Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1260386 (GSH)
 38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gastric peroxidase (GPO) was purified to apparent homogeneity to characterize its major physiological electron donor. The enzyme (RZ = 0.7), with a subunit molecular mass of 50 kDa, is a glycoprotein, with a relative abundance of aspartic and glutamic acid over arginine and lysine. It has a Soret maximum at 412 nm, which is shifted to 426 nm by H2O2 due to formation of compound II. Although the physiological electron donors I-, Br- and SCN-, but not Cl-, are oxidized by GPO optimally at acid pH, only I- and SCN- are oxidized appreciably at physiological pH. Considering that the I- concentration in stomach is less than 1 microM, whereas the SCN- concentration is about 250 microM, SCN- may act as a major electron donor for GPO. Moreover, SCN- oxidation remains unaltered in the presence of physiological concentrations of other halides. The second-order rate constant for the reaction of GPO with H2O2 (k1) and compound I with SCN- (k2) at pH 7 was found to be 8 x 10(7) M-1.s-1 and 2 x 10(5) M-1.s-1 respectively. GPO has significant pseudocatalase activity also in the presence of I- or Br-, but it is blocked by SCN-. The SCN- oxidation product OSCN- may be reduced back to SCN- by cellular GSH, and GSSG may be reduced back to GSH by glutathione reductase and NADPH. In a system reconstituted with pure glutathione reductase, NADPH, GSH, SCN- and H2O2. GPO-catalysed SCN- oxidation could be coupled to NADPH oxidation. This system where GPO utilizes SCN- as the major physiological electron donor may operate efficiently to scavenge intracellular H2O2.
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PMID:Thiocyanate, a plausible physiological electron donor of gastric peroxidase. 782 54

The rate of reaction of several radioprotective agents or their active metabolites with 4-hydroxynonenal (4HNE) was studied and compared to the rate of reaction with cysteine (Cys) and glutathione (GSH). The agents studied were: mercapto ethylamine (MEA); 2(3-aminopropyl) aminoethanethiol (WR1065); S-2-aminoethylisothiouronium bromide-hydrobromide (AET); 1,4-dithiothreitol (DTT); 1,4-dithioerythritol (DTE); N-2(2-mercaptopropionyl)-glycine (MPG); penicillamine hydrochloride (PA); N-acetylcysteine (NAC); 2-3 dimercapto-1 propane sulfonic acid (DMPS); 2,3-dimercaptopropanol (BAL), and meso 2,3 dimercapto succinic acid (DMS). All of them reacted with 4HNE. MEA and WR1065 were the most reactive thiols, and PA and DMS were the least reactive thiols. All the others reacted at rates comparable to or higher than that of cysteine or GSH. The potential role of this type of interactions in the protective action of these drugs against deleterious effects of radiation or carbon tetrachloride is analyzed.
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PMID:Reaction of 4-hydroxynonenal with some thiol-containing radioprotective agents or their active metabolites. 786 76

The role of glutathione (GSH) and protein thiols in the pathobiochemical process of CBrCl3 cytotoxicity was investigated in isolated hepatocytes. Administration of 0.5, 1.0 and 1.5 mmol/l CBrCl3 affected cellular viability as assessed by trypan blue exclusion, release of lactate dehydrogenase and loss of intracellular potassium in a dose-dependent manner. Intracellular glutathione and the capacity to reduce 3-(4,5-dimethylthiazolyl-2-)-2,5-diphenyltetrazolium bromide (MTT, thiazolyl blue) decreased almost independently of the CBrCl3 concentration. Protein thiols were not markedly oxidized in the presence of CBrCl3. However, compromising cellular defence mechanisms by either inhibition of glutathione regeneration or depletion of glutathione enhanced the cytotoxicity of CBrCl3 and induced a loss of protein thiols in the late phase of cellular injury. Under these conditions the thiol-dependent Na+,K+ATPase revealed high sensitivity towards CBrCl3. Thus, glutathione proved to exert effective cytoprotection, and sulfhydryl groups of particular proteins were supposed to be an important target of radical attack.
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PMID:The role of glutathione and protein thiols in CBrCl3-induced cytotoxicity in isolated rat hepatocytes. 797 37

