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PubMed1993

Modulation of glutathione and glutathione dependent antioxidant enzymes in mouse heart following doxorubicin therapy.

The toxicity of the antineoplastic agent doxorubicin (DOX) has been shown to be moderated by the antioxidant enzyme glutathione peroxidase. It has been reported that acute doses of DOX can cause an inhibition of glutathione peroxidase in cardiac tissue, that may render this tissue especially susceptible to further prooxidant damage. In this study, multiple DOX treatments at a therapeutic dose were assessed for their effect on the antioxidant enzyme status of cardiac and kidney tissue. DOX was administered i.p. (5 mg/kg) once a week for two weeks to male balb/c mice. The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPOX) and glutathione reductase (GR) were measured 1, 2 and 7 days following the second DOX treatment in both heart and kidney. Levels of reduced glutathione (GSH) were also measured in cardiac tissue at these same times. Cardiac levels of GPOX and GR showed a time-dependent decrease in activity, with 10% and 12% inhibition for GPOX and GR, respectively, at 7 days post second treatment. Cardiac levels of GSH also showed a significant decrease, approximately 15%, at 7 days post second treatment. Cardiac levels of SOD and CAT as well as kidney levels of all four antioxidant enzymes were not affected by DOX treatment. These data suggest that DOX given in a therapeutic regimen, at a therapeutic dose, can cause decreases in cardiac levels of GPOX, GR and GSH that could render the heart especially susceptible to further oxidative challenge.

Animals↗
PubMed1989

Increase in glutathione disulfide level regulates the activity of microsomal glutathione S-transferase in rat liver.

Glutathione disulfide stimulates the activity of rat liver microsomal glutathione S-transferase 2-fold after incubation at 25 degrees C for 10 min. When the microsomes were incubated with the disulfide for over 20 min, the transferase activity increased to the same extent as in the case of N-ethylmaleimide (6-fold). Even in the presence of reduced glutathione, some enhancement of the transferase activity was observed. The data presented here are evidence that increase in glutathione disulfide level, e.g. by lipid peroxidation, on endoplasmic reticulum causes the upregulation of microsomal glutathione S-transferase activity.

Animals↗
PubMed1988

Pulmonary and hepatic glutathione levels, glutathione shuttle enzymes and lipid peroxidation in rats exposed intratracheally to coal fly ash.

Fly ash and fly ash residue increased the formation of conjugated dienes and the levels of oxidized glutathione (GSSG) and reduced the levels of reduced glutathione (GSH) in lung and liver whereas fly ash extract administration had no effect on the formation of conjugated dienes and glutathione levels in lung and liver. Fly ash and fly ash residue reduced the activity of glutathione reductase both in lung and liver but did not alter the activity of glutathione peroxidase. Fly ash and fly ash extract significantly increased glucose-6-phosphate dehydrogenase activity in lung whereas in liver, fly ash and fly ash residue reduced the activity of glucose-6-phosphate dehydrogenase. Fly ash residue did not alter the activity of glucose-6-phosphate dehydrogenase in lung whereas fly ash extract was not effective in liver.

Animals↗
PubMed2002

1.3-A resolution structure of human glutathione S-transferase with S-hexyl glutathione bound reveals possible extended ligandin binding site.

Cytosolic glutathione S-transferases (GSTs) play a critical role in xenobiotic binding and metabolism, as well as in modulation of oxidative stress. Here, the high-resolution X-ray crystal structures of homodimeric human GSTA1-1 in the apo form and in complex with S-hexyl glutathione (two data sets) are reported at 1.8, 1.5, and 1.3A respectively. At this level of resolution, distinct conformations of the alkyl chain of S-hexyl glutathione are observed, reflecting the nonspecific nature of the hydrophobic substrate binding site (H-site). Also, an extensive network of ordered water, including 75 discrete solvent molecules, traverses the open subunit-subunit interface and connects the glutathione binding sites in each subunit. In the highest-resolution structure, three glycerol moieties lie within this network and directly connect the amino termini of the glutathione molecules. A search for ligand binding sites with the docking program Molecular Operating Environment identified the ordered water network binding site, lined mainly with hydrophobic residues, suggesting an extended ligand binding surface for nonsubstrate ligands, the so-called ligandin site. Finally, detailed comparison of the structures reported here with previously published X-ray structures reveal a possible reaction coordinate for ligand-dependent conformational changes in the active site and the C-terminus.

