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PubMed1993

Glutathione-related enzymes, glutathione and multidrug resistance.

This review examines the hypothesis that glutathione and its associated enzymes contribute to the overall drug-resistance seen in multidrug resistant cell lines. Reports of 34 cell lines independently selected for resistance to MDR drugs are compared for evidence of consistent changes in activity of glutathione-related enzymes as well as for changes in glutathione content. The role of glutathione S-transferases in MDR is further analyzed by comparing changes in sensitivity to MDR drugs in cell lines selected for resistance to non-MDR drugs that have resulting increases in glutathione S-transferase activity. In addition, results of studies in which genes for glutathione S-transferase isozymes were transfected into drug-sensitive cells are reviewed. The role of the glutathione redox cycle is examined by comparing changes in elements of this cycle in MDR cell lines as well as by analyzing reports of the effects of glutathione depletion on MDR drug sensitivity. Overall, there is no consistent or compelling evidence that glutathione and its associated enzymes augment resistance in multidrug resistant cell lines.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1990

The interaction of ethanol and zinc on hepatic glutathione and glutathione transferase activity in mice.

The effects of ethanol and/or zinc sulphate on liver glutathione and glutathione transferase activity were studied in mice. Ethanol suppressed glutathione transferase activity and had no significant effect on glutathione levels in the organ. Zinc sulphate administration dose-dependently increased glutathione transferase activity but did not affect hepatic glutathione content. Furthermore, the depressive action of ethanol on glutathione transferase activity was prevented by zinc sulphate pretreatment. It is suggested that zinc sulphate can reactivate glutathione transferase which in turn increases the excretion of the active metabolites produced by ethanol, through conjugation with glutathione in the liver. This action of zinc may alleviate the hepatic toxicity of ethanol in mice.

Animals↗
PubMed1996

Depletion of brain glutathione results in a decrease of glutathione reductase activity; an enzyme susceptible to oxidative damage.

Loss of the intracellular antioxidant glutathione (GSH) from the substantia nigra is considered to be an early event in the pathogenesis of Parkinson's disease (PD). While the cause of the loss is unclear, an imbalance in the enzymes associated with the synthesis, utilisation, degradation and translocation of GSH has been implicated. The enzyme glutathione reductase is also important in GSH homeostasis: it regenerates GSH from the oxidised from (GSSG). However, to date the activity and regulation of glutathione reductase in conditions such as PD have not been explored. In view of this we have measured the effects of GSH depletion on glutathione reductase activity of the rat brain. Other glutathione related enzymes were also measured. Using pre-weanling rats, brain GSH was depleted by up to 60% by subcutaneous administration of L-buthionine sulfoximine. The only enzyme affected by GSH depletion was glutathione reductase; its activity being reduced by approximately 40%. As GSH inactivates a number of oxidising species including peroxynitrite (ONOO-), we additionally investigated the susceptibility of glutathione reductase to ONOO- in vitro, using purified enzyme. ONOO- decreased glutathione reductase activity in a concentration dependent manner with an apparent 50% inhibition occurring at an initial concentration of 0.09 mM. These data suggest that GSH is important in the maintenance glutathione reductase activity. This may arise in part from its ability to inactivate oxidising agents such as ONOO-.

Animals↗
PubMed1992

Investigation of the active site of human placenta glutathione transferase pi by means of a spin-labelled glutathione analogue.

A spin-labelled analogue of glutathione (sl-glutathione) has been used in order to characterize the active site of human placenta glutathione transferase pi. The sl-glutathione shows a competitive inhibition towards glutathione (Ki = 14 microM). Binding of sl-glutathione to the enzyme, followed by electron paramagnetic resonance spectroscopy, gives a Kd of 3 microM and two identical binding sites for dimeric unit. Inhibition of the enzyme, by modification of the Cys-47 residue, completely prevents the binding of sl-glutathione. The same results are obtained by monitoring the binding of glutathione by means of fluorescence spectroscopy. It is concluded that integrity of the thiolate of Cys-47 is necessary to maintain an active conformation of the enzyme able to efficiently bind glutathione into the active site.

Binding Sites↗
PubMed1990

Endrin-induced depletion of glutathione and inhibition of glutathione peroxidase activity in rats.

