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PubMed2000

Hgt1p, a high affinity glutathione transporter from the yeast Saccharomyces cerevisiae.

A high affinity glutathione transporter has been identified, cloned, and characterized from the yeast Saccharomyces cerevisiae. This transporter, Hgt1p, represents the first high affinity glutathione transporter to be described from any system so far. The strategy for the identification involved investigating candidate glutathione transporters from the yeast genome sequence project followed by genetic and physiological investigations. This approach revealed HGT1 (open reading frame YJL212c) as encoding a high affinity glutathione transporter. Yeast strains deleted in HGT1 did not show any detectable plasma membrane glutathione transport, and hgt1Delta disruptants were non-viable in a glutathione biosynthetic mutant (gsh1Delta) background. The glutathione repressible transport activity observed in wild type cells was also absent in the hgt1Delta strains. The transporter was cloned and kinetic studies indicated that Hgt1p had a high affinity for glutathione (K(m) = 54 micrometer)) and was not sensitive to competition by amino acids, dipeptides, or other tripeptides. Significant inhibition was observed, however, with oxidized glutathione and glutathione conjugates. The transporter reveals a novel class of transporters that has homologues in other yeasts and plants but with no apparent homologues in either Escherichia coli or in higher eukaryotes other than plants.

Amino Acid Sequence↗

PubMed2002

Glutathione levels and BAX activation during apoptosis due to oxidative stress in cells expressing wild-type and mutant cystic fibrosis transmembrane conductance regulator.

Cystic fibrosis is characterized by chronic inflammation and an imbalance in the concentrations of alveolar and lung oxidants and antioxidants, which result in cell damage. Modifications in lung glutathione concentrations are recognized as a salient feature of inflammatory lung diseases such as cystic fibrosis, and glutathione plays a major role in protection against oxidative stress and is important in modulation of apoptosis. The cystic fibrosis transmembrane conductance regulator (CFTR) is permeable to Cl(-), larger organic ions, and reduced and oxidized forms of glutathione, and the DeltaF508 CFTR mutation found in cystic fibrosis patients has been correlated with impaired glutathione transport in cystic fibrosis airway epithelia. Because intracellular glutathione protects against oxidative stress-induced apoptosis, we studied the susceptibility of epithelial cells (HeLa and IB3-1) expressing normal and mutant CFTR to apoptosis triggered by H(2)O(2). We find that cells with normal CFTR are more sensitive to oxidative stress-induced apoptosis than cells expressing defective CFTR. In addition, sensitivity to apoptosis could be correlated with glutathione levels, because depletion of intracellular glutathione results in higher levels of apoptosis, and glutathione levels decreased faster in cells expressing normal CFTR than in cells with defective CFTR during incubation with H(2)O(2). The pro-apoptotic BCL-2 family member, BAX, is also activated faster in cells expressing normal CFTR than in those with mutant CFTR under these conditions, and artificial glutathione depletion increases the extent of BAX activation. These results suggest that glutathione-dependent BAX activation in cells with normal CFTR represents an early step in oxidative stress-induced apoptosis of these cells.

Amino Acid Substitution↗

PubMed2000

Kinetic and structural characterization of the glutathione-binding site of aldose reductase.

Aldose reductase (AR), a member of the aldo-keto reductase superfamily, has been implicated in the etiology of secondary diabetic complications. However, the physiological functions of AR under euglycemic conditions remain unclear. We have recently demonstrated that, in intact heart, AR catalyzes the reduction of the glutathione conjugate of the lipid peroxidation product 4-hydroxy-trans-2-nonenal (Srivastava, S., Chandra, A., Wang, L., Seifert, W. E., Jr., DaGue, B. B., Ansari, N. H., Srivastava, S. K., and Bhatnagar, A. (1998) J. Biol. Chem. 273, 10893-10900), consistent with a possible role of AR in the metabolism of glutathione conjugates of aldehydes. Herein, we present several lines of evidence suggesting that the active site of AR forms a specific glutathione-binding domain. The catalytic efficiency of AR in the reduction of the glutathione conjugates of acrolein, trans-2-hexenal, trans-2-nonenal, and trans,trans-2,4-decadienal was 4-1000-fold higher than for the corresponding free alkanal. Alterations in the structure of glutathione diminished the catalytic efficiency in the reduction of the acrolein adduct, consistent with the presence of specific interactions between the amino acid residues of glutathione and the AR active site. In addition, non-aldehydic conjugates of glutathione or glutathione analogs displayed active-site inhibition. Molecular dynamics calculations suggest that the conjugate adopts a specific low energy configuration at the active site, indicating selective binding. These observations support an important role of AR in the metabolism of glutathione conjugates of endogenous and xenobiotic aldehydes and demonstrate, for the first time, efficient binding of glutathione conjugates to an aldo-keto reductase.

