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)

Low arterial blood pH and sustained nitric oxide (NO) production are critical parameters in inflammatory events such as sepsis, and appropriate treatment is still under debate. Because the stability of nitrogen and oxygen intermediates is dependent on the surrounding pH, we investigated whether the relationship among NO, peroxynitrite (ONOO-), and reactive oxygen species production also depends on the pH value, particularly with respect to their effects on hepatocellular damage. Our studies demonstrate that the extracellular pH influences NO and hydroxyl radical (OH) production in hepatocytes. Acidification (pH 7.0) of the medium revealed a significant increase (P < 0.05) of OH-like radicals, enhanced hepatocellular damage, and a sharp drop in cellular glutathione (GSH) content compared with levels measured at physiological or alkaline pH conditions. Furthermore, inhibition of NO synthesis at all pH conditions resulted in decreased NO production and cellular GSH levels but a simultaneous increase of OH-like radicals and hepatocellular damage with a maximum seen at pH 7.0. Our results suggest that hepatocellular damage is in part regulated by the surrounding pH and that inhibition of NO synthesis at acidic conditions (e.g., in sepsis) leads to increased reactive oxygen-mediated cell injury.
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PMID:pH-dependent changes of nitric oxide, peroxynitrite, and reactive oxygen species in hepatocellular damage. 937 10

Glutathione transferase (GSTs) have been shown to be overexpressed in a number of tumor cell lines selected for resistance to chemotherapeutic drugs and have been implicated in some studies of clinical specimens. In tumor cell lines selected for resistance to chemicals that alkylate DNA, the isoform most frequently overexpressed is GST-Yc, a member of the alpha class GSTs. To date, two variations of the cDNA designated Yc1 with subtle differences have been described, and Yc2 is shown to be clearly distinct. Transfection of a Yc1 cDNA constitutively expressed in rat liver into rat mammary cancer cells confers resistance to alkylators, however, to a lesser extent than is observed in the cells selected for resistance. It has therefore been widely suggested that the GST that is overexpressed in selected resistant cells represents a distinct and novel isoform. We have previously described a rat mammary carcinoma cell line (MLNr) that is resistant to alkylating agents, and overexpresses a GST with characteristics similar to GST-Yc1 and not Yc2. It has many features common to the several other GST-Yc overexpressing alkylator resistant cell lines. We have cloned the specific Yc cDNA overexpressed in MLNr and analyzed it in detail and found that it is identical to one of the previously reported Yc1 cDNAs, suggesting that there is no additional Yc gene specifically induced by nitrogen mustards. Another hypothesis to explain the difference in the level of resistance in selected versus GST-Yc transfected cells is the lack of concurrent increased glutathione (GSH) in the transfectants, which is a common feature in the selected resistant cells. Experiments in which we modulated GSH levels suggest that this is not likely. These studies add to our speculation that other mechanisms may be involved in alkylator resistance.
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PMID:Identification of the Yc1 glutathione S-transferase mRNA as the overexpressed species in a nitrogen mustard-resistant rat mammary carcinoma cell line. 941 83

Hydroquinone, an intermediate used in the chemical industry and a metabolite of benzene, is a nephrocarcinogen in the 2-year National Toxicology Program bioassay in male Fischer 344 rats. Current evidence suggests that certain chemicals may induce carcinogenesis by a mechanism involving cytotoxicity, followed by sustained regenerative hyperplasia and ultimately tumor formation. Glutathione (GSH) conjugates of a variety of hydroquinones are potent nephrotoxicants, and we now report on the effect of hydroquinone and 2,3,5-(tris-glutathion-S-yl)hydroquinone, on site-selective cytotoxicity and cell proliferation in rat kidney. Male Fischer 344 rats (160-200 g) were treated with hydroquinone (1.8 mmol/kg or 4.5 mmol/kg, p.o.) or 2,3,5-(tris-glutathion-S-yl)hydroquinone (7.5 micromol/kg; 1.2-1.5 micromol/rat, i.v.), and blood urea nitrogen (BUN), urinary gamma-glutamyl transpeptidase (gamma-GT), alkaline phosphatase (ALP), glutathione-S-transferase (GST) and glucose were measured as indices of nephrotoxicity. Hydroquinone (1.8 mmol/kg, p.o.) is nephrotoxic in some rats, but not others, but cell proliferation (BrDU incorporation) in proximal tubular cells of the S3M region correlates with the degree of toxicity in individual rats. At 4.5 mmol/kg, hydroquinone causes significant increases in the urinary excretion of gamma-GT, ALP and GST. Pretreatment of rats with acivicin prevents hydroquinone-mediated nephrotoxicity, indicating that toxicity is dependent on the formation of metabolites that require processing by gamma-GT. Consistent with this view, 2,3,5-(tris-glutathion-S-yl)hydroquinone, a metabolite of hydroquinone, causes increases in BUN, urinary gamma-GT and ALP, all of which are maximal 12 h after administration of 2,3,5-(tris-glutathion-S-yl)hydroquinone. In contrast, the maximal excretion of GST and glucose occurs after 24 h. By 72 h, BUN and glucose concentrations return to control levels, while gamma-GT, ALP and GST remain slightly elevated. Examination of kidney slices by light microscopy revealed the presence of tubular necrosis in the S3M segment of the proximal tubule, extending into the medullary rays. Cell proliferation rates in this region were 2.4, 6.9, 15.3 and 14.3% after 12, 24, 48 and 72 h, respectively, compared to 0.8-2.4% in vehicle controls. Together with the metabolic data, the results indicate a role for hydroquinone-thioether metabolites in hydroquinone toxicity and carcinogenicity.
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PMID:Cytotoxicity and cell-proliferation induced by the nephrocarcinogen hydroquinone and its nephrotoxic metabolite 2,3,5-(tris-glutathion-S-yl)hydroquinone. 945 Apr 87