The effects of glutathione (GSH) and of purified human and rat GSH S-transferases (GSTs) on the covalent DNA binding of 3 putative ultimate food-borne carcinogens, the N-acetoxy derivatives of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP), 2-amino-3-methylimidazo(4,5-f)quinoline (IQ), and 2-amino-3,8-dimethylimidazo(4,5-f)quinoxaline (MeIQx), were studied in vitro. GSH (5 mM) alone slightly inhibited (10%) the DNA binding of N-acetoxy-PhIP (100 microM) at pH 7.5, but the binding could be strongly inhibited in the presence of both GSH and GSTs. Among human GSTs, the isozyme A1-1 (alpha-class) was most effective (90% inhibition) followed by A1-2 (40% inhibition); the effect of adding A2-2 was negligible, suggesting that the activity exists in subunit A1. In addition, human GST P1-1 (pi-class) also had some inhibitory effect (30%). Among the rat GSTs tested, GST 1-2 and GST 12-12 (theta-class), which are the equivalent of human A1-2 and T2-2, respectively, were able to inhibit DNA binding of N-acetoxy-PhIP (75 and 40%, respectively). This activity toward N-acetoxy-PhIP was dependent on enzyme concentration and was subject to inactivation by triethyltin bromide, a known GST inhibitor. In contrast, the binding of N-acetoxy-IQ or N-acetoxy-MeIQx to DNA was unaffected by addition of the human or rat GSTs; however, GSH alone significantly inhibited (40%) their binding to DNA. High-performance liquid chromatographic analyses of incubation mixtures containing N-acetoxy-PhIP, GSH, and GST A1-1 failed to detect GSH conjugates of PhIP. Only oxidized glutathione and the parent amine, PhIP, were detected as reaction products, suggesting a redox mechanism. GST activity in human hepatic and colon mucosal cytosols was subsequently examined using the synthetic or O-acetyltransferase-generated N-acetoxy derivatives of PhIP, IQ, and MeIQx as substrates. GST activity toward N-acetoxy-PhIP was expressed in all 8 livers but not in 6 colons. No activity toward N-acetoxy-IQ or N-acetoxy-MeIQx was detected in human liver cytosols. This study indicates that a GST-dependent detoxification pathway may be an important determinant for the organ specificity of the heterocyclic amine carcinogens. Moreover, the high specificity of the reaction for GST A1-1, which is known to be inducible by cruciferous and yellow-green vegetable consumption, is consistent with the protective effects of such diets against human colorectal cancer.
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PMID:Effects of human and rat glutathione S-transferases on the covalent DNA binding of the N-acetoxy derivatives of heterocyclic amine carcinogens in vitro: a possible mechanism of organ specificity in their carcinogenesis. 806 58

Lymphoblasts were separated from the peripheral blood or bone marrow of 19 children (age 1-15, median 4 years) and 13 adults (age 18-59, median 47 years) with acute lymphoblastic leukaemia (ALL). Twenty-one samples were examined at presentation (16 from children and five from adults) and 13 at relapse (three children and ten adults). Glutathione (GSH) levels in leukaemic blasts were compared with in vitro sensitivity to a variety of cytotoxic drugs assessed using 3-(4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) as an indicator of cell viability. There was a statistically significant positive correlation between GSH levels and in vitro sensitivity to daunorubicin (Spearman's rank correlation coefficient rs = 0.38, p < 0.04), melphalan (rs = 0.39, p < 0.04) and prednisolone (rs = 0.48, p < 0.01), but not mitozantrone, etoposide or 6-thioguanine. There was no statistically significant difference in median GSH levels between blasts from children and adults or between samples taken at presentation or relapse. The sample median GSH levels in blasts from patients who responded to therapy (n = 21) and those who did not (n = 7) were 1.05 fmol/cell (97.3% confidence interval (CI) 0.78-1.52) and 2.66 fmol/cell (98.4% CI 0.53-5) respectively, and this difference was statistically significant (p < 0.02, Mann-Whitney U test). In two patients for whom paired samples were available, GSH levels in blasts on relapse were greater than 2-fold higher than on presentation. These results provide evidence that elevation of GSH in leukaemic blasts may be associated with resistance to drugs used in the treatment of children and adults with ALL.
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PMID:Raised intracellular glutathione levels correlate with in vitro resistance to cytotoxic drugs in leukaemic cells from patients with acute lymphoblastic leukemia. 809 28