Aldehyde Reductase↗

PubMed1994

Glutathione S-transferases in liver metastases of colorectal cancer. A comparison with normal liver and primary carcinomas.

Glutathione S-transferase activity and levels of glutathione S-transferases-alpha, -mu and -pi were determined in 10 matched pairs of normal liver and liver metastasis from patients with colorectal cancer. For comparison, six matched pairs of colorectal cancer and normal mucosa were analysed. All metastases had a lower glutathione S-transferase activity when compared to the matched normal liver tissue (224 +/- 21 versus 900 +/- 95 nmol/min.mg protein respectively, P < 0.001). Mean activities in primary tumours and normal colorectal tissue were 176 +/- 22 and 150 +/- 13 nmol/min.mg protein respectively. When analysed by immunoblot techniques, each metastasis contained less glutathione S-transferase-alpha than the surrounding normal liver (mean values 3.3 +/- 0.8 versus 21.8 +/- 1.8 micrograms/mg protein respectively, P < 0.001). Glutathione S-transferase-alpha was undetectable in all primary tumours and normal colonic mucosa. Glutathione S-transferase-mu was detected in only two patients with liver metastases and in two patients with primary colorectal cancer. All metastases contained more glutathione S-transferase-pi than the surrounding normal liver tissue (3.7 +/- 0.5 versus 0.4 +/- 0.1 micrograms/mg protein respectively, P < 0.001). The values in the metastases were very similar to those in the primary colonic tumours (normal mucosa 2.3 +/- 0.3 and tumours 3.3 +/- 0.7 micrograms/mg protein). Immunohistochemical investigation of the metastases revealed that glutathione S-transferase-alpha is not located in the malignant cells, but only in hepatocytes in what macroscopically seemed to be pure metastatic tissue. Staining for glutathione S-transferase-pi reveals generally positive tumour cells and, except for the biliary epithelium, only faint staining of the hepatocytes. It is concluded that liver metastases of colorectal carcinomas have very similar glutathione S-transferase enzyme activities and composition as compared with primary tumours.

Adenocarcinoma↗

PubMed1977

Rat liver glutathione: possible role as a reservoir of cysteine.

Rat liver contains a high concentration (7-8mM) of reduced glutathione and its level changes rapidly when starving or feeding rats. We concluded that one of the functions of liver glutathione was to act as a reservoir of cysteine. When starved rats were fed a protein-free diet, the increase in liver glutathione was dependent on the amount of cysteine added to the diet. A cysteine-dependent increase of glutathione was also observed in rats fed a diet containing gelatin with cysteine, but the increase was relatively lowered compared with rats fed a protein-free diet containing the same amount of cysteine. This suppression of the increase in glutathione was observed much more clearly when the gelatin diet was fortified with tryptophan in addition to cysteine. In the presence of tryptophan, L-[35S]-cysteine in the diet appeared to be incorporated primarily into liver and serum proteins, and degradation of liver glutathione must also have been enhanced. Addition of excess cysteine to the diet masked the effects of gelatin and tryptophan, stimulated glutathione synthesis in the liver as well as incorporation of dietary cysteine into protein fractions. Prolonged starvation of rats or injection of dibutyryl-3',5'-cyclic AMP lowered the glutathione level,but the level did not decrease below 2 to 3 mM. These findings suggest that there may be at least two pools of glutathione. A labile fraction, constituting one-third to one-half the total liver glutathione, probably serves as a reservoir of cysteine which can be released by gamma-glutamyl-transferase when necessary.

Animals↗

PubMed1995

The role of the glutathione-dependent system in tumor sensitivity to cisplatin: a study of human tumor xenografts.

