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PubMed2005

Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis.

The specific role of endogenous glutathione in response to neuronal degeneration induced by trimethyltin (TMT) in the hippocampus was examined in rats. A single injection of TMT (8 mg/kg, i.p.) produced a rapid increase in the formation of hydroxyl radical and in the levels of malondialdehyde (MDA) and protein carbonyl. TMT-induced seizure activity significantly increased after this initial oxidative stress, and remained elevated for up to 2 weeks post-TMT. Although a significant loss of hippocampal Cornus Ammonis CA1, CA3 and CA4 neurons was observed at 3 weeks post-TMT, the elevation in the level of hydroxyl radicals, MDA, and protein carbonyl had returned to near-control levels at that time. In contrast, the ratio of reduced to oxidized glutathione remained significantly decreased at 3 weeks post-TMT, and the glutathione-like immunoreactivity of the pyramidal neurons was decreased. However glutathione-positive glia-like cells proliferated mainly in the CA1, CA3, and CA4 sectors and were intensely immunoreactive. Double labeling demonstrated the co-localization of glutathione-immunoreactive glia-like cells and reactive astrocytes, as indicated by immunostaining for glial fibrillary acidic protein. This suggests that astroglial cells were mobilized to synthesize glutathione in response to the TMT insult. The TMT-induced changes in glutathione-like immunoreactivity appear to be concurrent with changes in the expression levels of glutathione peroxidase and glutathione reductase. Ascorbate treatment significantly attenuated TMT-induced seizures, as well as the initial oxidative stress, impaired glutathione homeostasis, and neuronal degeneration in a dose-dependent manner. These results suggest that ascorbate is an effective neuroprotectant against TMT. The initial oxidative burden induced by TMT may be a causal factor in the generation of seizures, prolonged disturbance of endogenous glutathione homeostasis, and consequent neuronal degeneration.

Animals↗
PubMed1994

Glutathione conjugation and conversion to mercapturic acids can occur as an intrahepatic process.

By catalyzing the reaction of electrophilic compounds with the sulfhydryl group of glutathione, the glutathione S-transferases play physiologically important roles in the detoxication of potential alkylating agents. The glutathione S-conjugates thus formed are transported out of cells for further metabolism by gamma-glutamyltransferase and dipeptidases, ectoproteins that catalyze the sequential removal of the glutamyl and glycyl moieties, respectively. These ectoproteins are not found in all cells, but are localized predominantly to the apical surface of epithelial tissues. The resulting cysteine S-conjugates can be reabsorbed by specific cell types, and acetylated on the amino group of the cysteinyl residue by intracellular N-acetyl-transferases, to form the corresponding mercapturic acids (N-acetylcysteine S-conjugates). Mercapturic acids are then released into the circulation and delivered to the kidney for excretion in urine, or they may undergo further metabolism. Mercapturic acid biosynthesis is generally considered to be an interorgan process, with the liver serving as the major site of glutathione conjugation, and the kidney as the primary site for conversion of glutathione conjugates to cysteine conjugates. Cysteine conjugates formed in the kidney appear to be transported back to the liver for acetylation. This interorgan model of mercapturic acid synthesis is based largely on the interorgan distribution of the enzymes involved in their formation, and in particular of the enzyme gamma-glutamyltransferase. Rats have relatively low hepatic and high renal activities of gamma-glutamyltransferase, the only protein known to initiate the breakdown of glutathione S-conjugates. The low gamma-glutamyltransferase activity in rat liver limits the hepatic degradation of glutathione S-conjugates, particularly after large doses of xenobiotic. In contrast, hepatic gamma-glutamyltransferase is significantly higher in species such as rabbit, guinea pig, and dog, and as a consequence, nearly all of the glutathione and glutathione S-conjugates released by liver cells of these species is degraded within the liver. Recent studies demonstrate that glutathione S-conjugates synthesized within hepatocytes are secreted preferentially across the canalicular membrane into bile, and are broken down within biliary spaces to form cysteine S-conjugates. The latter are then reabsorbed by the liver, N-acetylated to form mercapturic acids, and reexcreted into bile, completing an intrahepatic pathway for mercapturic acid biosynthesis. The contribution of this intrahepatic pathway to overall mercapturate formation is dependent on dose of the electrophile, route of exposure, and the physicochemical properties of the glutathione S-conjugate formed, as well as the tissue distribution and activity of gamma-glutamyltransferase.(ABSTRACT TRUNCATED AT 400 WORDS)

Acetylcysteine↗
PubMed1978

Hepatic cytosolic non selenium-dependent glutathione peroxidase activity: its nature and the effect of selenium deficiency.