1. Recent studies have shown that endrin induces lipid peroxidation and may produce toxicity through an oxidative stress. We have therefore examined the effect of endrin administration to rats on glutathione content and the activities of glutathione metabolizing enzymes. 2. The oral administration of endrin resulted in dose- and time-dependent decreases in hepatic and renal glutathione content with maximum depletion (90%) occurring in liver at approximately 24 hr post-treatment. 3. Decreases in glutathione content were also observed in lung, brain, spleen and heart. 4. Endrin (4 mg/kg) decreased selenium dependent glutathione peroxidase activity in liver and kidney by 64 and 50%, respectively, while small increases were observed in the activities of glutathione reductase and glutathione S-transferase. 5. The toxicity of endrin may be at least in part related to oxidative tissue damage associated with depletion of glutathione and inhibition of glutathione peroxidase activity.

Animals↗
PubMed2000

Antral glutathione concentration and glutathione S-transferase activity in patients with and without Helicobacter pylori.

Previously we demonstrated an inverse relation between cancer of the gastrointestinal tract and glutathione S-transferase activity of the gastrointestinal mucosa. Chronic infection with H. pylori has been associated with an increased risk of gastric cancer. The aim of this study was to investigate the levels of glutathione and glutathione S-transferase activity in H. pylori-infected and noninfected antral mucosa. Glutathione and glutathione S-transferases were measured in antral biopsies of patients with nonulcer dyspepsia without H. pylori infection (A), with prior H. pylori infection who became H. pylori negative after eradication therapy (B) and with proven H. pylori infection (C). Glutathione concentration and glutathione S-transferase activity in group A were 31.0 (range 6.0-59.6) nmol/mg protein and 810 (range 165-1312) nmol/min/mg protein, in group B 27.0 (range 5.0-53.8) nmol/mg protein and 745 (range 403-1199) nmol/min/mg protein, and in group C 18.5 (range 1.6-55.8) nmol/mg protein and 572 (range 144-1047) nmol/min/mg protein, respectively. The glutathione and glutathione S-transferase values were significantly lower in patients infected with H. pylori than in patients who were H. pylori negative.

Adult↗
PubMed1997

Induction of nitric oxide synthesis in J774 cells lowers intracellular glutathione: effect of modulated glutathione redox status on nitric oxide synthase induction.

Under pathological conditions, the induction of nitric oxide synthase (NOS) in macrophages is responsible for NO production to a cytotoxic concentration. We have investigated changes to, and the role of, intracellular glutathione in NO production by the activated murine macrophage cell line J774. Total glutathione concentrations (reduced, GSH, plus the disulphide, GSSG) were decreased to 45% of the control 48 h after cells were activated with bacterial lipopolysaccharide plus interferon gamma. This was accompanied by a decrease in the GSH/GSSG ratio from 12:1 to 2:1. The intracellular decrease was not accounted for by either GSH or GSSG efflux; on the contrary, rapid export of glutathione in control cells was abrogated during activation. The loss of intra- and extracellular glutathione indicates either a decrease in synthesis de novo, or an increase in utilization, rather than competition for available NADPH. All changes in activated cells were prevented by pretreatment with the NOS inhibitor L-N-(1-iminoethyl)ornithine. Basal glutathione levels in J774 cells were manipulated by pretreatment with (1) buthionine sulphoximine (glutathione synthase inhibitor), (2) acivicin (gamma-glutamyltranspeptidase inhibitor), (3) bromo-octane (glutathione S-transferase substrate) and (4) diamide/zinc (thiol oxidant and glutathione reductase inhibitor). All treatments significantly decreased the output of NO following activation. The degree of inhibition was dependent on (i) duration of treatment prior to activation, (ii) rate of depletion or subsequent recovery and (iii) thiol end product. The level of GSH did not significantly affect the production of NO, after induction of NOS. Thus, glutathione redox status appears to plays an important role in NOS induction during macrophage activation.

Adenosine Triphosphate↗
PubMed1977

Relationship between the soluble glutathione-dependent delta 5-3-ketosteroid isomerase and the glutathione S-transferases of the liver.