BACKGROUND: Glutathione, the most important intracellular thiol, has been implicated in modulating tumor cell sensitivity to alkylating agents and cisplatin. However, the role of the glutathione-dependent detoxification system in mediating cisplatin resistance of human tumors remains unclear. DESIGN: Glutathione content and related enzyme activities were assessed in a series of human tumor xenografts representative of responsive (i.e., small-cell lung cancer and ovarian carcinoma) and resistant tumor types (i.e., non-small-cell lung cancer and colorectal carcinoma), in an attempt to establish a correlation with response to cisplatin treatment. RESULTS: The pattern of tumor response to cisplatin treatment for tumors selected in the two panels corresponded to the one expected from the clinical experience, since drug-induced tumor growth inhibition ranged from 70% to 100% in the group of sensitive tumors and from 20% to 60% in the group of resistant tumors. No correlation was observed between glutathione level and cisplatin response in the resistant tumor panel. An inverse correlation was found for glutathione-S-transferase activity level and tumor response only in the panel of chemoresponsive tumors. In the latter panel, the only unresponsive tumor (POCS) showed the highest glutathione level in the entire series investigated. No significant correlation was found between other enzymes investigated and tumor response to cisplatin treatment. In addition, a very low activity of gamma-glutamyltranspeptidase was found to be associated with sensitive tumors. CONCLUSIONS: Although glutathione may have a role in modulating cisplatin cell sensitivity, it is unlikely that alteration in glutathione level and metabolism is a primary mechanism of cisplatin resistance in human tumors, since: a) no significant correlations were found between glutathione level and response to cisplatin treatment in a series of chemosensitive and chemoresistant human tumor xenografts; b) a marked increase in glutathione level might be responsible for cisplatin resistance but, in contrast to findings on cell systems selected in vitro for resistance, it is not a frequent event in human tumors.

Animals↗

PubMed1997

Glutathione regulates nitric oxide synthase in cultured hepatocytes.

OBJECTIVE: The authors determine the relationship between glutathione and nitric oxide (NO) synthesis in cultured hepatocytes. SUMMARY BACKGROUND DATA: Glutathione is a cofactor for a number of enzymes, and its presence is essential for maximal enzyme activity by the inducible macrophage nitric oxide synthase (iNOS), which produces the reactive nitric oxide radical. Hepatocytes contain substantial quantities of glutathione, and this important tripeptide is decreased in hepatocytes stressed by ischemia/reperfusion or endotoxemia. Endotoxemia also induces the synthesis of inflammatory cytokines that result in the production of nitric oxide from hepatocytes by iNOS, suggesting that hepatocytes may be attempting to synthesize nitric oxide at times when intracellular glutathione is reduced. METHODS: Hepatocytes were cultured with buthionine sulfoximine and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU) to inhibit glutathione. After exposure to cytokines, NO synthesis was assessed by supernatant nitrite levels, cytosolic iNOS enzyme activity, and iNOS mRNA levels. RESULTS: Inhibition of glutathione synthesis with buthionine sulfoximine or inhibition of glutathione reductase activity with BCNU inhibited nitrite synthesis. Both buthionine sulfoximine and BCNU inhibited the induction of iNOS mRNA, as detected by Northern blot analysis. Exogenous glutathione increased cytokine-stimulated iNOS induction, overcame the inhibitory effects of BCNU, and increased nitrite production by intact hepatocytes, induced hepatocyte cytosol, and partially purified hepatocyte iNOS. CONCLUSIONS: In cultured hepatocytes, adequate glutathione levels are required for optimal nitric oxide synthesis. This finding is predominantly due to an effect on iNOS mRNA levels, although glutathione also participates in the regulation of iNOS enzyme activity.

Animals↗

PubMed1997

Skeletal muscle glutathione is depleted in critically ill patients.