Recent work had indicated the presence of a non selenium-dependent glutathione peroxidase activity in rat liver in addition to the selenium-dependent activity. The present study was undertaken to learn whether the glutathione S-transferases are reponsible for the non selenium-dependent glutathione peroxidase activity and to study the effect of selenium deficiency on those enzymes. Glutathione S-transferase B was purified by an established method using carboxymethyl cellulose ion exchange chromatography and studied. It exhibited glutathione peroxidase activity toward cumene hydroperoxide and t-butyl hydroperoxide. A limiting Km of 0.55 mM was determined for cumene hydroperoxide. Sulfobromophthalein was found to be a competitive inhibitor with respect to cumene hydroperoxide of the glutathione peroxidase activity of glutathione S-transferase B. Selenium deficiency caused an increase in glutathione S-transferase activity. These results establish that glutathione S-transferase B contributes to the non selenium-dependent glutathione peroxidase activity in rat liver and show that it increases in selenium deficiency when the selenium-dependent glutathione peroxidase is decreased.

Animals↗
PubMed1996

Chrysotile inhibits glutathione-dependent protection against the onset of lipid peroxidation in rat lung microsomes.

The glutathione and vitamin E dependent protection of lipid peroxidation in an NADPH (0.4 mM) and chrysotile (500 micrograms/ml) containing system were investigated in vitro in rat lung microsomes. Addition of 1 mM glutathione to the above reaction system containing microsomes supplemented with vitamin E (1 nmol/mg protein) reduced lipid peroxidation. Similar protection by glutathione could be observed in normal unsupplemented microsomes though the degree of protection was less pronounced. Addition of free radical scavengers such as, superoxide dismutase (100 units/ml), catalase (150 units/ml), mannitol (1 mM) and beta-carotene (0.5 mM) to the reaction system showed an insignificant effect on lipid peroxidation. When the reaction was carried out in absence of glutathione, vitamin E content of peroxidizing microsomes decreased rapidly. In this system a concomitant increase in the activity of microsomal glutathione-S-transferase was observed which may serve as an alternative pathway to detoxify lipid peroxides. Addition of glutathione alone to the reaction system prevented both against the loss in vitamin E content and increase in the activity of glutathione-S-transferase. Supplementation of both vitamin E and glutathione was found to be effective in lowering glutathione-S-transferase activity to that of normal basal level. Our results suggest that chrysotile-mediated stimulation of NADPH-dependent lipid peroxidation may be due to hampering of glutathione-dependent protection which may ultimately exhaust membrane bound vitamin E. Our data further suggest that the lung tissue may have an inbuilt mechanism whereby glutathione-S-transferase may be triggered to cope with the excessive production of lipid peroxides.

Animals↗
PubMedDate not supplied

Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity.

N4-oxidation of sulfonamides has been implicated in the pathogenesis of idiosyncratic reactions to these antimicrobials. In vitro toxicity assays employing mononuclear leukocytes as target cells have shown that the toxicity of sulfamethoxazole hydroxylamine (SMX-HA) is inhibited by exogenous glutathione, suggesting that conjugation with glutathione is an important detoxification pathway. However, in these experiments, significant depletion of cellular glutathione only occurred at concentrations of SMX-HA greater than or equal to 300 microM. At concentrations of SMX-HA which produce 50% toxicity in mononuclear leukocytes (approximately 100 microM), there was not a significant loss of glutathione. SMX-HA also caused a small but significant increase in oxidized glutathione concentrations. In cell-free experiments, reduced glutathione (GSH) prevented the autooxidation of SMX-HA to nitrososulfamethoxazole (nitroso-SMX). During this process, oxidized glutathione was formed. GSH rapidly reacted with nitroso-SMX to form a labile semimercaptal conjugate. Physiologically relevant concentrations of GSH (i.e. 1 mM) favored thiolytic cleavage of the semimercaptal to form SMX-HA. Isomerization of the semimercaptal to the more stable sulfinamide occurred at low GSH concentrations. Purified glutathione transferases had no effect on the reaction of SMX-HA with GSH. Therefore, glutathione is important in protecting cells from the toxicity of SMX-HA largely by preventing its further oxidation to nitroso-SMX. Stable glutathione conjugates are likely to be formed only in small quantities under physiological conditions. Conjugation with glutathione would not be expected to be a major pathway for clearance of the hydroxylamine and nitroso metabolites of sulfonamides.

