (>30% decrease; P < 0.01) while having no effect on the parental CCRF-CEM cells. However, treatment with etoposide or vincristine (at similar molar concentrations) caused a 20% decrease in glutathione. Verapamil-stimulated glutathione transport correlated with MRP1 expression in a series of drug-resistant cells, and glutathione was quantitatively recovered in the extracellular media. Further, verapamil-stimulated glutathione transport was rapid (50% decrease in 10 min), dose-dependent, and inhibited by vanadate, an inhibitor of ATPase activity, but not by sulphobromophthalein (BSP) or methionine, inhibitors of hepatic glutathione transporters. Incubation of CCRF-CEM/E1000 cells in 25 mM glutathione not only showed that verapamil-mediated efflux occurred against the concentration gradient, but also demonstrated the MRP1-mediated uptake of glutathione (P < 0.01 compared to the parental CCRF-CEM cells), which was not inhibited by vanadate. These results demonstrate that while MRP1 transports glutathione in the presence of inhibitors of drug transport, there is no convincing evidence for co-transport of glutathione with drug. They further demonstrate that MRP1 mediates the facilitated transport of glutathione into the MRP1-overexpressing CEM/E1000 cells, suggesting that MRP1 may play a major role in cellular glutathione homeostasis.

ATP-Binding Cassette Transporters↗
PubMed1997

Glutathione S-transferases in human ovarian follicular fluid.

OBJECTIVE: To study the levels of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 in human preovulatory ovarian follicular fluid (FF) and pooled granulosa and cumulus cells. DESIGN: The relation of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 with P and 17 beta-E2 concentrations were studied. SETTING: The Department of Obstetrics and Gynecology, the Department of Gastroenterology, and the Laboratory of Endocrinology and Reproduction of the University Hospital Nijmegen in Nijmegen, the Netherlands. PATIENT(S): Infertile women participating in an IVF program. RESULT(S): Detectable amounts of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 were found in ovarian FF and pooled cumulus and granulosa cells. Concentrations of glutathione S-transferase Alpha 1-1 were always much higher than those of glutathione S-transferase Pi 1-1. Both ovarian FF concentrations of glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 did not correlate with ovarian FF concentrations of 17 beta-E2 and P. CONCLUSION(S): The high FF concentrations of glutathione S-transferase Pi 1-1 and especially of glutathione S-transferase Alpha 1-1 suggest that these enzymes may play an important role in the detoxification processes in the follicles. The lack of correlation between follicular P and 17 beta-E2 and glutathione S-transferase Alpha 1-1 and glutathione S-transferase Pi 1-1 indicates that both enzymes presumably are not present as a result of the high steroid levels.

Estradiol↗
PubMed2001

Role of glutathione-dependent peroxidase in regulation of lipoperoxide utilization in malignant tumors.

Glutathione content, the activity of glutathione-dependent enzymes (glutathione reductase, glutathione peroxidase, and glutathione S-transferase), and also SOD (superoxide dismutase) and catalase were studied in human malignant tumors (uterus, breast, and ovaries) and normal tissues. Glutathione level and the activity of glutathione-dependent enzymes were 2-3 times higher in the malignant tumors than in normal tissues. A negative correlation between the level of glutathione and glutathione-dependent enzymes (glutathione peroxidase and glutathione S-transferase) in tumors and the efficacy of postoperative chemotherapy may characterize the degree of tumor resistance to chemotherapy and therefore may have prognostic value. Low SOD and catalase activity and high activity of glutathione-dependent enzymes in tumors suggest that glutathione peroxidase and glutathione S-transferase play a major role in peroxide utilization in malignant tumors.

Catalase↗
PubMed2005

Impaired glutathione-conjugating capacity by cryopreserved human and rat hepatocytes.