Soluble, glutathione-stimulated delta 5-3-ketosteroid isomerase (EC 5.3.3.A) activity of human and rat liver resides in very basic proteins with molecular weights of about 45,000 which are present in high concentrations in these tissues. Physiochemical and immunological evidence is presented for the identity of the proteins responsible for this enzymatic activity with the glutathione S-transferases (RX:glutathione R-transferase, EC 2.5.1.18) that conjugate glutathione with a variety of electrophilic compounds. In the rat, the steroid isomerase is associated principally with the major transferase (B), which is also known as ligandin, and has the versatility to bind various hydrophobic compounds such as bilirubin, corticosteroids, and metabolites of a number of carcinogens. Other rat liver-glutathione S-transferase species are far less active in the steroid isomerization reaction. The delta 5-3-ketosteroid isomerase activity of human liver is more uniformly distributed among the five glutathione S-transferases that have been described. Steroid isomerization differs fundamentally from other reactions promoted by glutathione S-transferases in that glutathione is not consumed in the reaction. However, because the transferase enzymes promote nucleophilic attack by glutathione on a variety of largely foreign organic substrates, a similar mechanism may be involved in the isomerase reaction. Delta 5-3-ketosteroids are among the few known naturally occurring substrates for these enzymes.

Animals↗
PubMed1996

Binding of the aflatoxin-glutathione conjugate to mouse glutathione S-transferase A3-3 is saturated at only one ligand per dimer.

The binding of two different reaction products (p-nitrobenzyl glutathione and the aflatoxin-glutathione conjugate) to mouse glutathione S-transferase A3-3 (mGSTA3-3) has been measured using equilibrium dialysis and a direct fluorescence quenching technique. As expected, p-nitrobenzyl glutathione was found to bind with a stoichiometry of 2.24 +/- 0.17 mol/mol of dimeric enzyme. However, the much larger aflatoxin-glutathione conjugate, 8, 9-dihydro-8-(S-glutathionyl)-9-hydroxyl-aflatoxin B1 (AFB-GSH), was found to bind with a stoichiometry of 1.12 +/- 0.08 mol/mol of dimeric enzyme. p-Nitrobenzyl glutathione bound mGSTA3-3 with a dissociation constant (Kd) of 59 +/- 17 microM while the aflatoxin-glutathione conjugate bound the enzyme with a Kd of 0.86 +/- 0.19 microM. Glutathione competitively inhibited binding of AFB-GSH to mGSTA3-3 with a Ki of 1.5 mM, suggesting that AFB-GSH was binding to the enzyme active site. Although AFB-GSH bound to mGSTA3-3 with a stoichiometry of 1 mol/mol of dimeric enzyme, AFB-GSH completely inhibited activity toward 1-chloro-2, 4-dinitrobenzene, indicating that AFB-GSH binding to one active site alters affinity for 1-chloro-2,4-dinitrobenzene in the active site of the other subunit. To our knowledge, this is the first report of a glutathione S-transferase reaction product which binds to the enzyme with a stoichiometry of 1 mol/mol of dimer.

Aflatoxin B1↗
PubMed1998

Liver glutathione content and glutathione-dependent enzymes of two species of freshwater fish as bioindicators of chemical pollution.

Glutathione content and glutathione-dependent enzymes were measured in the liver of two fish species, gudgeon (Gobio gobio) and roach (Rutilus arcasii), from the river Bernesga (Spain) caught downstream and upstream of the waste site of several chemical industries. Animals from contaminated sites display a reduced glutathione concentration and a tendency to the decrease of glutathione S-transferase activity. Glutathione peroxidase activity was significantly elevated only in the liver of Gobio gobio and glutathione reductase activity in that of Rutilus arcasii. Our data indicate that the glutathione system constitutes a sensitive biochemical indicator of chemical pollution. Relative changes of glutathione and glutathione-dependent enzymes in both fish species suggest a different susceptibility to toxins.

Animals↗
PubMed2004

Induction of PR-1 accumulation accompanied by runaway cell death in the lsd1 mutant of Arabidopsis is dependent on glutathione levels but independent of the redox state of glutathione.