Cell-Free System↗
PubMed1987

Stimulation of biliary glutathione secretion by sulfonylureas.

In isolated perfused rat livers, infusion of the sulfonylureas, glyburide (2.5 microM) and tolbutamide (0.5 mM), stimulated by 2-fold the rate of biliary glutathione secretion. This increase was mainly the result of an apparent increase in the rate of reduced glutathione release by the liver since oxidized glutathione levels in the bile remained unchanged. Sulfonylurea infusion into perfused livers did not alter the rate of glutathione release in the perfusate, indicating that sinusoidal release was not perturbed. N-Benzylimidazole (0.2 mM), an inhibitor of cytochrome P-450, blocked the tolbutamide-mediated increase in biliary release of glutathione. However, the cytochrome P-450 inhibitor did not alter the glyburide-induced increase in biliary glutathione secretion. Glyburide infusion into perfused livers also decreased tissue oxidized glutathione content without altering the total tissue levels of glutathione. The stimulation of biliary glutathione release by sulfonylureas is probably the result of excretion of labile conjugates of glutathione and sulfonylurea metabolites. Although the precise identity of these metabolites is presently unknown, formyltolbutamide and hydroxyglyburide formed during metabolism of tolbutamide and glyburide, respectively, may be the prime candidates for forming labile glutathione conjugates.

Animals↗
PubMed1984

Role of microsomal and cytosolic glutathione S-transferases in the conjugation of hexachloro-1:3-butadiene and its possible relevance to toxicity.

The mechanism of hexachloro-1:3-butadiene (HCBD)-induced glutathione depletion in male and female rats has been investigated in rat liver and kidney preparations in vitro in order to characterize the enzymes involved and to study the relationship between this effect and the nephrotoxic action of this compound. HCBD caused a marked reduction in glutathione concentration when incubated with male or female hepatic microsomal or cytosolic fractions fortified with glutathione. In contrast with that reported for other halo-olefin's, the depletion of glutathione in the microsomal fraction is not related to the formation of metabolites via cytochrome P-450. The microsomal rate of depletion appeared to be due to a direct reaction catalyzed by a microsomal glutathione S-transferase. A glutathione adduct of HCBD was isolated by thin-layer chromatography and mass spectral analysis strongly indicates the structure to be as S-(1,1,2,3,4-pentachloro-1,3-butadienyl)glutathione, confirming a direct substitution reaction without prior oxidation. This conjugate was formed at a faster rate by the hepatic microsomal fraction than by the cytosolic fraction suggesting a major role for the microsomal glutathione S-transferases in the disposition of this compound. A second more polar glutathione-dependent adduct which may be a double conjugate was formed with cytosol. Glutathione adducts were also formed by male and female kidney cytosol and microsomal fractions but at a slower rate than in liver fractions. It is suggested that the glutathione conjugate of HCBD may be converted to the cysteine derivative, the structure of which is similar to that of S-dichloro-vinyl-L-cysteine and therefore may be nephrotoxic by a similar mechanism.

Animals↗
PubMed1998

Glutathione-dependent biotransformation of the alkylating drug thiotepa and transport of its metabolite monoglutathionylthiotepa in human MCF-7 breast cancer cells.