Apoenzymes↗
PubMed1995

Reversible conjugation of isothiocyanates with glutathione catalyzed by human glutathione transferases.

Rates were determined for the nonezymatic (second order rate constants) and enzyme-catalyzed conjugations with glutathione of four isothiocyanates that are present in edible plants (allyl-, benzyl-, phenethyl-isothiocyanates, and sulforaphane). Of four cloned human glutathione transferases studied, GSTP1-1 and GSTM1-1 were the most efficient catalysts. GSTA1-1 was less efficient, and GSTM2-2 was the least efficient. Conjugation of benzyl-NCS is the most rapid and that of sulforaphane [CH3S(O)(CH2)4-NCS] is the slowest. The large enzymatic rate enhancements and the abundance of the enzymes suggest that the glutathione transferases play important roles in the metabolic disposition of isothiocyanates in humans. Enzymatic cleavage of the GSH conjugates of isothiocyanates (dithiocarbamates) is catalyzed by glutathione transferases. The importance of these reverse reactions is probably limited because they are slow and inhibited by high intracellular concentrations of glutathione.

Glutathione↗
PubMed1994

Molecular structure at 1.8 A of mouse liver class pi glutathione S-transferase complexed with S-(p-nitrobenzyl)glutathione and other inhibitors.

The three-dimensional crystal structure of pi class glutathione S-transferase YfYf from mouse liver complexed with the inhibitor S-(p-nitrobenzyl)glutathione has been determined at 1.8 A resolution by X-ray diffraction. In addition two complexes with glutathione sulphonic acid and S-hexylglutathione have been determined at resolutions of 1.9 and 2.2 A, respectively. The high resolution of the S-(p-nitrobenzyl)glutathione complex allows a detailed analysis of the active site including the hydrophobic (H-) subsite. The nitrobenzyl moiety occupies a hydrophobic pocket with its aromatic ring sandwiched between Phe8 and the hydroxyl group of Tyr108. An insertion of two residues Gly41 and Leu42, with respect to the pig enzyme, splits helix alpha B into an alpha-helix and a 3(10) helix. Water bridges between carbonyl oxygen atoms of the alpha-helix at its C terminus and the amide NH groups of the 3(10) helix at its N terminus provide structural continuity between these two secondary elements. Tyr7 appears to be the only residue close to the sulphur atom of glutathione, while three conserved water molecules lie in the surrounding area in all complexes. The enzyme mechanism is discussed on the basis of the structural analysis.

Amino Acid Sequence↗
PubMed1995

Changes in levels of glutathione and related compounds and activities of glutathione-related enzymes during rat liver regeneration.

The levels of glutathione and glutathione disulfide increased during the regeneration process of rat liver, reaching a maximum (about twice the control value) on day 2 and reverting to the normal level within 5 days. During this regeneration process, changes in the hepatic level of cysteine, glycine and glutamate, the substrates for glutathione synthesis, were determined. The cysteine level in liver increased, reaching a maximum on day 2 and returned to the normal level after 5 days. The levels of glycine and glutamate did not change. The enzyme activities of cystathionine-beta synthase and gamma-cystathionase for cysteine synthesis, and of gamma-glutamylcysteine synthetase, which is a limiting enzyme for glutathione synthesis, were clearly increased in regenerating liver. The increase of glutathione level could be clearly accounted for by the elevation of these enzyme activities.

Animals↗
PubMed1990

The action of the glutathione transferase substrate, 1-chloro-2,4-dinitrobenzene on synaptosomal glutathione content and the release of hydrogen peroxide.

We studied the action of the glutathione transferase substrate, 1-chloro-2,4-dinitrobenzene (CDNB) on the synaptosomal production of H2O2. We found that CDNB (30-40 microM) readily depletes the cytosolic glutathione but is almost without effect on the mitochondrial fraction. The depletion of the cytosolic glutathione induced by CDNB affords the detection in the extracellular space of H2O2 produced intrasynaptosomally upon increasing the cytosolic Ca2+ concentration that is otherwise destroyed by glutathione peroxidase. Higher concentrations of CDNB induce a H2O2 production which is not related to the glutathione content. This H2O2 is of mitochondrial origin and requires that NAD be reduced. The primary product of the mitochondrial CD-NB-dependent oxygen reduction is at least in part the superoxide anion.