The lesions simulating disease (lsd) mutants of Arabidopsis spontaneously develop hypersensitive-response-like lesions in the absence of pathogens. To address the function of the redox regulator glutathione in disease resistance, we examined the relationship between endogenous glutathione and PR-1 accumulation using one of these mutants, lsd1, as a disease resistance model. Lesion formation on lsd1 was suppressed by weak light and initiated by the subsequent transition to normal light. The application of buthionine sulfoximine, a specific inhibitor of glutathione biosynthesis, suppressed conditionally induced runaway cell death and expression of the PR-1 gene, suggesting that glutathione regulates the conditional cell death and PR-1 gene expression. The application of reduced (GSH) or oxidized (GSSG) glutathione to lsd1 upregulated the level of total glutathione ([GSH]+[GSSG]) accompanied by hastened accumulation of PR-1, and the basal level of total glutathione in lsd1 was higher than that in wild-type plants. The glutathione redox state defined as [GSH]/([GSH]+[GSSG]) decreased following the conditional transition, but the suppression of this decrease by the application of GSH did not inhibit the accumulation of PR-1. Taken together, conditional PR-1 accumulation in lsd1 is regulated not by the redox state but by the endogenous level of glutathione.

Arabidopsis↗
PubMed1991

Nitroglycerin relaxes coronary artery of the pig with no change in glutathione content or glutathione S-transferase activity.

1. The role of glutathione content and glutathione S-transferase activity in vascular relaxant responses to nitroglycerin was evaluated in potassium (30 mM)-contracted coronary artery strips of the pig by measuring changes in tension, glutathione content and glutathione S-transferase activity. 2. Prior exposure of coronary artery strips to nitroglycerin (10(-5)M or 10(-4)M for 20 min) resulted in tachyphylaxis to subsequent relaxation to nitroglycerin (10(-8)-10(-5)M). 3. The glutathione content and glutathione S-transferase activity of the arterial strips rendered tachyphylactic by prior exposure to nitroglycerin (10(-5)M for 20 min or 10(-3)M for 120 min) were not significantly different from those of control strips. 4. Treatment with diethyl maleate (10(-4)M or 10(-3)M for 60 min) markedly depleted arterial glutathione content in a concentration-dependent manner with no change in glutathione S-transferase activity. 5. The relaxant response of coronary artery strips to nitroglycerin (10(-8)-10(-5)M) was completely unaffected following treatment with diethyl maleate (10(-4)M or 10(-3)M for 60 min). 6. The results suggest that vascular glutathione content does not play an important role in vascular relaxation or tolerance development to nitroglycerin, at least in pig isolated coronary artery.

Animals↗
PubMed1986

Role of cardiac glutathione transferase and of the glutathione S-conjugate export system in biotransformation of 4-hydroxynonenal in the heart.

There is a remarkable difference in the isozyme pattern between cardiac and hepatic glutathione S-transferases in rat (Ishikawa, T., and Sies, H. (1984) FEBS Lett. 169, 156-160), and one near-neutral isozyme (pI = 6.9) of the cardiac glutathione S-transferases was found to have a significantly high activity toward 4-hydroxynonenal. The isozyme was inhibited by the resulting glutathione S-conjugate of 4-hydroxynonenal competitively with GSH and noncompetitively with 4-hydroxynonenal. The kinetic parameters estimated for the isozyme were: kcat = 460 mol X min-1 X mol enzyme-1, Km = 50 microM for 4-hydroxynonenal, Ki = 85 microM. When the heart was perfused with 4-hydroxynonenal, a marked decrease was observed in the intracellular GSH level, accompanied by an increase of glutathione S-conjugate of 4-hydroxynonenal in the heart. The rate of the conjugation reaction was more than 30 times the rate of the spontaneous reaction, the half-life of 4-hydroxynonenal in the heart being less than 4 s. The glutathione S-conjugate of 4-hydroxynonenal was released from the heart into the perfusion medium. Saturation kinetics were observed for the release with respect to the intracellular level of the S-conjugate (Vmax = 12 nmol X min-1 X g heart-1), and there was a competition by the S-conjugate for GSSG release. The release of the glutathione S-conjugate is considered as a carrier-mediated process and to be important not only in interorgan glutathione metabolism but also in diminishing the inhibitory effect of the S-conjugate on glutathione S-transferases and glutathione reductase.

Aldehydes↗
PubMed1985

Altered mouse bone marrow glutathione and glutathione transferase levels in response to cytotoxins.