GSH interacts with Cu(II) in the vicinity of DNA (pH approximately 7) to form the DNA-Cu(I) complex, which can be quantified by characteristic absorption changes [e.g. delta epsilon 295 = 4516 cm-1.M-1 Cu(I)]. Under initial conditions of Cu(II)/GSH >> 1 and DNA(base)/Cu(II) >> 5, the stoichiometry is 1 DNA-Cu(I) per SH group (also for other thiols). Stopped-flow kinetics show that the complex is formed with half-lives of 1-30 s, depending on the environment, but independent of O2. DNA-Cu(I) generation is much slower, less efficient, and O2-dependent at Cu(II)/GSH < 1, or when GSH interacts with Cu(II) before the addition of DNA. Interaction of GSH with Cu(II) in the presence of DNA [at Cu(II)/GSH > 1] leads to DNA-associated transients, probably DNA-GS(-)-Cu(I); DNA-Cu(I) formation under these conditions is proposed to occur by ligand exchange: DNA-GS(-)-Cu(I)+Cu(II)<-->DNA-Cu(I)+GS(-)-Cu(II). There is no evidence for generation of free thiyl radicals (GS.) on reaction of Cu(II) with GSH. Formation of DNA-Cu(I) is, in our opinion, a primary step involved in DNA-strand cleavage by GSH in the presence of Cu(II) [Reed and Douglas (1991) Biochem. J. 275, 601-608]. In this context the question of the pro-oxidative and/or antioxidative activity of GSH, when combined with copper, is discussed. GSH also generates Cu(I) complexes with other nucleic acids. An updated order of affinities of various nucleic acids for Cu(I) is presented. Cu(I) exhibits a high preference for alternating dG-dC sequences and might even be a Z-DNA inducer. The poly(C)-Cu(I) complex seems to form a base-paired structure at pH approximately 7, as demonstrated by intercalation of ethidium bromide.
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PMID:Interaction between glutathione and Cu(II) in the vicinity of nucleic acids. 809 88

Glutathione conjugates of 2-bromohydroquinone (GSyl-BHQ) cause renal proximal tubular necrosis that is dependent upon the activity of gamma-glutamyl transferase (GGT). GGT is present in embryonic yolk sac and its activity increases with gestational age, suggesting that the developing embryo might be at risk from maternal exposure to glutathione conjugates or compounds which are shown to form glutathione conjugates. Studies in pregnant rats exposed on Day 9 of gestation to 400 or 800 mumol/kg BHQ or 20 mumol/kg 2-Br-(di-GSyl)HQ and examined on Day 11 of gestation suggested that the parent compound (BHQ) or a metabolite was nephrotoxic in the adult and dysmorphogenic in the embryo and that 2-Br-(di-GSyl)HQ was nephrotoxic but not dysmorphogenic at the dose tested (20 mumol/kg). We therefore exposed Day 9 rat embryos to BHQ, 2-Br-6-(GSyl)HQ, or 2-Br-(di-GSyl)HQ in vitro for 48 hr to determine the relative dysmorphogenic activity of the parent compounds and the two conjugates. In vitro exposure to BHQ (0-40 microM) resulted in dose-related decreases in somite number (SN), total protein, and developmental score (DEVSC), with no effect on yolk sac diameter (YSD), crown rump length (CR), head length (HL), or percentage abnormal embryos (%AE); 60 microM BHQ was embryolethal. Embryos exposed to 2-Br-6-(GSyl)HQ (0-120 microM) were not affected at concentrations below 120 microM, at which dose there were significant effects on protein, YSD, CR, HL, DEVSC, SN, and %AE. Embryos exposed to 2-Br-(di-GSyl)HQ had a significantly lower DEVSC at the 80 microM concentration and significantly lower YSD, protein, and DEVSC and significantly higher %AE at the 10, 25, and 120 microM concentrations. CR, HL, and SN were not affected at any exposure level with this compound. In conclusion, BHQ was found to be developmentally toxic in vitro and in vivo at doses which also produced severe maternal renal necrosis. The doses of 2-Br-(di-GSyl)HQ in vivo which caused only mild maternal renal necrosis did not produce developmental toxicity. Conjugation of BHQ with either one or two molecules of GSH decreased the embryolethality of BHQ. The conjugates appeared to be of comparable toxicity as measured by the incidence of abnormal embryos in vitro. The role of maternal toxicity and GSH conjugation in 2-BHQ-mediated developmental toxicity remains to be determined.
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PMID:Developmental toxicity of bromohydroquinone (BHQ) and BHQ-glutathione conjugates in vivo and in whole embryo culture. 809 63