Animals↗
PubMed1977

Purification by affinity chromatography of yeast glutathione reductase, the enzyme responsible for the NADPH-dependent reduction of the mixed disulfide of coenzyme A and glutathione.

Glutathione reductase (NAD(P)H : oxidised-glutathione oxidoreductase, EC 1.6.4.2) was purified from baker's yeast by a new procedure involving affinity chromatography on 2',5'-ADP-Sepharose 4B. The yield was 65% of essentially homogeneous enzyme. The activity was assayed with both glutathione disulfide (GSSG) and the mixed disulfide of coenzyme A and glutathione (CoAssg). The two disulfide substrates gave coinciding activity profiles and a constant ratio of the activities in different chromatographic and electrophoretic systems. No evidence was obtained for the existence of a reductase specific for CoASSG distinct from glutathione reductase. It is concluded that normal baker's yeast contains a single reductase active with both GSSG and CoASSG.

Adenosine Diphosphate↗
PubMed1990

Inhibition of rat and human glutathione S-transferase isoenzymes by ethacrynic acid and its glutathione conjugate.

Ethacrynic acid, a potent inhibitor of glutathione S-transferases (GST), has been shown to enhance the cytotoxicity of chlorambucil in drug resistant cell lines, but a definite mechanism has not been established. Both covalent binding to GST and reversible inhibition of GST have been reported. In the present study no irreversible inhibition was observed: for all rat GST tested, inactivation was complete within 15 sec at 0 degree, and dialysis of GST after incubation with ethacrynic acid gave complete recovery of enzyme activity for all isoenzymes tested. Moreover, the inhibition was competitive towards 1-chloro-2,4-dinitrobenzene and non-competitive towards glutathione for rat isoenzyme 1-1. Strong inhibition of both human and rat GST of the alpha-, mu- and pi-classes was obtained with ethacrynic acid, while conjugation of ethacrynic acid with glutathione did not abolish its inhibiting properties. For the alpha-, mu- and pi-class I50 values (microM) were 4.6-6.0, 0.3-1.9 and 3.3-4.8, respectively for ethacrynic acid, and 0.8-2.8, less than 0.1-1.2 and 11.0, respectively for its glutathione conjugate. Of all isoenzymes tested the human isoenzyme mu is most sensitive to the action of both ethacrynic acid and its glutathione conjugate.

Animals↗
PubMed1991

Irreversible inhibition of human glutathione S-transferase isoenzymes by tetrachloro-1,4-benzoquinone and its glutathione conjugate.

The quinones tetrachloro-1,4-benzoquinone (1,4-TCBQ) and its glutathione conjugate (GS-1,4-TCBQ) are potent irreversible inhibitors of most human glutathione S-transferase (GST) isoenzymes. Human pi, psi, and mu are almost completely inhibited at a molar ratio 1,4-TCBQ/GST = 2/1. The isoenzyme B1B1 was inhibited up to 75%, and higher concentrations (1,4-TCBQ/GST = 6/1) were needed to reach this maximum effect. For these isoenzymes 75-85% of the maximal amount of inhibition was already reached on incubation of equimolar ratios of 1,4-TCBQ and subunit GST, while approximately 1 nmol (0.82-0.95) 1,4-[U-14C]TCBQ per nmol subunit GST could be covalently bound. These results suggest that these GST isoenzymes possess only one cysteine in or near the active site of GST, which is completely responsible for the inhibition. In agreement, human isoenzyme B2B2 which possesses no cysteine, was not inhibited and no 1,4-TCBQ was bound to it. The rate of inhibition was studied at 0 degrees: 1,4-TCBQ, trichloro-1,4-benzoquinone and GS-1,4-TCBQ all inhibit GST very fast. Especially for B1B1, the inhibition by the glutathione conjugate is significantly faster than inhibition by 1,4-TCBQ: the glutathione moiety seems to target the quinone to the enzyme. For the other isoenzymes only minor differences are observed between 1,4-TCBQ and its glutathione conjugate under the conditions used.

Chloranil↗
PubMed1993

The role of metallothionein, glutathione, glutathione S-transferases and DNA repair in resistance to platinum drugs in a series of L1210 cell lines made resistant to anticancer platinum agents.

