UMLS:C0432222 - FACTA Search

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Query: UMLS:C0432222 (SEM)
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Chloramines, compounds made up of chlorine and ammonia, when present in tap water used for dialysis cause methemoglobinemia and hemolysis. Ascorbic acid addition has been reported to effectively neutralize chloramines in vitro and in patients dialyzed with the single batch dialysis delivery system. We extended these observations to patients dialyzed with the proportioning dialysis delivery system where exposure time of ascorbic acid to chloramines is shorter. This may be important since we found that the half time of the reaction between ascorbic acid and chloramines is 4 minutes. Red cell oxidant sensitivity in 15 patients was assessed by incubating red cells with ascorbate-cyanide and measuring methemoglobin which averaged 2.17 +/- 0.42 g/100 ml (SEM) before dialysis and 2.87 +/- 0.52 g/100 ml after dialysis (NS). Reduced glutathione (GSH) levels were also measured as an index of red cell oxidant damage. GSH decreased from a mean of 7.40 +/- 0.59 micromoles/g Hb before dialysis to 6.98 +/- 0.52 micronmoles/g Hb after dialysis (P less than 0.01). In 2 patients there was no change in 51Cr red cell survival when dialyzed on either the proportioning system or other chloramine free systems. We conclude that addition of ascorbic acid to neutralize chloramines in tap water is also effective when using the proportioning dialysis delivery system.
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PMID:Prevention of chloramine-induced hemolysis in dialyzed patients. 69 6

The spontaneous reaction of 110 microM chlorambucil (4-[p-[bis(2-chloroethyl)amino]phenyl]-butanoic acid; CHB) with 5 mM GSH at 37 degrees C in physiological phosphate-buffered saline for 35 min gave primarily the monoglutathionyl derivative, 4-[p-[N-2-chloroethyl,N-2-S-glutathionylethyl]amino]phenyl]-butano ic acid; CHBSG) and the diglutathionyl derivative, 4-[p-[bis(2-S-glutathionylethyl]amino]phenyl]-butanoic acid (CHBSG2) with small amounts of the hydroxy-derivatives: 4-[p-[N-2-chloroethyl,N-2-hydroxy-ethyl]amino] phenyl-butanoic acid (CHBOH) and 4-[p-[N-2-S-glutathionylethyl-2-hydroxyethyl]amino]phenyl]-butanoi c acid (CHBSGOH). The inclusion of approximately physiological amounts of human glutathione S-transferases (GSTs) A1-1, A2-2, P1-1, M1a-1a M3-3 or P1-1 (for nomenclature see Mannervik et al., 1992, Biochem. J., 282, 305) had little or no catalytic effect on these reactions as determined by loss of CHB. However, GTSs A1-1 and A2-2 were associated with a significant increase of CHBSG at the expense of CHBSG2 + CHBSGOH suggesting that these GTs sequestered CHBSG at the active site. This interpretation was supported by inhibition studies which showed that CHBSG was a pure competitive inhibitor of the activity of GSTs A1-1 and A2-2 towards 1-chloro-2,4-dinitrobenzene with Ki's of 1.3 and 1.2 microM respectively. GSH transferases P1-1 and M1a-1a were inhibited by CHBSG above 10 microM. Incubation of 2 microM CHB, a concentration which may be of more significance for chemotherapy, in the presence or absence of GST A1-2 (20-50 microM) showed catalysis of GSH monoconjugation equivalent to 18% of the spontaneous rate. However, the dominant effect again was the sequestration of CHBSG which reached 74.3 +/- 1.5 (SEM)% of the total reactants at 60 min compared to 28.9 +/- 0.3(SEM)% in controls. CHBSG, although possessing a potential electrophilic centre, showed no detectable alkylation of plasmid DNA but indirect evidence was obtained that it alkylated other cellular macromolecules. It is concluded that the contribution of GSTs to catalysis of CHB detoxication will depend on factors not previously considered, namely the relative molarities of CHB, CHBSG and GSTs, and the cellular capacity to excrete CHBSG to relieve product inhibition.
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PMID:Chlorambucil-monoglutathionyl conjugate is sequestered by human alpha class glutathione S-transferases. 152 May 81