In addition to the broad repertoire of regulatory functions nitric oxide (NO) serves in mammalian physiology, the L-arginine:NO pathway is also involved in numerous pathophysiological mechanisms. While NO itself may actually protect cells from the toxicity of reactive oxygen radicals in some cases, it has been suggested that reactive nitrogen oxide species formed from nitric oxide synthase (NOS) can be cytotoxic. In addition to NO, the one electron reduction product NO- has been proposed to be formed from NOS. We investigated the potential cytotoxic role of nitroxyl (NO-), using the nitroxyl donor Angelis's salt, (AS; sodium trioxodinitrate, Na2N2O3) as the source of NO-. As was found to be cytotoxic to Chinese hamster V79 lung fibroblast cells over a concentration range of 2-4 mM. The presence of equimolar ferricyanide (Fe(III)-(CN6)3-), which converts NO- to NO, afforded dramatic protection against AS-mediated cytotoxicity. Treatment of V79 cells with L-buthionine sulfoximine to reduce intracellular glutathione markedly enhanced AS cytotoxicity, which suggests that GSH is critical for cellular protection against the toxicity of NO-. Further experiments showed that low molecular weight transition metal complexes associated with the formation of reactive oxygen species are not involved in AS-mediated cytotoxicity since metal chelators had no effect. However, under aerobic conditions, AS was more toxic than under hypoxic conditions, suggesting that oxygen dramatically enhanced AS-mediated cytotoxicity. At a molecular level, AS exposure resulted in DNA double strand breaks in whole cells, and this effect was completely prevented by coincubation of cells with ferricyanide or Tempol. The data in this study suggest that nitroxyl may contribute to the cytotoxicity associated with an enhanced expression of the L-arginine:NO pathway under different biological conditions.
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PMID:The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO. 950 20

Changes in the integrity, ultrastructure, phagocytosis capacity, and production of H2O2, O2.- and NO2- were evaluated in cultured neutrophils. The activities of the antioxidant enzymes (catalase-CAT, superoxide dismutase-SOD and glutathione-dependent peroxidase-GSH-Px) were measured under similar conditions. The integrity of the cells remained unchanged up to 18 h. After 24 h, the number of viable cells in culture dropped by 16 per cent. The percentage of viable cells in culture was of 72 per cent even after 72 h. An ultrastructural analysis of the cells was carried out after 3, 6, 12, 24, 48, and 72 h in culture. Neutrophils started developing morphologic changes after 24 h: decreased cell volume, abundant vacuoles (mainly around the nucleus), and also the presence of autophagic vacuoles. This period was then chosen for the study of neutrophil function and antioxidant enzyme activities. Neutrophils cultured for 24 h presented reduced phagocytosis capacity. The rates of production of H2O2 and O2.- remained unchanged after 24 h in culture. Concomitantly, these cells were also able to produce NO in significant amounts. The production of O2.- in response to PMA stimulus was lowered in 24-h cultured cells. Possibly, the production of oxygen and nitrogen reactive species accomplished with a decrease in the activities of CAT and GSH-Px play a key role for the process of apoptosis which takes place in neutrophils under these conditions.
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PMID:Percentage of phagocytosis, production of O2.-, H2O2 and NO, and antioxidant enzyme activities of rat neutrophils in culture. 951 59