We studied the location of alpha-tocopherol (alpha-Toc) in the liposome membranes, and the dynamics of its radical scavenging and recycling by ascorbic acid. The quenching efficiency of alpha-Toc fluorescence by acrylamide, a water soluble quencher with a very low capacity to penetrate through phospholipid bilayers, was very low in dimyristoyl-phosphatidylcholine (DMPC) liposomes with and without charges, but relatively high in sodium dodecylsulphate (SDS) or tetradecyl-trimethylammonium bromide (TTAB) micelles. These findings indicate the low exposure of the chromanol at the surface of the liposome membranes. alpha-Toc was oxidized by positively charged Fe3+ more slowly in DMPC liposomes negatively charged with dicetylphosphate (DCP) (1st order rate constant, 1.41 x 10(-3) sec-1) than in negatively charged SDS micelles (7.14 x 10(-1) sec-1). Assuming that 100% of the OH-groups of alpha-Toc are at the membrane surface of the SDS micelles, as the oxidation rate of alpha-Toc in liposomes is 0.32 microM sec-1, which is about 150 times slower than that in micelles (49.3 microM sec-1), only 0.65% of the OH-groups of alpha-Toc are probably present at the membrane surface of the liposomes. The fluorescence of alpha-Toc was most effectively quenched by interaction with the spin group of the probe 5-(N-oxyl-4,4'-dimethyloxazolidin-2-yl) stearic acid (5-NS), indicating that its OH-group was located in a position corresponding to an inner 5-methylene carbon under the membrane surface. Ascorbic acid (AsA) was rapidly oxidized by 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN) when it was ionically trapped at the positively charged membrane surface of egg yolk phosphatidylcholine (egg PC) liposomes with stearylamine (SA), but was scarcely oxidized in negatively charged egg PC-DCP liposomes because it was present in the bulk water phase. These findings suggest that lipid peroxy-radicals move from the hydrophobic region to near the membrane surface, where they are trapped by alpha-Toc. The electron spin resonance (ESR) spectra of 5-NS and 16-NS labeled in DMPC or DMPC-DCP liposomes were not changed by the addition of AsA in the buffer solution of pH 7.0, indicating that negatively charged AsA could not penetrate into neutrally or negatively charged membranes. alpha-Toc inhibited AMVN-induced lipid peroxidation and AsA extended its inhibition period, but glutathione (GSH) did not affect this inhibition period.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Location, antioxidant and recycling dynamics of alpha-tocopherol in liposome membranes. 816 71

We have developed a polymerase chain reaction (PCR)-based method to measure glutathione peroxidase (GSH-Px) mRNA levels. Expression was measured by multiplex competitive PCR amplification of (a) cDNA from GSH-Px and the "housekeeping" gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and (b) two internal standards consisting of single-base mutants of GSH-Px and GAPDH cDNA that cause either a loss (GSH-Px) or a gain (GAPDH) of an EcoRI restriction endonuclease recognition site. RNA extracted from a human papillomavirus-immortalized human bronchial epithelial cell line (BEP2D) was reverse transcribed. Serial dilutions of cDNA were PCR amplified in the presence of GSH-Px and GAPDH primers and quantified amounts of mutated internal standards. The amplified DNA was restriction digested with EcoRI and electrophoresed on an agarose gel stained with ethidium bromide, separating native from mutated products. Densitometry was performed to quantitate the bands. Our studies demonstrate that this technique measures the relative expression of GSH-Px to GAPDH precisely and reproducibly for studies done with the same master mixture and dilution of internal standards. Ratios of relative gene expression varied less than 25% from the mean. This technique will be useful to measure changes in gene expression, particularly when the amount of study sample is limited or the level of gene expression is low.
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PMID:Measurement of gene expression by multiplex competitive polymerase chain reaction. 823 2

The simultaneous addition of dithiothreitol (DTT), mercaptoethanol, and glutathione (30 microM each) and CH3Hg+ to Nostoc calcicola cells reduced CH3Hg+ uptake in the order GSH > DTT > mercaptoethanol. However, the preexposure of cyanobacterial cells to similar thiols resulted in different pattern of CH3Hg+ uptake in the sequence: GSH > mercaptoethanol > DTT. Light-grown cyanobacterial cells demonstrated a faster initial uptake of CH3Hg+ (rate 0.619 mumol CH3Hg+ mg-1 protein min-1, 10 min) with a biphasic pattern saturating at 30 min (bioconcentration factor = 2.7 x 10(3)). 3-(3,4-Dichlorophenyl)-1,1'-dimethyl urea (30 microM) reduced the uptake rate by 5% with a corresponding 33% reduction in CH3Hg+ accumulation. Dark exposure (24 hr) of cells reduced the CH3Hg+ uptake rate (22.3%) accompanied by a considerable decline in the bioconcentration factor (1.4 x 10(3)). Of the four permeabilizers used, p-chloromercuribenzoate (1 microM) proved most effective in altering the CH3Hg+ uptake kinetics while dimethyl sulfoxide (5%) and cetyl trimethylammonium bromide (1%) lowered the bioconcentration factor to 2.2 x 10(3) and 1.2 x 10(3), respectively. After toluene exposure, however, the cells revealed no sign of CH3Hg+ uptake. The data have been discussed in light of the role(s) of thiols, photoautotrophy, and membrane integrity in regulating the cellular influx of CH3Hg+.
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PMID:Factors regulating methyl mercury uptake in a cyanobacterium. 856 82


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