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At least 1,009 records · Page 56Linked to original sources
PubMed1986

Cationic glutathione S-transferase of human erythrocytes has unique kinetic characteristics among human glutathione S-transferases.

The cationic glutathione S-transferase (GST sigma) of human erythrocytes is activated when incubated with 1 mM N-ethylmaleimide or other sulfhydryl blocking agents. Other GST isoenzymes of human tissues were inhibited by these reagents under similar conditions. At higher concentrations of NEM, GST sigma was also inhibited. Dithiothreitol, 2-mercaptoethanol, and sodium borohydride also caused several fold activation of GST sigma but noe of the other human GST isoenzymes were activated by these reagents.

Cations↗
PubMed1990

Glutathione depletion and formation of glutathione-protein mixed disulfide following exposure of brain mitochondria to oxidative stress.

t-Butyl hydroperoxide was utilized to alter the thiol homeostasis in rat brain mitochondria. Following exposure to t-butyl hydroperoxide (50-500 microM), intramitochondrial GSH content decreased rapidly and irreversibly with a major portion of the depleted GSH being accounted for as protein-SS-Glutathione mixed disulfide. Formation of GSSG was not observed nor was efflux of GSSG or GSH from the mitochondria detected in the incubation medium. The loss of intramitochondrial GSH was accompanied by loss of protein thiols. Unlike liver mitochondria, which can reverse t-butyl hydroperoxide induced formation of GSSG, addition of 50 microM t-butyl hydroperoxide resulted in irreversible loss; indicating greater susceptibility of brain mitochondria to oxidative stress than liver mitochondria.

Animals↗
PubMed1983

Effect of butylated hydroxytoluene on glutathione S-transferase and glutathione peroxidase activities in rat liver.

When rats were fed a diet containing 0.4% (w/w) butylated hydroxytoluene (BHT), glutathione (GSH) S-transferase activity towards 1-chloro-2,4-dinitrobenzene (CDNB) increased approximately 3-fold in the liver. Immunotitration studies using the antibodies raised against rat liver GSH S-transferase B and GSH S-transferase A and C indicated that the increase in GSH S-transferase activity was probably due to de novo protein synthesis. Since some forms of rat liver GSH S-transferases express GSH peroxidase II activity, a concomitant increase in GSH peroxidase II was expected. However, GSH peroxidase II activity in the liver of BHT-treated rats remained unchanged. Gel filtration of supernatant fractions from livers of control and BHT-treated rats, followed by isoelectric focusing, indicated that BHT induced the activity of hepatic GSH S-transferases, without any apparent effect on GSH peroxidase II activity.

Animals↗
PubMed1986

Propylthiouracil inducible glutathione transferases. Selective induction of ligandin (glutathione transferase 1-1).

Repeated administration of propylthiouracil (PTU) resulted in an increase in glutathione (GSH) transferases activity in rat liver cytosol toward various substrates except for epoxy(p-nitrophenoxy)propane. The enzyme from rat treated with PTU showed high activity with 1-chloro-2,4-dinitrobenzene (CDNB) and ethacrynic acid. GSH transferases were separated into five forms by CM-Sephadex C-50 column chromatography to detect which isozymes were induced by PTU treatment. Although the activity of the unretained fraction obtained from the column was slightly increased by PTU treatment, the treatment markedly elevated the activity of GSH transferase 1-1. On the other hand, the activities of GSH transferases 1-2, 3-3 and 2-2 were little changed. In addition, an analysis of GSH transferase 1-1 from CM-Sephadex C-50 using SDS-PAGE confirmed that it comprised the 1-1 homodimer. This fraction was then further purified by passing it through a hydroxylapatite column and the partially purified GSH transferase 1-1 from rats treated with PTU was found to have the same characteristics as the control, e.g. the same Km values for GSH and CDNB and the same substrate spectrum. It was concluded that PTU specifically induced GSH transferase 1-1 among the cationic transferases.

Animals↗
PubMed1989

Glutathione conjugation of the alpha-bromoisovaleric acid enantiomers in the rat in vivo and its stereoselectivity. Pharmacokinetics of biliary and urinary excretion of the glutathione conjugate and the mercapturate.