Inorganic mercury has a high affinity for the kidneys and causes acute renal failure. The present investigation was designed to determine the cause of the strain difference in sensitivity of mice to the renal toxicity of inorganic mercury. Renal damage caused by HgCl2 was estimated by histopathological and biochemical assessment, such as increase in blood urea nitrogen and plasma creatinine levels, and was found to be more remarkable in C3H/He than in C57BL/6 mice. Increase in renal lipid peroxidation in C3H/He was greater than that in C57BL/6 mice. However, no strain difference was observed in renal activities of glutathione (GSH) peroxidase, superoxide dismutase and GSH S-transferase in HgCl2-untreated mice. The GSH content and activities of catalase and GSSG reductase in kidney of HgCl2-untreated mice were higher in C3H/He than in C57BL/6. Background level of renal metallothionein content and the extent of metallothionein induction by HgCl2 showed no strain difference. On the other hand, renal mercury accumulation was higher and urinary mercury excretion was lower in C3H/He than in C57BL/6. The activity of renal gamma-glutamyltranspeptidase (gamma-GTP), which plays a key role in renal mercury accumulation, was higher in C3H/He than in C57BL/6. Furthermore, the increase in blood urea nitrogen by HgCl2, renal mercury accumulation and renal gamma-GTP activity in B6C3F1 mice were intermediate between those of the parent strains. These results suggest that the strain difference in renal toxicity of inorganic mercury seems to be caused by the discrepancy in renal mercury accumulation, and therefore, renal gamma-GTP may be an important factor determining the susceptibility of mice to the toxic action of inorganic mercury.
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PMID:Strain difference in sensitivity of mice to renal toxicity of inorganic mercury. 953 29

To determine if diesel exhaust (DE) exposure modifies the antioxidant defense network within the respiratory tract lining fluids, a randomized, single blinded, crossover control study using nasal lavage and flexible video bronchoscopy with bronchial and bronchoalveolar lavage was performed. Fifteen healthy, non-smoking, asymptomatic subjects were exposed to filtered air or diluted diesel exhaust (300mg m(-3) particulates, 1.6ppm nitrogen dioxide) for one hour on 2 separate occasions, at least three weeks apart. To examine the kinetics of any DE-induced antioxidant reactions, nasal lavage fluid and blood samples were collected prior to, immediately after, and 5 1/2 hours post exposure. Bronchoscopy was performed 6 hours after the end of DE exposure. Ascorbic acid, uric acid and reduced glutathione (GSH) concentrations were determined in nasal, bronchial, bronchoalveolar lavage and plasma samples. Malondialdehyde (MDA) and protein carbonyl concentrations were determined in plasma and bronchoalveolar lavage samples. Nasal lavage ascorbic acid concentration increased 10-fold during DE exposure [1.02 (0.26-2.09) Vs 7.13 (4.66-10.79) micromol/L(-1)], but returned to basal levels 5.5 hours post-exposure [0.75 (0.26-1.51) micromol/L(-1)]. There was no significant effect of DE exposure on nasal lavage uric acid or GSH concentration. DE exposure did not influence plasma, bronchial wash, or bronchoalveolar lavage antioxidant concentrations and no change in MDA or protein carbonyl concentrations were found. The physiological response to acute DE exposure is an increase in the level of ascorbic acid in the nasal cavity. This response appears to be sufficient to prevent further oxidant stress in the respiratory tract of normal individuals.
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PMID:Nasal cavity lining fluid ascorbic acid concentration increases in healthy human volunteers following short term exposure to diesel exhaust. 955 33