In this study, the role of glutathione S-transferase (GST) P1-1, the cellular reduced glutathione (GSH) status, and ATP-dependent efflux pumps in the cellular glutathione-dependent biotransformation of thiotepa and transport of the main metabolite monoglutathionylthiotepa in relation to cytotoxicity was studied in control and GST-P1-1-transfected MCF-7 cell lines. It was demonstrated that an enhanced cellular level of GST-P1-1 leads to an enhanced formation of monoglutathionylthiotepa, which is transported out of the cell into the medium. Monoglutathionylthiotepa was able to reversibly inhibit the activity of purified GST-P1-1, but only at nonphysiological concentrations, indicating that feedback inhibition of GST by its metabolites is not a relevant process in vivo. The GST activity, cellular GSH level, and/or ATP-dependent efflux of monoglutathionylthiotepa were modulated using ethacrynic acid, D,L-buthionine-S,R-sulfoximine, probenecid, and verapamil to understand the interplay between GSTs, glutathione conjugation, and efflux of glutathione conjugates in more detail. Inhibition of the GSH biosynthesis by D,L-buthionine-R,S-sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, significantly reduced the glutathione conjugation of thiotepa and potentiated the cytotoxicity of thiotepa. Pretreatment of cells with ethacrynic acid resulted in decreased formation of monoglutathionylthiotepa as a result of inhibition of GST in the GST-P1-1 transfectant. In addition, the intracellular amount of monoglutathionylthiotepa increased in both of the cell lines on exposure to ethacrynic acid, indicating that transport of the glutathione conjugate was partially inhibited by the glutathione conjugate of ethacrynic acid. Transport activity of monoglutathionylthiotepa could also be inhibited by probenecid and verapamil, inhibitors of organic anion transport, without influencing the biotransformation capacity of the cells. It was demonstrated that inhibition of glutathione conjugate efflux by probenecid and verapamil leads to enhanced cytotoxicity, which indicates that besides thiotepa, monoglutathionylthiotepa is also cytotoxic for the cells. Only enhanced biotransformation and subsequent transport of the glutathione conjugate into the medium (which occurs with the GST-P1-1 transfectant) results in enhanced viability. Therefore, it was concluded that only enhanced biotransformation of thiotepa represents a real detoxification pathway when the resulting conjugate is transported out of the cells. Altogether, the results indicate that it is not the overexpression of GST per se but the interplay between GSH/GST and glutathione conjugate efflux pumps that results in increased resistance to alkylating anticancer drugs such as thiotepa.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats.

Ageing is characterized by a failure to maintain homeostasis under conditions of physiological stress, with an increasing susceptibility to disease and death. The accumulation of errors committed by faulty biochemical reactions over a vast period generates the cumulative effect observed during ageing. The most notable among the effects of ageing are the age-related disorders where free radicals are the major cause. When the level of free radicals increases because of diet, lifestyle, environment or other influences, it results in subsequent reduction of antioxidants. Reduced glutathione is one of the most fascinating molecules virtually present in all animal cells in often quite higher concentrations. An essential mechanism that accounts for most of the metabolic and cell regulatory properties of glutathione is the thiol disulfide exchange equilibria. We evaluated the age-associated alterations in glutathione dependent enzymes, glutathione and hydroxyl radicals in young and aged rats with respect to lipoate supplementation. In aged rats, activities of glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase and the level of glutathione were low, whereas the level of hydroxyl radical was higher than in the young ones. Administration of DL-alpha-lipoic acid, a thiol antioxidant intraperitoneally to the aged rats, led to a time-dependent reduction in hydroxyl radicals and elevation in the activities/level of glutathione systems. Hence it can be suggested that lipoate, a dithiol prevents the oxidation of reduced glutathione and protects its related enzymes from peroxidative damage.

Aging↗
PubMedDate not supplied

Effect of in vivo hyperoxia on the glutathione system in neonatal rat lung.

Relative resistance to oxygen toxicity in newborn animals of some species has been associated with a rapid increase in antioxidants in lung tissue homogenate. This study investigated the effect of hyperoxia on the glutathione system antioxidants in lung tissue of neonatal rats exposed to hyperoxia for 15 days. Neonatal rats were exposed to either 100% oxygen or air for 0, 3, 6, 9, 12, and 15 days prior to sacrifice for determination of glutathione and the glutathione system antioxidant enzymes in whole lung homogenate. There were significantly higher levels of total glutathione at 3, 6, and 9 days and of reduced glutathione at 3 and 6 days in oxygen-exposed animals compared to air-exposed controls. These differences were no longer present after 12 or 15 days of exposure to hyperoxia. Glutathione peroxidase and glucose-6-phosphate dehydrogenase remained higher in lung tissue from oxygen-exposed animals from 6 through 12 days of hyperoxia. The failure to maintain sustained high levels of total glutathione during hyperoxia might suggest that glutathione depletion is a factor in the timing of death from oxygen toxicity in these animals. The absence of a sustained increase in oxidized glutathione disulfide is more consistent with other explanations for this transient increase in total glutathione.