The glutathione (GSH) conjugation of (R)-and (S)-alpha-bromoisovaleric acid (BI) in the rat in vivo, and its stereoselectivity, have been characterized. After administration of racemic [1-14C]BI two radioactive metabolites were found in bile: only one of the possible diastereomeric BI-GSH conjugates, (R)-I-S-G (35 +/- 2% of the dose), and an unidentified metabolite "X" (6 +/- 1%). In urine, only one of the possible BI-mercapturates, (R)-I-S-MA (14 +/- 1%), minor unidentified polar metabolites (5 +/- 1%) and unchanged BI (13 +/- 2%) were excreted. When (R) or (S)-BI were administered separately, the same metabolites were found. However, a ten-fold difference in excretion half lives of the biliary metabolites was observed following (S)-and (R)-BI administration, (S)-BI being more rapidly excreted. The excretion of the mercapturate in urine shows the same difference in excretion rate: its half life after administration of (R)-BI was more than 10 times longer than after a dose of (S)-BI. More of the dose of (S)-BI was excreted after 5 hr in bile and urine: 58% and 23% respectively for (S)- and (R)-BI. Therefore, a pronounced stereoselectivity in GSH conjugation exists for the (R) and (S) enantiomers of BI in the rat in vivo, which is a major determinant of their pharmacokinetics. The results suggest that (slow) inversion of the chiral centre of BI occurred in the rat in vivo.

Acetylcysteine↗
PubMed1990

Cellular glutathione as a determinant of sensitivity to mercuric chloride toxicity. Prevention of toxicity by giving glutathione monoester.

Depletion of glutathione (GSH) by treatment of mice with buthionine sulfoximine (BSO), an effective inhibitor of gamma-glutamylcysteine synthetase, markedly enhanced (about 10-fold) the lethal and renal toxicity of mercuric chloride. The lethal toxicity of HgCl2 was prevented by administration of GSH monoester; this was observed in mice pretreated with BSO and given a low dose of HgCl2, and also in untreated mice that were given a much higher dose of HgCl2. In contrast, administration of GSH did not protect. Since administered GSH is not transported effectively into cells, whereas GSH monoester is transported and split intracellularly to GSH, the findings indicate that protection against HgCl2 requires intracellular GSH. The experimental approaches used here suggest that cellular GSH is a major determinant of sensitivity to HgCl2 toxicity, and also that administration of GSH esters may be useful for prevention of HgCl2 toxicity.

Animals↗
PubMed1993

Synthesis rates of glutathione and activated sulphate (PAPS) and response to cysteine and acetaminophen administration in glutathione-depleted rat hepatocytes.

The effects of cysteine and acetaminophen (AA) on the synthesis rates of glutathione (GSH), adenosine 3'-phosphate 5'-phosphosulphate (PAPS, activated sulphate) and the AA metabolites, AA-GSH and AA-sulphate were studied in rat hepatocytes depleted of GSH by diethyl maleate (DEM). The synthesis rates were determined simultaneously by a previously described radioactive tracer method. Preincubation of the hepatocytes with 0.7 mM DEM for 30 min depleted GSH by 59% (P < 0.05) and PAPS by 28% (P < 0.05). Incubation with a toxic AA concentration resulted in GSH synthesis at a rate of 95 nmol/(10(6) cells.min) which increased to 281 nmol/(10(6) cells.min) (P = 0.05) after addition of cysteine. However, increased GSH synthesis was not followed by increased AA-GSH synthesis [4.7 vs 4.8 nmol/(10(6) cells.hr)]. Also, PAPS synthesis increased after cysteine administration [10.2 to 19.1 nmol/(10(6) cells.min)] (P < 0.05) without any change in AA-sulphate synthesis 18.5 vs 18.3 nmol/(10(6) cells.hr)]. Thus, in contrast to hepatocytes with normal GSH concentration, cysteine stimulated both GSH and PAPS synthesis rates in GSH-depleted rat hepatocytes incubated with a toxic AA concentration without stimulation of AA-GSH or AA-sulphate synthesis rates, indicating that the hepatoprotective effect of cysteine on AA toxicity is primarily due to stimulation of a GSH-mediated reduction of the reactive AA metabolite N-acetyl-p-benzoquinoneimine back to AA.

Acetaminophen↗
PubMed1993

Simultaneous measurements of glutathione and activated sulphate (PAPS) synthesis rates and the effects of selective inhibition of glutathione conjugation or sulphation of acetaminophen.