Hepatic glutathione (GSH) plays an important role in the detoxification of reactive molecular intermediates. Because of evidence that the intrahepatic turnover of glutathione in the rat may be largely accounted for by efflux from hepatocytes into the general circulation, the quantitation of plasma GSH turnover in vivo could provide a noninvasive index of hepatic glutathione metabolism. We developed a method to estimate plasma glutathione turnover and clearance in the intact, anesthetized rat using a 30-min unprimed, continuous infusion of 35S-labelled GSH. A steady state of free plasma glutathione specific radioactivity was achieved within 10 min, as determined by high-pressure liquid chromatography with fluorometric detection after precolumn derivatization of the plasma samples with monobromobimane. The method was tested after two treatments known to alter hepatic GSH metabolism: 90 min after intraperitoneal injection of 4 mmol/kg buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis, and after a 48-h fast. Liver glutathione concentration (mean +/- SEM) was 5.00 +/- 0.53 mumol/g wet weight in control rats. It decreased to 3.10 +/- 0.35 mumol/g wet weight after BSO injection and to 3.36 +/- 0.14 mumol/g wet weight after fasting (both p less than 0.05). Plasma glutathione turnover was 63.0 +/- 7.46 nmol.min-1.100 g-1 body weight in control rats, 35.0 +/- 2.92 nmol.min-1.g-1 body weight in BSO-treated rats, and 41.7 +/- 2.28 nmol.min-1.g-1 body weight after fasting (both p less than 0.05), thus reflecting the hepatic alterations. This approach might prove useful in the noninvasive assessment of liver glutathione status.
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PMID:Plasma glutathione turnover in the rat: effect of fasting and buthionine sulfoximine. 186 7

Cellular glutathione (GSH) levels were measured from 27 human lung tumor biopsies, enzymatically disaggregated, and compared with cells isolated from normal lung of the same patients. GSH levels from normal lung were similar among patients with a mean value of 11.20 +/- 0.58 (SEM) nmol GSH/mg protein (24 patients) with a range from 6.1 to 17.5 nmol GSH/mg protein. GSH levels varied considerably within and across histological tumor types with the following values: adenocarcinomas, 8.83 +/- 0.96 nmol/mg protein (8 patients); large cell carcinomas, 8.25 +/- 2.51 nmol/mg protein (3 patients); and squamous cell carcinomas, 23.25 +/- 5.99 nmol/mg protein (8 patients). The cyclic GSH reductase assay gave only average GSH values and could not distinguish possible GSH variation among subpopulations of cells isolated. Cell volume measurements and microscopic evaluation of cells isolated from both tumors and normal lung revealed heterogeneity with respect to cell types present. To determine the extent of thiol variation among tumor cell subpopulations, tumor cell suspensions were stained with the thiol-specific stain, monochlorobimane (MCB). The accuracy of MCB staining was tested by flow cytometric analysis of 12 in vitro human tumor cell lines and 3 rodent cell lines. A linear relationship was found between the bimane cellular fluorescence and the cyclic GSH reductase assay for cell lines having less than 80 nmol GSH/mg protein (R2 = 0.82). Above 80 nmol GSH/mg protein the rate of change of the bimane fluorescence intensity with respect to increasing GSH concentrations was much reduced. However, by labeling cells with MCB it was possible to distinguish between cell lines with low versus high GSH content. MCB staining of tumor samples revealed multiple populations of cells with respect to thiol levels. In particular, 2 of 8 squamous cell carcinomas had a proportion of cells with elevated fluorescence intensities (from 10 to 35% of the population) suggesting the presence of cells with greatly elevated thiol levels. These findings underscore the complexity of quantitating intracellular GSH levels from tumor biopsies. The combined use of MCB with flow cytometry and conventional GSH assays may help to delineate subpopulations of cells within tumors with different thiol levels.
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PMID:Cellular glutathione and thiol measurements from surgically resected human lung tumor and normal lung tissue. 186 49