OBJECTIVE: To investigate the concentrations of reduced and total glutathione in relation to the muscle free amino acid pattern in critically ill patients and matched healthy controls. DESIGN: Prospective case control. SETTING: University hospital intensive care unit (ICU). PATIENTS: Eleven critically ill patients in the intensive care unit were studied after a stay of at least 4 days. Eleven age- and gender-matched metabolically healthy patients undergoing elective surgical procedures served as controls. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Reduced and total glutathione concentrations were determined in skeletal muscle, in plasma, and in whole blood, together with muscle free amino acid concentrations. In the ICU group, reduced and total glutathione values were 57% and 62%, respectively, of the values seen in the control group (p < .001). In addition, a decreased ratio between reduced and total glutathione compared with the controls was seen (0.80 as compared with 0.91, p < .001). The glutamine concentration in skeletal muscle in the ICU group was 72% lower compared with that value seen in healthy controls (p < .001). Correlations were found between the concentrations of glutamine and the total muscle glutathione (r2 = .46, p < .001), as well as between glutamine and the ratio of reduced and total glutathione (r2 = .45, p < .001) in skeletal muscle, suggesting that the redox status of glutathione and the glutamine status of the tissue are related. CONCLUSIONS: Critical illness is associated with alterations in muscle glutathione metabolism. The muscle-reduced glutathione concentrations decrease and, in addition, the ratio between reduced and total glutathione decreases, indicating a situation of oxidative stress in this tissue. This decrease may impair the defense of muscle against oxygen free radicals and influence amino acid transport, thus contributing to the loss of balance between protein synthesis and protein degradation that is characteristic of protein catabolism.

Adult↗

PubMed1995

Identification of the electrophilic substrate-binding site of glutathione S-transferase P by photoaffinity labeling.

We determined the electrophilic substrate-binding site of rat glutathione S-transferase P (GST-P) by photoaffinity labeling using the photosensitive compound S-[2-(2-fluoro-4-nitrophenoxy)ethyl]glutathione. This photosensitive glutathione analogue inhibited the catalytic activity in a competitive manner against both glutathione and 1-chloro-2,4-dinitrobenzene, a putative electrophilic substrate. The enzyme kinetics indicated that the photoactivatable glutathione analogue was specifically bound at the active site, which consisted of glutathione-binding (G-site) and the electrophilic substrate-binding (H-site) regions. The procedure involved the following steps: S-[2-(2-fluoro-4-nitrophenoxy)ethyl]glutathione was photochemically reacted with a purified recombinant GST-P expressed in Escherichia coli using ultraviolet irradiation for 30 min on ice. After the reaction, only the GST-P complexed with the glutathione analogue was prepared with glutathione-immobilized agarose. The GST-P covalently bound with the analogue was digested with lysyl endopeptidase (Achromobacter protease I), and the peptides were separated by high-performance liquid chromatography. Only a single major peak with appreciable absorbance at 340 nm was observed by peptide mapping. The peptide was collected and analyzed using an automated peptide sequencer (ABI 477A). Amino acid sequence analysis showed that this peptide consisted of seven amino acid residues corresponding to the sequence at positions 122-128 of GST-P (Ala-Leu-Pro-Gly-Xaa-Leu-Lys). No appreciable phenylthiohydantoin-amino acid was detected at the fifth cycle, which indicated that His126 was chemically labeled with the photosensitive glutathione analogue. It was concluded that His126 was one of the amino acid residues forming the electrophilic substrate-binding site of GST-P.

Amino Acid Sequence↗

PubMed1993

Inhibition of acetaminophen oxidation by cimetidine and the effects on glutathione and activated sulphate synthesis rates.

The aim of the present study was to examine the effects of the hepatotoxic drug, acetaminophen, on the synthesis rates of glutathione, activated sulphate (PAPS, adenosine 3'-phosphate 5'-phosphosulphate) and the acetaminophen metabolites, acetaminophen-glutathione and acetaminophen-sulphate after inhibition of cytochrome P-450 drug oxidation by cimetidine in isolated rat hepatocytes. The synthesis rates of glutathione and PAPS were determined simultaneously by an established method based on trapping of radioactivity (35S) in the prelabelled glutathione and PAPS pools. Preincubation of the hepatocytes with 60 micrograms/ml cimetidine for 30 min. did not affect PAPS (1.71 versus 1.78 nmol/10(6) cells) nor glutathione concentration (16.0 versus 16.4 nmol/10(6) cells). The subsequent incubation with 5 mM acetaminophen resulted in decreased PAPS synthesis in the cimetidine treated cells [0.79 x 10(3) versus 0.92 x 10(3) nmol/(10(6) cells.hr)] (P < 0.05). There was no difference in PAPS concentration or acetaminophen-sulphate synthesis [1.73 versus 1.79 nmol/10(6) cells and 13.0 versus 12.9 nmol/(10(6) cells.hr), respectively]. Decreased PAPS synthesis may be related to decreased ATP supply or may be the result of a feed-back regulation due to diversion of sulphur from glutathione synthesis to sulfoxidation. The glutathione synthesis was not significantly affected by cimetidine treatment [57 x 10(3) versus 27 x 10(3) nmol/(10(6) cells.hr)]. As expected acetaminophen-glutathione synthesis decreased by 38% [1.66 versus 2.68 nmol/(10(6) cells.hr)] (P < 0.01). Also the glutathione concentration was lower in cimetidine treated cells [15.2 versus 15.9 nmol/10(6) cells] (P < 0.05). We have previously shown that glutathione synthesis was reduced if substrate availability decreased (acetaminophen concentration lowered).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗

PubMed1993

Effect of glutathione on canine myocardial ischaemia without reperfusion.

The present study was to evaluate the effect of exogenous glutathione on myocardial damage resulting from permanent (no reperfusion) coronary ligation (3 or 6 h) in anaesthetized dogs. Haemodynamics, infarct size and myocardial glutathione content were determined. Erythrocyte superoxide dismutase (SOD) activity was also determined in coronary venous blood samples. Glutathione was administered by the intraperitoneal route, 100 mg kg-1 as initial dose given 5 min before coronary ligation, and successive doses of 25 mg kg-1 every 40 min throughout the study period. Saline-treated dogs showed myocardial infarction, a decrease in myocardial glutathione content, and a transient increase in SOD activity. Three hours occlusion in glutathione-treated dogs resulted in a small reduction of infarct size, and no changes in myocardial glutathione content and SOD activity. By contrast, administration of glutathione failed to reduce infarct size and failed to prevent myocardial glutathione decrease in dogs subjected to 6 h occlusion. These results indicate that exogenous glutathione is of minor beneficial effect for myocardial damage resulting from permanent coronary occlusion and suggest that endogenous glutathione has a limited role in protecting against myocardial ischaemia without reperfusion.

Animals↗

PubMed2001

Raised blast glutathione levels are associated with an increased risk of relapse in childhood acute lymphocytic leukemia.

A preliminary study has linked raised blast glutathione levels with chemoresistance in acute myeloid and lymphoblastic leukemia in adults and children. In this study, therefore, the relationship between leukemic blast glutathione levels and prognosis in childhood acute lymphoblastic leukemia (ALL) was investigated. A total of 77 childhood ALL samples were analyzed, 62 at initial presentation and 15 at relapse. A 20-fold interindividual variation in glutathione levels at presentation (median, 6.54 nmol/mg protein; range, 1.37 to 27.9) was demonstrated. The median level in T-lineage ALL was 2. 3-fold higher than in B-lineage ALL (Mann-Whitney test, P <.0001). There was a significant correlation between presenting white cell count (WBC) and glutathione level (Spearman rank correlation coefficient, rho = 0.45, P =.001). A high DNA index correlated with low glutathione levels (Mann-Whitney test, P =.013). There was no significant relationship between glutathione levels and in vitro drug sensitivity. Patients with glutathione levels above the median had a significantly greater risk of relapse (log-rank test statistic, 5.55; P =.018), and the overall survival rate was significantly reduced (log-rank test statistic, 4.38; P =.04). Multivariate analysis demonstrated that glutathione concentration was of independent prognostic value when assessed in conjunction with age, gender, WBC, and immunophenotype. The association of elevated blast glutathione levels with an increased risk of relapse suggests that glutathione-depleting agents may be of therapeutic value in patients who present with a high WBC.

Actuarial Analysis↗

PubMed1999

Survival of guinea pig pups in hyperoxia is improved by enhanced nutritional substrate availability for glutathione production.