The mouse bone marrow has been used as a model for the investigation of the response of cells to cytotoxins and carcinogens. The effects of cyclophosphamide, 1-beta-D-arabinofuranosylcytosine, and X-irradiation on the levels of glutathione and glutathione transferases have been studied. A high dose of cyclophosphamide (500 mg/kg) caused a significant depletion of glutathione levels in marrow, liver, and blood. A lower dose, 75 mg/kg, caused a similar depletion but only in marrow and liver. In this case, 5 to 7 days following treatment, the glutathione content of surviving cells was 1.8- to 3-fold higher than in controls. Glutathione transferase activity was also increased at this time (2- to 3-fold). 1-beta-D-Arabinofuranosylcytosine and X-irradiation also caused a depletion of marrow glutathione and glutathione transferase levels followed increased cellular levels (approximately 2-fold) 3 to 4 days later. Animals given cyclophosphamide (75 mg/kg) survived an otherwise lethal dose of this compound administered 5 to 7 days later. The time course of this effect closely paralleled the higher glutathione and glutathione transferase levels, suggesting a correlation between these effects.

Animals↗
PubMed1998

Glutathione-dependent antioxidant enzyme activities and glutathione content in the rat brain at different stages of oestrous cycle.

Enzymatic activities of glutathione peroxidase, glutathione-S-transferase, glutathione reductase and catalase, as well as the glutathione content were measured in the brain tissue of regularly cycling rats at dioestrus, proestrus and estrus. The activity of glutathione peroxidase was found to be suppressed at proestrus, whereas that of catalase was increased at dioestrus. Glutathione transferase and glutathione reductase activities, as well as the glutathione content appeared to be stable during the oestrous cycle. These results suggest that, in the female rat, glutathione peroxidase and catalase activities in the brain tissue are influenced by the ovarian hormone status.

Animals↗
PubMed1993

Glutathione and glutathione linked enzymes in human small cell lung cancer cell lines.

Glutathione levels and several glutathione-linked enzyme activities have been variably correlated with cisplatin chemosensitivity in cultured neoplastic cells. In order to determine the relative contribution of the glutathione-linked enzymes towards mediating inherent cisplatin resistance in cancer cells, we have measured the chemosensitivity to cisplatin, glutathione levels and activities of glutathione S-transferase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase in 8 cultured human small cell lung cancer (SCLC) cell lines with widely differing cisplatin sensitivities. Of these parameters, only glutathione S-transferase activity correlated with degree of cisplatin resistance in a linear fashion.

Carcinoma, Small Cell↗
PubMed1987

Role of glutathione metabolizing enzymes in nickel mediated induction of hepatic glutathione.

The administration of nickel to rats resulted in a dose-dependent increase in the level of hepatic glutathione and in the activities of glutathione reductase and glutathione-S-transferase with a concomitant decrease in the activities of glutathione peroxidase and gamma-glutamyl transpeptidase. The increase in hepatic glutathione may be due to the decrease in the activities of glutathione utilizing enzymes and increase in the activity of glutathione reductase leading to the increased turnover of glutathione.

Animals↗
PubMed1991

Age-related cysteine uptake as rate-limiting in glutathione synthesis and glutathione half-life in the cultured human lens.

The study included human lenses of ages ranging from newborn to 92 years. Protein-free reduced glutathione decreased 14-fold, whereas protein-free oxidized glutathione increased 2.6-fold with increasing age. L-Cyst(e)ine uptake g-1 lens of very old cultured lenses decreased 70% from that exhibited in newborn lenses, demonstrating a marked decline of L-cyst(e)ine uptake as a function of age. In these same lenses the synthesis of reduced glutathione (mumol g-1 lens) decreased 73% with age. It was concluded that the glutathione decrease observed in the aging human lens was associated with decreased uptake of L-cyst(e)ine, decreased glutathione synthesis and possibly an increase in protein-free oxidized glutathione. The high correlation of L-cyst(e)ine uptake and glutathione synthesis supports the hypothesis that L-cyst(e)ine uptake is a rate-limiting factor of glutathione synthesis in the intact human lens. By the use of buthionine sulfoximine, the half-life of glutathione was estimated to be 90 hr in the cultured human lens.

Adolescent↗