In a previous study we have shown a role for reactive oxygen metabolites in glycerol-induced acute renal failure, a well-established model for myoglobinuric acute renal failure. In the present study we examined the role of glutathione in this model of acute renal failure. Administration of 50% (vol/vol) glycerol at a dose of 10 ml/kg of body weight to rats intramuscularly resulted in significant renal failure associated with depletion of total kidney glutathione (GSH) from 2.6 +/- 0.1 mumol/g (mean +/- SEM control level) to 1.7 +/- 0.1 mumol/g after 6 hr (P less than 0.001). If GSH were important in glycerol-induced acute renal failure, one would anticipate that exogenously administered GSH should afford protection, while injury should be potentiated if endogenous GSH is depleted. We examined the effect of i.p. administration of L-buthionine-(S,R)-sulfoximine (BSO) at 2 mmol/kg (which results in depletion of kidney GSH) and the effect of increasing renal GSH by i.v. administration of reduced GSH (2 mmol/kg every 3 hr) on kidney function in glycerol-treated rats. Glycerol-injected rats treated with BSO showed significantly worse renal failure than did rats given glycerol alone, while administration of GSH resulted in significant amelioration of glycerol-induced acute renal failure [glycerol treatment alone, blood urea nitrogen (BUN) = 96 +/- 10 and creatinine = 2.5 +/- 0.4 mg/dl; BSO + glycerol treatment, BUN = 123 +/- 7 and creatinine = 3.5 +/- 0.1 mg/dl (n = 9, P less than 0.05); GSH + glycerol treatment, BUN = 78 +/- 10 and creatinine = 1.25 +/- 0.2 mg/dl (n = 8, P less than 0.05)]. In separate experiments 1,3-bis(chloroethyl)-1-nitrosourea (BCNU) [which interferes with the enzyme GSH reductase and prevents recycling of oxidized GSH (GSSG) into GSH] resulted in worsening of glycerol-induced acute renal failure similar to that produced by BSO. These functional differences between GSH-depleted and GSH-repleted rats were further substantiated by significant histological differences in tubular injury. Taken together, these results provide evidence for an important role of GSH in glycerol-induced acute renal failure.
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PMID:Role of glutathione in an animal model of myoglobinuric acute renal failure. 194 9

Based on the identification of intracellular esterase activity as one early target of sulfamethoxazole hydroxylamine (SMX-HA), we wished to determine if the metabolite affected immune functions which involve esterases. The natural killer (NK) activity of human peripheral blood mononuclear cells (PBMC) was assessed with a cell concentration fluorescence technique following exposure to SMX-HA. When K562 target cells were incubated (4 hr/37 degrees) with various ratios of untreated PBMC effector to K562 target cells (E:T), NK activity increased from 17.8 +/- 3.1% (mean +/- SEM; N = 12) at an E:T ratio of 5:1 to 46.2 +/- 2.0% at an E:T ratio of 40:1. Pretreatment of fresh PBMC with 0.1 to 1.0 mM SMX-HA produced a concentration-dependent inhibition of NK activity (E:T ratio 40:1) reaching approximately 80% at 1 mM SMX-HA. Maximum suppression of NK activity was completed within a 60-min pretreatment period with measurable inhibition detected within 30 min. The viability of effector cells was not affected by the metabolite during the pretreatment period. Therefore, the SMX-HA effects could not be directly attributed to decreased viability of the effector cells; they were irreversible and could be prevented by the inclusion of exogenous reduced glutathione (GSH) in a concentration-dependent manner. Given the important roles of NK cells in immune responsiveness and host resistance, our findings of rapid functional inactivation of the cytolytic effector function provide a possible link between idiosyncratic drug toxicity and drug effects directly on components of the immune system.
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PMID:Cellular toxicity of sulfamethoxazole reactive metabolites--II. Inhibition of natural killer activity in human peripheral blood mononuclear cells. 199 6

Starvation for 24 h causes a striking fall in glutathione content from 3.19 +/- 0.27 to 1.88 +/- 0.14 (X +/- SEM) mumol/g tissue and of GGT activity from 31.75 +/- 4.17 to 19.49 +/- 3.13 (X +/- SEM) nmol/min/mg protein in the homogenate from whole mucosa of the upper small intestinal segments. This was associated with a significant increase in GSH-Px activity and the content of lipid peroxides (measured by the thiobarbituric assay). On semi-synthetic iron-supplemented diet the activities of GSH-T and GGT were significantly decreased as compared with crude diet. On semisynthetic iron-depleted diet GSH-T and GGT activities were further depressed, but this was accompanied with an additional depression of GSH, glutathione reductase (GSSG-R), and glutathione peroxidase (GSH-Px) activities and lipid peroxide concentrations. Food deprivation significantly lowers the mucosal GSH-content and could lead to a destabilization of this system presumably by increased oxidative stress. As compared to normal "crude" diet, semisynthetic diets and oral iron depletion have been shown to cause a depression of the intestinal GSH system. As a consequence of these effects, the resistance of the small intestinal mucosa toward exogeneous dietary toxins might be reduced.
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PMID:Glutathione and its related enzymes in the small intestinal mucosa of rats: effects of starvation and diet. 256 68