Animals↗
PubMedDate not supplied

[Activity of glutathione-dependent enzymes and superoxide dismutase in peptic ulcer].

Activity of Cu, Zn-superoxide dismutase, glutathione-S-peroxidase, glutathione-S-transferase, glutathione reductase, glucoso-6-phosphate dehydrogenase and content of glutathione reduced in blood of patients with gastric and duodenal ulcer depending on the age and parallel lesion of the hepatobiliary system have been studied. Considerable inhibition of superoxide dismutase, glucoso-6-phosphate-dehydrogenase activity and decrease of the content of reduced glutathione, the most pronounced in patients with parallel lesion of the hepatobiliary system, have been revealed. Glutathione reductase activity is high in all the patients, except for aged and old people with parallel lesions of the liver and biliferous tracts. Glutathione peroxidase is essentially active in adult patients, especially in case of combined pathology. Glutathione peroxidase activity is lower in aged and old patients as compared to the age norm, while the level of glutathione-S-transferase activity is high; at the same time there are no considerable changes in the glutathione-S-transferase activity in adult patients. The mechanisms of compensation and decompensation of functioning of enzymatic antiradical and antioxidant system under the peptic ulcer depending on the age of patients and concomitant lesions of the hepatobiliary system are discussed.

Adult↗
PubMed1984

Blood glutathione as a measure of exposure to toxic compounds.

Blood and liver glutathione levels were measured under the effect of an acute exposure to high doses of glutathione-depleting substances. Among direct-acting glutathione-depleting substances, diethyl maleate (0.3, 0.7 and 1.4 ml kg-1) caused a marked reduction of both blood and liver glutathione, whereas methyl iodide (320 mg kg-1) led to a decrease in liver glutathione stores immediately and in blood stores with a longer latency. Indirectly glutathione-depleting substances, like paracetamol (0.5-1.0 g kg-1) and styrene (250 mg kg-1), caused a reduction of liver glutathione, but not a similar reduction of blood glutathione. Blood glutathione is not a good measure of organ glutathione stores when dealing with indirect-acting glutathione-depleting substances.

Acetaminophen↗
PubMed1989

Can glutathione-S-transferases function as intracellular heme carriers?

The possibility that glutathione-S-transferases can serve as heme carriers in cells was studied via the following two characteristics: the ability to bind hemin reversibly and the coordination between heme and glutathione-S-transferases level in the cell. two erythroleukemic cell lines that can be induced to synthesize hemoglobin were studied, K-562 and Friend murine erythroleukemia cells. It was found that hemin-associated glutathione-S-transferase tends to lose its native structure as expressed by partial irreversible inhibition of glutathione conjugation activity. In K-562 cells, a small increase in heme synthesis was induced, but under no condition could glutathione-S-transferase be elevated. In addition, introduction of high hemin from without caused large hemoglobin production but did not induce changes in the glutathione-S-transferase content. Dimethyl sulfoxide-induced Friend murine erythroleukemia cells synthesized a large amount of endogenous hemin that had to be transported from the mitochondria for hemoglobin synthesis. Although a concomitant increase in glutathione-S-transferase level (20-40%) was observed, it was only short-lived, unlike hemin, which continued to increase. These data indicate a lack of correlation between glutathione-S-transferase and hemin or hemoglobin levels. Finally, dimethyl sulfoxide-induced cells were treated with succinyl acetone to inhibit heme synthesis. These cells showed the same increased levels and time-dependent pattern of glutathione-S-transferase as untreated cells. A similar phenomenon was observed when different substrates were used to measure the activities of glutathione-S-transferases. These results raise doubts about the possibility of glutathione-S-transferases functioning as heme carriers in cells.