We hypothesized that unexplained increases in nucleoside triphosphates (NTP) observed by 31P magnetic resonance spectroscopy (MRS) after treatment of tumours by DNA-damaging agents were related to chemotherapy-induced up-regulation of the bcl-2 gene and DNA damage prevention and repair processes. To test this hypothesis, we treated HT-29 cells with 10(-4) M nitrogen mustard (HN2) and performed sequential perchloric acid extractions in replicate over 0-18 h. By reference to an internal standard (methylene diphosphonic acid), absolute changes in 31P-detectable high-energy phosphates in these extracts were determined and correlated with changes in bcl-2 protein levels, cell viability, cell cycle, apoptosis and total cellular glutathione (GSH) (an important defence against DNA damage from alkylating agents). After HN2 administration, bcl-2 protein levels in the HT-29 cell line rose at 2 h. Cell viability declined to 25% within 18 h, but apoptosis measured using fluorescence techniques remained in the 1-4% range. Increased cell division was noted at 4 h. Two high-energy interconvertible phosphates, NTP (P < or = 0.006) and phosphocreatine (PCr) (P < or = 0.0002), increased at 2 h concurrently with increased levels of bcl-2 protein and glutathione. This study demonstrates that bcl-2 and glutathione are up-regulated by HN2 and links this to a previously unexplained 31P MRS phenomenon: increased NTP after chemotherapy.
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PMID:Nitrogen mustard up-regulates Bcl-2 and GSH and increases NTP and PCr in HT-29 colon cancer cells. 965 54

Metallothioneins (MTs) are major zinc-binding protein thiols that are readily inducible and whose functions remain unclear. Recent evidence supports a role for MT as an antioxidant. Mechanisms underlying this function may include direct interception of free radicals, complexation of redox sensitive transition metals, altered zinc homeostasis or interaction with glutathione (GSH). MT overexpression after direct gene transfer in cultured cells, decreases cytotoxicity, to partially reduce reactive oxygen and nitrogen species and markedly attenuates intracellular oxidation of reporter molecules including dichlorofluorescein and cis-parinaric acid. Conversely, enhanced intracellular oxidation is seen in cells derived from mice lacking both functional MTI and MTII genes. GSH levels are unaffected in MT null cells relative to wildtype, suggesting the antioxidant function of MT is independent of GSH. In tumor cells there is at least a 400-fold range in MT levels and a 10-fold difference in the ratio of nuclear to cytoplasmic distribution. No correlation exists between MT levels and GSH levels demonstrating the autonomous regulation of intracellular thiol pools. This may be important for cancer chemotherapies since MT overexpression is seen in human tumor cells with acquired drug resistance. The authors found no evidence for altered MT isoform profiles in drug resistant cells that overexpress MT. Recent evidence suggests MT subcellular location may dictate functionality and MT may help determine the threshold for apoptosis. Thus, MT is a stress-inducible protein with antioxidant attributes that may participate independently or in conjunction with GSH to protect cells against injurious agents.
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PMID:The protein thiol metallothionein as an antioxidant and protectant against antineoplastic drugs. 967 59

Although free radicals have been traditionally implicated in cell injury, and associated to pathophysiological processes, recent data implicate them in cell signaling events. Free radicals are naturally occurring oxygen-,nitrogen-and sulfur-derived species with an unpaired electron, such as superoxide, hydroxyl radical or nitric oxide. In order to assess the role of free radicals in cell signaling, we have studies the modulator effect of oxygen and nitrogen active species on liver methionine adenosyltransferase (MAT), a key metabolic enzyme. The presence of 10 cysteine residues per subunit, makes liver MAT a sensitive target for oxidation/nitrosylation. Here we show that purified MAT from rat liver is nitrosylated and oxidized in vitro. Incubation with H202 or the NO donor S-nitrosylated GSH (GSNO), diminish MAT activity in a dose-and time-dependent manner. Furthermore, the inactivation derived from both oxidation and nitrosylation, was reverted by GSH. MAT inactivation originates on the specific and covalent modification of the sulphydryl group of cysteine residue 121. We also studied how free radicals modulate MAT activity in vivo. It was previously shown that MAT activity is strongly dependent on cellular GSH levels. Generation of oxygen and nitrogen active species in rats by injection of LPS, induced a decrease of liver MAT activity. This effect might derive from nitrosylation and/or oxidation of the enzyme. Modulation of liver MAT by NO is further supported by the inactivation of this enzyme observed in experimental models in which NO is produced; such as the administration of NO donors to rats and in hepatocytes cultured in hypoxia, a condition that induces the expression of the inducible nitric oxide synthase (iNOS). Oxidation also controls liver MAT activity in a cell environment as shown in CHO cells stably transfected with rat liver MAT cDNA upon addition of H2O2 to the culture medium. This effect depends upon the generation of the hydroxyl radical. On the basis of the metabolic implications of liver MAT, together with the structural features accounting for the sensitivity of this enzyme to active oxygen and nitrogen species, we propose that modulation of MAT by these agents could be a mechanism to regulate the consumption of ATP in the liver, and thus preserve cellular viability under different stress conditions.
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PMID:Specific interaction of methionine adenosyltransferase with free radicals. 969 5


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