Filtered glutathione (gamma-glutamyl-cysteinyl-glycine or GSH) is rapidly hydrolyzed by brush-border enzymes facing the tubular lumen and is reabsorbed in the form of the constituent amino acids. The first step of hydrolysis is catalyzed by gamma-glutamyltransferase (gamma-GT). We investigated localization and capacity of the rat renal glutathione degradation/reabsorption during elevation of the filtered load (intravenous infusion of 12 resp. 18 mumol GSH/min). Fractional excretion went up from about 0.003 to 0.31 +/- 0.02 SEM during infusion of the lower and to 0.49 +/- 0.03 SEM during infusion of the higher glutathione dose. GSH degradation/reabsorption took place along the entire proximal tubule and was partially saturated by a 150-200-fold elevation of the normal filtered load. Net reabsorption of GSH up to the last accessible superficial loop was significantly lower during infusion of 18 mumol GSH/min (0.3 mumol/min) than during infusion of 12 mumol GSH/min (1.6 mumol/min). In further experiments, infusion of 18 mumol GSH/min was preceded by the i.v. administration of acivicin (0.5 mmol/kg body wt.), an inhibitor of gamma-GT. In these experiments, fractional glutathione deliveries to late proximal and early distal tubules did not significantly differ from 1, fractional excretion of GSH at the same time was 1.46 +/- 0.11 SEM, revealing net secretion of GSH with the final urine. Tubular secretion of GSH in the acivicin-treated animals occurred either in distal tubules and/or collecting ducts or in the proximal tubules of deep nephrons which are not accessible to micropuncture.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Renal tubular transport of glutathione in rat kidney. 278 Feb 19

Glutathione (GSH) concentration of whole mucosa was 2.96 +/- 0.26 (mean +/- SEM) mumol/g wet weight in all segments: however the tip cell layer contained significantly less GSH than the lower mucosal cells. GSH S-transferase (GSH-T) activities displayed a striking gradient with highest values in the duodenum and lowest in the terminal ileum. gamma-glutamyl transpeptidase (GGT) activities were also highest in the proximal segment but lowest in the fifth segment among eight divided segments. Along the villus/crypt axis GGT and to a lesser degree GSH-T were also polarized with highest activities in the villus tip cell region. GSH peroxidase (GSH-Px) and glutathione reductase (GSSG-R) had an even distribution along the intestinal tube and among the mucosal cell populations. This distinct pattern of distribution suggests a functional adaptation of GSH and its related enzymes; GSH-T might be important for detoxification of exogenous luminal compounds which enter the body in the upper intestinal segments while GSH-Px might be responsible for peroxidation of endogenously produced compounds.
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PMID:Distribution of glutathione and its related enzymes in small intestinal mucosa of rats. 286 46

Prostaglandin (PG) formation in 16 atherosclerotic human carotid endarterectomy specimens was compared systematically with that of normal carotid artery from seven white pigs and six rhesus monkeys. Prostacyclin (PGI2) formation (picomoles 6-keto-PGF1a/2 min/100 micrograms homogenate protein plus 2 mM glutathione [GSH]) of nonatheromatous intima adjacent proximal (276 +/- 32, mean +/- SEM) or distal (271 +/- 14) to carotid plaque was comparable to that of normal carotid artery from white pig (272 +/- 25, NS) and rhesus monkey (219 +/- 41, NS), and was greater than stenotic intima (156 +/- 17, p less than 0.01), subintimal plaque (168 +/- 14, p less than 0.01), and ulceration (65 +/- 16, p less than 0.01). GSH modulated PGI2 synthesis in all carotid specimens except areas of ulceration (p less than 0.05), but did not restore PGI2 formation in atheromatous fractions to basal level. No detectable arterial thromboxane A2 (TXA2) formation or GSH-dependent PGE2 isomerase activity was observed. The decrement in atherosclerotic carotid artery PGI2 formation was focal (confined to the plaque) and may have been related to loss of effective GSH modulation. These conditions could contribute to a localized imbalance between arterial PGI2 and platelet TXA2 with adverse vascular thromboregulatory consequences.
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PMID:Prostacyclin, thromboxane A2, and prostaglandin E2 formation in atherosclerotic human carotid artery. 327 12

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