The activity of glutathione transferase was measured in sonicates of fresh rat hepatocytes and of cryopreserved rat, human and dog hepatocytes in the presence of added glutathione and by using 1-chloro-2,4-dinitrobenzene (CDNB) as non-selective substrate. The glutathione-conjugating capacity was also investigated in the presence of CDNB alone (without glutathione) with intact fresh rat hepatocytes and cryopreserved rat and human hepatocytes. Finally, the intracellular level of glutathione was measured in these hepatocytes. The specific activity of glutathione transferase in sonicates of fresh rat hepatocytes (in the presence of added GSH and CDNB) was about 415 nmol/min/10(6) cells. The corresponding activities in cryopreserved rat, human and dog hepatocytes were approximately 320, 440 and 540 nmol/min/10(6) cells, respectively. In contrast, glutathione conjugation by the intact cryopreserved human and rat hepatocytes in the presence of CDNB alone was less than 10% of the corresponding conjugation by fresh rat hepatocytes, indicating that glutathione was depleted in these cryopreserved hepatocytes. Glutathione depletion was confirmed after analytical measurement of the glutathione levels in fresh and cryopreserved hepatocytes. In fresh rat hepatocytes the level of glutathione was 44 nmol/10(6) cells, whereas it was 2.5 and 4.4 nmol/10(6) cells in cryopreserved rat and human hepatocytes, respectively. In summary, glutathione transferase was active in these cryopreserved hepatocytes but the cryopreservation procedure likely causes depletion in the intracellular level of glutathione, resulting in an overall reduced glutathione conjugating capacity.

Animals↗
PubMed1999

Stereoselective formation of glutathione S-conjugates from halovinylmercapturate sulphoxides.

1. The glutathione S-transferase catalysed formation of glutathione S-conjugates from halovinylmercapturate sulphoxides was investigated in rat liver and kidney cytosol, with purified glutathione S-transferases and in rat in vivo. 2. The two diastereomers of the sulphoxides of N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine, N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine show different reactivities with glutathione and glutathione S-transferases. Rat liver and kidney cytosol catalyses the formation of a 1:1 mixture of two diastereomers of (E)-N-acetyl-S-(2-glutathione-S-yl-2-chlorovinyl)-L-cysteine sulphoxide from N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine sulphoxide and of (E)-N-acetyl-S-(2-glutathione-S-yl-1,2-dichlorovinyl)-L-cysteine sulphoxide from N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine sulphoxide. In contrast, only one diastereomer of the Z-isomers was formed. 3. N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulphoxide reacted spontaneously with glutathione at high rates, a 1:1 mixture of both diastereomers of N-acetyl-S-(2-glutathione-S-yl-1-chlorovinyl)-L-cysteine sulphoxide was formed. 4. Metabolism of N-acetyl-S-(2,2-dichlorovinyl)-L-cysteine sulfoxide and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide under by alpha-class glutathione S-transferases yielded identical products as observed with the cytosolic enzymes. No reaction was observed in the presence of rat liver mu class glutathione S-transferases or human glutathione S-transferase M1. 5. Formation of these glutathione conjugates was also observed in the bile of rat after i.p. administration of the mercapturic acid sulphoxides. The results obtained show that stereochemical aspects may govern the regioselectivity and substrate specificity in glutathione S-transferase-catalysed reactions.

Acetylcysteine↗
PubMed1999

Glutathione synthetic activity in the lungs in newborn guinea pigs.

Depletion of glutathione, a key antioxidant, accelerates lung injury. Glutathione concentrations are reduced significantly in premature infants with respiratory distress syndrome, leaving them at greater risk of bronchopulmonary dysplasia. A study was designed to verify if the increased glutathione synthetic activity observed in oxygen-dependent and ventilated newborn infants was caused by their postsurgical state. Our objective was to evaluate the role of a general surgical procedure as a factor affecting lung glutathione. One-day-old guinea pig pups, a well characterized animal model for the study of neonatal lung disease, were divided between those undergoing a standardized surgical procedure and those that did not. The pups were fed by their mother. After 4 days the lungs were sampled to determine total glutathione content, activities of gamma-glutamyltranspeptidase, glutathione peroxidase, and reductase as well as the glutathione synthetic activity. The surgical procedure was associated with a specific stimulatory effect limited to glutathione synthetic activity (p < 0.02) leading to an increased (p < 0.02) pulmonary glutathione content. Glutathione concentration was significantly correlated (r2 = 0.67) with the synthetic activity. We concluded that in this animal model an invasive procedure such as a general surgical procedure affects lung glutathione metabolism in a fashion similar to that of hyperoxia. In the lungs, the synthetic activity is a stronger determinant of glutathione concentrations than the activities of the other enzymes involved in maintaining glutathione levels.

Animals↗