The aim of the present study was to examine the effects of the hepatotoxic drug acetaminophen (AA) on the synthesis rates of glutathione (GSH), activated sulphate (PAPS; adenosine 3'-phosphate 5'-phosphosulphate) and the AA metabolites AA-GSH and AA-sulphate after selective inhibition of GSH biosynthesis or sulphation in isolated rat hepatocytes. Selective inhibition of the two interdependent metabolic pathways was accomplished by buthionine sulphoximine (BSO) and 2,6-dichloro-4-nitrophenol (DCNP). The synthesis rates of GSH and PAPS were determined simultaneously by a previously described method based on trapping of radioactivity (35S) in the pre-labelled GSH and PAPS pools. Pre-incubation with 10 mM BSO for 30 min depleted GSH by 38% (P < 0.05) and PAPS by 27% (P < 0.05). The depletion resulted in increased PAPS synthesis at low, non-toxic [5-19 nmol/(10(6) cells.min)] (P < 0.05) and at high, toxic [7-30 nmol/10(6) cells.min)] (P < 0.05) AA concentrations. In both cases sulphur is diverted from GSH biosynthesis to sulphoxidation and PAPS synthesis, thereby maintaining the PAPS pool and preserving the sulphation capacity. This corresponds to the finding that AA sulphation was unaffected by BSO irrespective of AA concentration [6 vs 5 and 20 vs 17 nmol/(10(6) cells.hr), respectively]. Even though the GSH synthesis was halved after BSO pre-incubation, the GSH conjugating capacity of AA was well preserved. Incubation with 200 microM DCNP and 5 mM AA diminished PAPS synthesis from 24 to 10 nmol/(10(6) cells.min) (P < 0.02) and reduced AA-sulphate synthesis by 67% compared to experiments without DCNP incubation [4.8 vs 14.7 nmol/(10(6) cells.hr)] (P < 0.05). GSH and AA-GSH synthesis rates did not change compared to control experiments in which sulphation was not inhibited [1165 vs 1487 nmol/(10(6) cells.min), respectively] and [1.7 vs 1.7 nmol/(10(6) cells.hr), respectively]. This indicates that increased sulphur availability due to decreased PAPS synthesis is unable to raise the cysteine pool and stimulate the gamma-glutamyl cycle and GSH synthesis.

Acetaminophen↗
PubMed1993

Glutathione and bile acid synthesis. II. Effect of hepatic glutathione content on the activity and mRNA levels of cholesterol 7 alpha-hydroxylase in the rat.

Hepatic cholesterol 7 alpha-hydroxylase (CH-7 alpha) activity in intact rats depleted of glutathione (GSH) was reduced significantly (P < 0.007) compared with that in untreated controls. Northern blot analysis of poly A+ mRNA isolated from GSH-depleted and control rat livers showed that there was a reduction in mRNA for CH-7 alpha in treated rats that was commensurate with the reduction in CH-7 alpha activity. The fact that the level of transferrin mRNA was unaltered by the depletion of GSH suggests that the change in steady-state CH-7 alpha mRNA content is specifically sensitive to GSH content. This observation extends previous in vitro findings and provides strong justification for a more detailed biochemical investigation into the interaction between GSH levels and the regulation of CH-7 alpha mRNA levels.

Animals↗
PubMed1989

Careful consideration of the effects induced by glutathione depletion in rat liver and heart. The involvement of cytosolic and mitochondrial glutathione pools.

One of the most widely used mechanisms by which the role of glutathione (GSH) in cellular functions has been withdrawn, is to deplete GSH intracellularly. The importance of the procedure and xenobiotic chosen to get it is discussed. Mitochondrial GSH plays certainly an important role in maintaining cellular homeostasis. This contribution varies depending on the tissue and the conclusions obtained about the functions of this GSH pool in one organ may not be applied to others. Original data on the subcellular distribution of GSH in myocardial tissue of the rat are presented, and the effect of phorone on both cardiac GSH pools is compared with the effect in liver. The mechanical failure of myocardium after ischemic or reperfusion damage might involve mitochondrial GSH, in view of the literature data referring to the role of thiol groups in energy transfer from mitochondria to cytosol.

Animals↗
PubMed1991

Oral glutathione increases tissue glutathione in vivo.