The imbalance between high oxidant loads and immature antioxidant defenses is associated with long-term complications of prematurity. Glutathione is a central element among the antioxidants. Depletion of pulmonary glutathione accelerates the development of oxygen-induced lung injury in neonatal animal models. After the observation that newborn infants exposed to oxygen have low glutathione levels, a study was designed to test the hypothesis that in neonates from a species susceptible to oxygen toxicity, the lethal effect of hyperoxia is related to a low availability of substrates for glutathione production rather than an impairment in synthetic activity. One-day-old guinea pigs, randomly assigned to room air or oxygen (>95%), were fed by their mothers (n = 16) or i.v. by dextrose (n = 14) or by total parenteral nutrition (TPN, n = 20). After 3 d, glutathione and activities of enzymes involved in maintaining intracellular glutathione levels were determined in lungs and liver. The lethal effect of oxygen (p < 0.05) observed in animals without TPN was not related to glutathione depletion, as oxygen induced a 33% increase in lung glutathione, positively correlated (r2 = 0.35) with enhanced synthesis. With TPN, the animals were protected against the lethal effects of hyperoxia and lung glutathione increased by 67% in oxygen. The results suggest that the glutathione demand by the lungs in the presence of an oxidant stimulus was met by the increased (p < 0.001) hepatic production supported by TPN. Under hyperoxic conditions, early nutritional support is of vital importance.

Animals↗

PubMed1998

Elevation of whole-blood glutathione in peritoneal dialysis patients by L-2-oxothiazolidine-4-carboxylate, a cysteine prodrug (Procysteine).

Glutathione is a major cellular antioxidant that protects protein thiols and inhibits cellular damage due to oxygen free radicals. It has been reported previously that patients undergoing dialysis have low levels of blood glutathione, which may lead to increased susceptibility to oxidant stress. L-2-oxothiazolidine-4-carboxylic acid (OTZ) is a cysteine prodrug that raises cellular glutathione levels by increasing delivery of cysteine, the rate-limiting substrate for glutathione synthesis. This study investigates the effect of OTZ on blood glutathione in a blinded, placebo-controlled study of patients with chronic renal failure treated by peritoneal dialysis. Twenty patients were randomly selected to receive OTZ (0.5 g three times a day orally with meals) or placebo for 14 d. Patients visited the clinic for predose blood collection and safety evaluation at baseline (days 3, 7, and 14 and again at 14 d from the last dose [follow-up]). Glutathione concentrations were determined in whole blood by HPLC. OTZ resulted in a significant rise in whole-blood glutathione at days 7 (594 +/- 129 mumol/L) and 14 (620 +/- 108 mumol/L) compared with baseline (544 +/- 139 mumol/L) (P < 0.01 and P < 0.05, respectively). Glutathione was also significantly increased at days 7 and 14 when normalized by hematocrit (Hct) or hemoglobin to correct for anemic status (e.g., 20.7 +/- 5.7 mumol/L per % Hct [day 7] and 20.9 +/- 4.0 mumol/L per % Hct [day 14] versus 18.0 +/- 4.2 mumol/L per % Hct [baseline]; P < 0.05). Glutathione levels did not change in the placebo group at any patient visit, and levels in the OTZ-treated group returned to baseline at follow-up. There were no serious adverse events attributable to OTZ, and the drug appeared to be well tolerated by patients with renal failure treated by continuous ambulatory peritoneal dialysis. Our results show that OTZ increases blood glutathione levels, which may improve antioxidant status in dialysis patients.

Administration, Oral↗

PubMed1996

Investigations into the loss of glutathione from lenses in organ culture.

PURPOSE: To investigate possible causes and implications of the decrease in glutathione concentration in rat lenses during organ culture. METHODS: Freshly excised lenses were incubated in modified TC-199 medium. Ellman's Reagent or the GSH-400 assay were used to assay glutathione levels in lenses cultured for different times and under a variety of altered culture conditions. RESULTS: In lenses from young rats the glutathione decrease was not ameliorated by reduction of oxygen tension in the incubator, nor by supplementation of the culture medium with various antioxidants or sulfhydryl compounds, nor with the amino acid precursors of glutathione. Addition of 2-mercaptoethanol stimulated cysteine transport into the lens but had only a modest effect in maintaining the level of glutathione. The decrease in glutathione concentration was less in cultured lenses from older rats. Lenses from rhesus monkeys exhibited no decrease in glutathione levels when maintained in organ culture for up to 48 h. CONCLUSIONS: The basis for the decreased glutathione in cultured young rat lenses is still uncertain. The data from the present study indicate a definite relationship between glutathione loss and age for cultured rat lenses, with young lenses being much more susceptible. The resistance of cultured monkey lenses to loss of glutathione demonstrates species differences in this property which may be relevant to previously reported differences in susceptibility to oxidative damage.