The glutathione contents, glutathione S-transferase activities and metallothionein contents have been measured in a series of L1210 cell lines which show decreased sensitivities to platinum drugs. Resistance to cisplatinum cisDDP, cis-diamminedichloroplatinum (II)] and chip [ioproplatin, cisdichloro-bis-isopropylamine-trans dihydroxy platinum IV] was found to correlate with glutathione levels but not metallothionein. Conversely, resistance to tetraplatin was found to be correlated with metallothionein but not glutathione levels. However, depletion of glutathione by buthionine 1-sulphoximine sensitizes all cell lines to the effects of cisDDP, chip and tetraplatin [d,1-trans-tetrachloro-1,2-diamino-cyclohexanplatinum (IV)]. Inhibition of DNA repair by aphidicholin or caffeine also partially restored sensitivity to these platinum drugs. These results indicate the complexity of the changes occurring upon the development of drug resistance.

Animals↗
PubMed1984

A role for glutathione and glutathione reductase in control of corneal hydration.

We have assessed the importance of the glutathione redox system of the corneal endothelial cells in the control of stromal hydration. The ability of freshly isolated corneas to maintain normal hydration during perfusion, while the activity of glutathione reductase was inhibited with 1.3-bis(2-chloroethyl)-1-nitrosourea (BCNU), was tested under a number of conditions. BCNU at 125 microM led to mild swelling and at 500 microM to more severe swelling. Swelling was also severe when 50 microM H2O2 was added together with 125 microM BCNU. The concentration of total glutathione (GSH + GSSG) in the endothelia of these corneas was decreased and the fraction found in the oxidized form was higher than in controls without BCNU. Glutathione reductase activity was inhibited in the perfused endothelia by 90%. With the addition of 0.5 mM GSSG during perfusion, swelling due to 125 microM BCNU was at a slightly lower rate and reductase activity was inhibited only 79%. Complete protection was afforded against 125 microM BCNU induced swelling by 1.0 mM GSH, corneas maintaining normal thickness for over 4 hr. The endothelial surface of the perfused corneas was shown by scanning electron microscopy to be little disturbed by the low concentration of BCNU, but at high concentration, or with H2O2 added, the cells were collapsed and had a heavily pitted appearance. We conclude that when the cornea is under oxidative stress (e.g. in the presence of H2O2) a rapid turnover of endothelial GSH via glutathione reductase and the hexose monophosphate shunt is required. Under conditions of less stress, the reduced need for GSH to counteract oxidative threats can be supplied either exogenously or by the partially inhibited reductase.

Animals↗
PubMed1990

Non-selenium glutathione peroxidase without glutathione S-transferase activity from bovine ciliary body.

A glutathione peroxidase was purified from bovine ciliary body by ammonium sulfate fractionation. Sephacryl S-300 gel filtration, diethylaminoethyl (DEAE)-cellulose chromatography and hydroxyapatite chromatography. The purified enzyme has an apparent mw of 112 kDa by gel filtration and 29 kDa by SDS-polyacrylamide gel electrophoresis. The enzyme therefore is composed of four identical subunits. The ciliary enzyme is active with H2O2 (25), cumene hydroperoxide (170), t-butyl hydroperoxide (22), triphenylcarbinyl hydroperoxide (12), linoleic hydroperoxide (34) and 5-phenylpentenyl hydroperoxide (22): the numbers after substrates are K'm in microM. Glutathione is essential for the reaction; L-cysteine, dithiothreitol and 2-mercaptoethanol are inactive. Mercaptosuccinate (10 microM) inhibits the enzyme competitively (Ki = 7 microM) when cumene hydroperoxide is substrate, and uncompetitively (Ki = 10 microM) when H2O2 is substrate. No selenium was found in the enzyme by the fluorometric assay with 2.3-diaminonaphthalene. The enzyme demonstrates no glutathione S-transferase activity when tested with 1-chloro-2,4-dinitrobenzene, and several other compounds. A partial sequence of the enzyme shows some similarities both to Se-glutathione peroxidases and a glutathione S-transferase isozyme.

Amino Acid Sequence↗
PubMed1988

Relaxed thiol substrate specificity of glutathione transferase effected by a non-substrate glutathione derivative.

Rat glutathione transferase 4-4 catalyzed the conjugation of 2-mercaptoethanol with 1-chloro-2,4-dinitrobenzene in the presence of S-methyl-glutathione. The reaction was linearly dependent on enzyme concentration and saturation was seen with respect to both 2-mercaptoethanol and S-methyl-glutathione concentration. High concentrations of S-methyl-glutathione were inhibitory. The results suggest that the natural substrate glutathione has two distinct functions in the normal catalytic reaction, (i) induction of a catalytically competent conformation of the enzyme and (ii) provision of the substrate sulfhydryl group in the reaction catalyzed.