Mice were given an oral dose of glutathione (GSH) (100 mg/kg) and concentrations of GSH were measured at 30, 45 and 60 min in blood plasma and after 1 h in liver, kidney, heart, lung, brain, small intestine and skin. In control mice, GSH concentrations in plasma increased from 30 microM to 75 microM within 30 min of oral GSH administration, consistent with a rapid flux of GSH from the intestinal lumen to plasma. Under these GSH-sufficient conditions, no increases over control values were obtained in GSH concentrations in most tissues except lung over the same time course. Mice pretreated for 5 days with the GSH synthesis inhibitor, L-buthionine-S,R-sulfoximine (BSO, 80 mumol/day) had substantially decreased tissue concentrations of GSH. Oral administration of GSH to these GSH-deficient animals gave statistically significant increases in GSH concentrations in kidney, heart, lung, brain, small intestine and skin but not in the liver. Administration of the equivalent amount of the constituent amino acids, glutamate, cysteine, and glycine, resulted in little change in GSH concentrations in all tissues in GSH-deficient animals. Thus, the results show that oral GSH can increase GSH concentrations in several tissues following GSH depletion, such as can occur in toxicological and pathological conditions in which GSH homeostasis is compromised.

Administration, Oral↗
PubMed1986

Improved assay of the enzymes of glutathione synthesis: gamma-glutamylcysteine synthetase and glutathione synthetase.

New methods for the estimation of red cell gamma-glutamylcysteine synthetase and glutathione synthetase have been developed. gamma-32P ATP is allowed to equilibrate until the gamma and beta phosphate groups are equally labelled. The amount of 32Pi released in the presence of glutamic acid and cysteine, the substrates for GC-S or in the presence of gamma-glutamylcysteine and glycine, the substrates of GSH-S, is measured. This is accomplished by extraction of the phosphomolybdate complex into isobutanol-benzene. The methods are linear with time and hemolysate concentration. Normal values are presented.

Adenosine Triphosphate↗
PubMed1992

Mitochondrial glutathione in hypermetabolic rats following burn injury and thyroid hormone administration: evidence of a selective effect on brain glutathione by burn injury.

Cerebral cortex, heart, skeletal muscle, and liver mitochondrial glutathione (GSH) levels in severely burned rats are decreased to between approximately 50% to 70% of sham-operated, normally fed controls. In semistarved rats, weight-matched with burned rats, mitochondrial GSH levels in these tissues are decreased to between approximately 70% to 91% of those in sham-operated rats. Total GSH levels in peripheral tissues and brain are decreased to approximately 60% to 65% of control levels in rats with burn injury and food restriction, suggesting a higher mitochondrial GSH turnover in burned rats than in semistarved rats, probably because of higher "stress hormone" levels in burned rats than in semistarved rats. Cerebral cortex mitochondrial GSH levels are unaffected by variations in thyroid hormone status, but liver mitochondrial GSH levels are decreased by triiodothyronine and increased by propylthiouracil. The present results suggest that mitochondrial GSH is not only regulated by the rate of GSH synthesis in the cytosol, but seems to be under hormonal influence as well; stress hormones and triiodothyronine may decrease mitochondrial GSH by increasing mitochondrial oxygen consumption with increased reactive oxygen species formation or by increasing GSH exchange between mitochondria and the cytosol. These findings may be of importance therapeutically in increasing antioxidative defenses to limit oxidative stress injury in hypermetabolic patients.

Animals↗
PubMed1995

Glutathione conjugation of bromosulfophthalein in relation to hepatic glutathione content in the rat in vivo and in the perfused rat liver.

The relation between the rate of glutathione (GSH) conjugation and hepatic GSH content was studied in the rat in vivo and the in situ single-pass-perfused rat liver preparation with bromosulfophthalein (BSP) as the model substrate. The biliary excretion of the BSP-GSH conjugate and the hepatic GSH content were monitored simultaneously during intravenous infusions with BSP in the rat in vivo, and during liver perfusions with BSP-containing perfusion medium. Rats were pretreated with single or multiple doses of buthionine sulfoximine, an inhibitor of the de novo synthesis of GSH. Surprisingly, the excretion of the BSP-GSH conjugate was sustained at a high rate, despite a virtually complete depletion of hepatic GSH, both in the rat in vivo as well as in the perfused rat liver. The results indicate that GSH was still available for conjugation with BSP after apparent depletion of the hepatic GSH pool, presumably because of a residual de novo synthesis of GSH in the liver. Despite the multiple pretreatment with buthionine sulfoximine, the de novo GSH synthesis was sufficient to sustain a high rate of GSH conjugation of BSP. The cosubstrate-Km for GSH conjugation of BSP in the liver was estimated to be very small (approximately 0.3 mumol/g): the excretion rate of the BSP-GSH conjugate was only impaired at minimal hepatic GSH levels.