Aging↗

PubMedDate not supplied

The role of glutathione in the gastrointestinal tract: a review.

The primary role of glutathione is to protect cells from oxidative stress. It is abundantly distributed in the mucosal cells of gastrointestinal tract both in animals and man. The highest concentration is found in the duodenum. The amount of glutathione ingested with foods, age and drug or ethanol consumption affect glutathione concentration. The detoxifying capability of glutathione is directly related to its thiol group and to its function as a substrate for enzymatic activity; in fact, glutathione regulates the action of glutathione-peroxidases and glutathione-transferases. It has been documented that a direct relation between glutathione concentration and mucosal damage or between glutathione-related enzymes and cancer occurrence is present in various pathological conditions of the gastrointestinal tract (from oesophagus to rectum). The present review underlines: a) the role of oxidative stress in numerous physiological and pathological conditions in experimental animals and man; b) the need to maintain a normal antioxidant potential in the mucosal cells of the gastrointestinal tract; and c) the possibility to evaluate, through clinical studies, how glutathione concentration, food intake, and gastrointestinal diseases are associated.

Animals↗

PubMed2000

Inhibition of selenite cataract by S-diethylsuccinyl glutathione isopropyl ester.

PURPOSE: Previous studies have demonstrated that glutathione derivatives can partially prevent loss of hepatic glutathione levels, in vivo, during periods of oxidative stress. Since cataracts in animal model systems and in humans are thought to be the direct result of oxidative insult, the following study tested the possibility that treatment with these glutathione analogues may affect the progression of lens opacification. METHODS: Glutathione esters were tested for their ability to inhibit the selenite-induced cataract in rats. RESULTS: The S-alkyl glutathione ester Et(2)Sc-GS-iPr, but not a similar glutathione derivative S-succinyl glutathione (Sc-GS), at 0.5 mmoles/kg body weight, had anti-cataract activity in the selenite-induced cataract of rats. Analysis of lenses from treated and untreated animals demonstrated that Et(2)Sc-GS-iPr partially prevented the loss of reduced glutathione levels. CONCLUSIONS: The results demonstrate for the first time that an S-alkylated glutathione ester has anti-cataractogenic potential in the selenite-treated rat, and suggest possible mechanisms involving glutathione in the prevention of this lens opacification.

Animals↗

PubMed1990

Cysteamine increases homocysteine export and glutathione content by independent mechanisms in C3H/10T1/2 cells.

Several thiols, including homocysteine and cysteamine, have been shown to increase glutathione levels in C3H/10T1/2 Cl 8 cells [Biochem. Pharmacol. 39:421-429 (1990)]. The present paper shows that cysteamine also increases homocysteine export from these cells. Cellular glutathione content and export of glutathione and homocysteine increased with increasing doses of cysteamine. Twenty-four hours after addition, 300 microM cysteamine increased both glutathione content and homocysteine export 3-4-fold. No change in the ratio between reduced and oxidized glutathione could be detected, suggesting that the cysteamine effect was not due to reduction of pools of oxidized glutathione. The elevation of glutathione occurred rapidly but declined between 24 and 48 hr after addition of cysteamine, whereas the homocysteine export increased momentarily after cysteamine exposure and then proceeded at a rate similar to that from untreated control cells. The cysteamine-induced increase in glutathione was completely prevented by the gamma-glutamylcysteine synthetase inhibitor buthionine sulfoximine but was not affected by inhibition of homocysteine formation by 3-deazaaristeromycin. Buthionine sulfoximine did not prevent the increase in homocysteine export by cysteamine, and only a small increase in homocysteine export was observed when the cells were exposed to 3-deazaaristeromycin before treatment with cysteamine. Two major conclusions were drawn. 1) Increase of glutathione content and homocysteine export by cysteamine were independent events, indicating that glutathione status and homocysteine formation are regulated by independent mechanisms in C3H/10T1/2 Cl 8 cells. 2) S-Adenosylhomocysteine catabolism was the main source of the homocysteine export induced by cysteamine.

Animals↗