Animals↗
PubMed1992

Mutational substitution of residues implicated by crystal structure in binding the substrate glutathione to human glutathione S-transferase pi.

Site-directed substitution mutations were introduced into a cDNA expression vector (pUC120 pi) that encoded a human glutathione S-transferase pi isozyme to non-conservatively replace four residues (Tyr7, Arg13, Gln62 and Asp96). Our earlier X-ray crystallographic analysis implicated these residues in binding and/or chemically activating the substrate glutathione. Each substitution mutation decreased the specific activity of the enzyme to less than 2% of the wild-type. Glutathione-binding was also reduced; however, the Tyr7----Phe mutant still retained 27% of the wild-type capacity to bind glutathione, underlining the primary role that this residue is likely to play in chemically activating the glutathione molecule during catalysis.

Amino Acid Sequence↗
PubMedDate not supplied

Effects of development and ageing on pulmonary NADPH-cytochrome c reductase, glutathione peroxidase, glutathione reductase and thioredoxin reductase activities in male and female rats.

The behaviour of the principal NADPH-consuming detoxification enzymes (NADPH-cytochrome c reductase, glutathione peroxidase-glutathione reductase system, and thioredoxin reductase) was studied during development and senescence of the rat lung. We have also studied the influence of sex on the development and senescent values. The NADPH-cytochrome c reductase activity increases at birth and afterwards remains constant until the 25th day after birth, at which age there is a maximum activity. Its activity decreases during the ageing period in both sexes. The glutathione reductase and thioredoxin reductase activities show significant differences with respect to sex during the adult stage, however during ageing these differences disappear. These enzymes show maximum activity at 25 days after birth, and afterwards the activity decreases continuously until the adult levels are reached. The activity of glutathione reductase is increased during the ageing period, especially in the female rats, however, in senescence the levels of thioredoxin reductase are lower than in the adult stage. The glutathione peroxidase shows a significant difference between both sexes during senescence and in the male its activity in this stage is higher than during development and adulthood.

Aging↗
PubMed1989

Expression of glyoxalase, glutathione peroxidase and glutathione S-transferase isoenzymes in different bovine tissues.

(1) The tissue-specific expression of various glutathione-dependent enzymes, including glutathione S-transferase (GST), glutathione peroxidase and glyoxalase I, has been studied in bovine adrenals, brain, heart, kidney, liver, lung and spleen. Of the organs studied, liver was found to possess the greatest GST and glyoxalase I activity, and spleen the greatest glutathione peroxidase activity. The adrenals contained large amounts of these glutathione-dependent enzymes, but significant differences were observed between the cortex and medulla. (2) GST and glyoxalase I activity were isolated by S-hexylglutathione affinity chromatography. Glyoxalase I was found in all the organs examined, but GST exhibited marked tissue-specific expression. (3) The alpha, mu and pi classes of GST (i.e., those that comprise respectively Ya/Yc, Yb/Yn and Yf subunits) were all identified in bovine tissues. However, the Ya and Yc subunits of the alpha class GST were not co-ordinately regulated nor were the Yb and Yn subunits of the mu class GST. (4) Bovine Ya subunits (25.5-25.7 kDa) were detected in the adrenal, liver and kidney, but not in brain, heart, lung or spleen. The Yc subunit (26.4 kDa) was expressed in all those organs which expressed the Ya subunit, but was also found in lung. The mu class Yb (27.0 kDa) and Yn (26.1 kDa) subunits were present in all organs; however, brain, lung and spleen contained significantly more Yn than Yb type subunits. The pi class Yf subunit (24.8 kDa) was detected in large amounts in the adrenals, brain, heart, lung and spleen, but not in kidney or liver. (5) Gradient affinity elution of S-hexylglutathione-Sepharose showed that the bovine proteins that bind to this matrix elute in the order Ya/Yc, Yf, Yb/Yn and glyoxalase I. (6) In conclusion, the present investigation has shown that bovine GST are much more complex than previously supposed; Asaoka (J. Biochem. 95 (1984) 685-696) reported the purification of mu class GST but neither alpha nor pi class GST were isolated.

Adrenal Glands↗