Animals↗
PubMed1998

Role of glutathione in cisplatin resistance in osteosarcoma cell lines.

This study was designed to examine whether and how glutathione and catalase increase the resistance of osteosarcoma cells to the toxicity of cisplatin. Eight osteosarcoma cell lines were exposed to varying concentrations of cisplatin, and a [3H]thymidine incorporation study then estimated their drug sensitivity. Cells were pretreated with aminotriazole and buthionine sulfoximine to depress catalase and glutathione activities and then entered into the same protocol to assess their sensitivity to cisplatin. Intracytoplasmic levels of catalase and glutathione were measured before and after the treatments. Cisplatin-glutathione conjugates were created to examine how glutathione might depress the toxicity of cisplatin. Although the cell lines differed in the magnitude of their response to cisplatin, there was a statistical correlation between intrinsic glutathione content and cisplatin resistance. Pretreatment with aminotriazole reduced catalase activity by 84% but did not change the sensitivity to cisplatin. Depletion of glutathione activity by 70% increased the sensitivity of the cells to the cytotoxicity of cisplatin. In addition, cisplatin was detoxified following conjugation with glutathione. The increased sensitization to cisplatin toxicity caused by the depletion of glutathione and cisplatin detoxification after the in vitro reaction of glutathione to cisplatin indicated that the formation of the glutathione-cisplatin conjugate was an important mechanism in the cellular resistance to cisplatin. These data also demonstrated that catalase activity did not contribute to resistance to cisplatin and suggested that H2O2-induced oxidative stress did not significantly contribute to the cytotoxicity of cisplatin in osteosarcoma cells.

Adenosine Triphosphate↗
PubMed1994

Glutathione-dependent defense in channel catfish (Ictalurus punctatus) and brown bullhead (Ameriurus nebulosus).

Glutathione-dependent defense against xenobiotic toxicity is a multifaceted phenomenon that has been well characterized in mammals. This study undertakes a comparison of two benthic fish species, the channel catfish and brown bullhead, in terms of characteristics of the glutathione system. The channel catfish, a species that has seldom been observed to express pollutant-mediated neoplasia in field studies, was observed to have significantly higher constitutive levels of hepatic total glutathione and reduced glutatione (GSH). Brown bullhead, a species that is often observed to express neoplasia in contaminated systems, had significantly higher hepatic levels of glutathione disulfide. Furthermore, catfish expressed higher levels of activity of the enzymes gamma-glutamylcysteine synthetase (GCS), glutathione reductase (GR), and glutathione S-transferase, whereas bullhead expressed higher hepatic glutathione peroxidase (GPOX) activity. Both species responded to treatment with the redox active quinone, menadione, by expressing elevated hepatic content of total glutathione. However, the induction response was more rapid and more extensive in catfish compared to that in bullhead. This is attributable to the observed interspecific difference in GCS activity. Following treatment with the organic peroxide, tert-butyl hydroperoxide (t-BOOH), bullhead hepatic glutathione was depleted up to 4 hr post-treatment, whereas catfish demonstrated no significant depletion of glutathione in response to t-BOOH. The differing responses to t-BOOH are attributable to interspecific differences in hepatic GPOX and GR activity. Bullhead, therefore, appear to be more susceptible to the effects of GSH arylators and oxidants based upon constitutive levels of glutathione, related enzyme activities, and the response of this system to model xenobiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

The effect of glutathione depletion on methyl mercury-induced microtubule disassembly in cultured embryonal carcinoma cells.