Animals↗
PubMed1992

Glutathione-binding proteins identified by monoclonal antibodies which depress the behavioral response evoked by glutathione in Hydra.

Hydra shows at least 5 components of the behavioral response (R1-R5) which are evoked at different concentrations of S-methylglutathione (GSM). We have prepared several monoclonal antibodies (mAbs), each of which depressed specific responses and visualized specific structures. In this paper, we analyzed molecules participating in the signaling pathway of R5 response with use of three mAbs (J245, J5 and J5/1), all of which depressed the response. A behavioral analysis of the response in the presence of mixtures of these mAbs suggested that J245 and J5 both acted on a component of the receptor-effector system which was not affected by J5/1. Correspondingly, an immunoblotting analysis showed two 220 kDa proteins which reacted with both J245 and J5 but not with J5/1. ELISA analyses also showed that the J245 antigens formed only a portion of the J5 antigens. A labeled major peak was found in the 220 kDa protein fraction by gel permeation HPLC after immunoprecipitation of the J245 antigen photolabeled with [35S]-S-(p-azidophenacyl)-glutathione. Competition of the photolabeling by the ligands GSM and L-glutamate (a competitive inhibitor of the R5 response) indicated dissociation constants for their binding to the protein of 55 and 90 microM, respectively. These values were consistent with those expected from behavioral experiments. The 220 kDa proteins therefore appear to be candidates for the receptor molecules mediating R5.

Affinity Labels↗
PubMed1987

Effect of lead toxicity on the organ concentration of glutathione and glutathione-related free amino acids in the chick.

Total non-protein sulfhydryl (NPSH) and glutathione (GSH) concentrations in liver and kidney and GSH-related free amino acid concentrations in liver, kidney and plasma were examined in the chick following intoxication with 2000 ppm dietary lead (Pb). After 3 weeks, NPSH content was significantly (P less than 0.05) increased by Pb in both liver and kidney while only liver GSH was increased by Pb treatment. The concentrations of glutamate, glycine and methionine were elevated in liver by Pb while glycine, cysteine and cystathionine concentrations were increased in the kidney. In plasma, Pb significantly decreased cysteine, taurine and cystathionine concentrations.

Amino Acids↗
PubMed1992

Plasma glutathione level in paracetamol daily abuser patients. Changes in plasma cysteine and thiol groups after reduced glutathione administration.

Since plasma reduced glutathione (GSH) seems to reflect liver GSH content, we have assessed plasma GSH in patients using paracetamol daily. In these patients a significant lower plasma GSH concentration was found with respect to controls. After the i.v. administration of GSH free plasma cysteine was 12 fold higher than in basal condition and all the pattern of plasma thiol groups was modified. This work suggests that the possible protective effect of GSH administration is due to the availability of plasma thiol compounds that enter the cell rather than GSH itself.

Acetaminophen↗
PubMed1995

Characterization of cisplatin-glutathione adducts by liquid chromatography-mass spectrometry. Evidence for their formation in vitro but not in vivo after concomitant administration of cisplatin and glutathione to rats anc cancer patients.

After incubation of equimolar amounts of cisplatin (CDDP) and glutathione (GSH) in phosphate buffer pH 7.4 at 37 degrees C, we detected two CDDP-GSH adducts whose structures, characterized by LC-MS, corresponded to cis-[Pt(NH3)2Cl(SG)] and cis-([Pt(NH3)2Cl]2(mu-SG))+. The latter is a new CDDP-GSH adduct, which was postulated but never structurally characterized so far. Rats and patients were given a 15-min intravenous infusion of CDDP (10 mg/kg to rats and 25 mg/m2 to patients) preceded by a GSH intravenous administration (200 mg/kg to rats as a bolus and 1.5 g/m2 to patients as a 15-min infusion). After the administrations, CDDP-GSH adducts were absent in rat and human plasma ultrafiltrates. The discrepancy between in vitro and in vivo findings can be explained based on pharmacokinetic considerations.

Animals↗