Microtubule (MT) assembly and stability are thought to be dependent on intracellular glutathione for the maintenance of critical sulfhydryl groups. Since methyl mercury (MeHg) is a sulfhydryl-binding toxicant, it is possible that alteration of intracellular glutathione status might enhance the toxic effects of MeHg on microtubules. The influence of MeHg on the relationship between intracellular glutathione and the structural integrity of interphase microtubules was assessed in embryonal carcinoma cells by immunofluorescence microscopy, using antibodies to tyrosinated and acetylated alpha-tubulins. Intracellular glutathione concentrations were reduced by treatment with 10 microM buthionine sulfoximine (BSO; an inhibitor of gamma-glutamyl cysteine synthetase) for 18-24 hr. BSO-treated cells displayed little change in the pattern of microtubule staining, despite reduction of glutathione levels to less than 10% of control levels. Similarly, a combination of BSO and the nonspecific glutathione-depleting agent diethylmaleimide (DEM) had little effect on microtubule networks, except at the highest concentrations of DEM where nonspecific cytotoxicity was observed. The susceptibility of microtubules to MeHg-induced disassembly was determined in normal and glutathione-depleted cells incubated with 1.0 to 7.5 microM MeHg for 2 hr. MeHg treatment alone resulted in concentration-dependent disassembly of microtubules; depletion of glutathione with BSO prior to MeHg treatment did not enhance MT damage. Further, BSO-pretreated cells exposed to MeHg still showed substantial recovery of microtubule networks following removal of MeHg from culture media, even when glutathione levels remained less than 5% of control levels. These data indicate that the integrity of interphase microtubules is largely unaffected by reductions in glutathione concentration and that susceptibility of microtubules to MeHg-induced disassembly is not directly dependent on intracellular glutathione content.

Animals↗
PubMed1989

Age-related effect induced by oxidative stress on the cerebral glutathione system.

In the forebrain from male Wistar rats aged 5, 15 and 25 months, age-related putative alterations in the glutathione system (reduced and oxidized glutathione; redox index) were chronically induced by the administration in drinking water of free radical generators (hydrogen peroxide, ferrous chloride) or of inhibitors of endogenous free radical defenses (diethyl-dithio-carbamate, an inhibitor of superoxide dismutase activity). In hydrogen peroxide administered rats, both reduced glutathione and the cerebral glutathione redox index markedly declined as a function of aging, whereas oxidized glutathione consistently increased. In contrast, chronic iron intake failed to modify the reduced glutathione in forebrain from the rats of the different ages tested, whereas the oxidized glutathione was increased in the older brains. The chronic intake of diethyl-dithio-carbamate enhanced the concentrations of reduced glutathione in the forebrains from the rats of the different ages tested, the oxidized glutathione being unchanged. In 15-month-old rats submitted to chronic oxidative stress, ergot alkaloids (and particularly dihydroergocriptine) interfered with cerebral glutathione system, while papaverine was always ineffective. The comprehensive analysis of the data indicates that: (a) both the type of oxidative stress and the age of the animals modulate the cerebral responsiveness to the putative modifiers in the level of tissue free radicals; (b) aging magnifies the cerebral alterations induced by oxidative stress; the (c) cerebral glutathione system may be modified by metabolic rather than by circulatory interferences; (d) a balance between the various cerebral antioxidant defenses is present, the perturbation of an antioxidant system resulting in the compensatory modified activity of component(s) of another system.

Administration, Oral↗
PubMed2000

Relationship between colorectal cancer glutathione levels and patient survival: early results.

PURPOSE: Elevated glutathione is a cause of resistance to anticancer agents and x-rays. The purpose of this study was to determine the frequency and clinical significance of glutathione elevation in human colorectal cancer. METHODS: Glutathione levels were measured in 41 colon cancers, 24 rectal cancers, and corresponding normal tissues. The patients were then followed up prospectively for tumor recurrence and survival. Survival was analyzed by the Kaplan-Meir method and Cox proportional hazards regression. RESULTS: Glutathione levels in primary colorectal cancers were significantly higher than in the corresponding normal tissues. Elevated glutathione levels had a significant negative effect on survival in patients with colorectal cancer, whether based on the mean (P = 0.02) or median (P = 0.04) normal tissue levels. A negative effect of glutathione levels on survival was apparent in patients with colorectal cancer, whether or not they were treated with postoperative therapy. The larger the ratio of tumor glutathione to normal tissue glutathione, the poorer the prognosis. When adjusted for other covariates, glutathione was still a significant predictor of survival. CONCLUSIONS: An elevated tumor glutathione level at the time of diagnosis appears to confer a poor prognosis in patients with colorectal cancer. Longer-term study using a larger number of patients will be required to confirm these findings. Knowledge of tumor glutathione content may help identify patients requiring more intensive therapy.

Adult↗