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)

Arsenic is metabolized by living systems using oxidation-reduction and methylation reactions, and reduced glutathione (GSH) has been shown to be important in that metabolism. In this study, the solution reactions between GSH and arsenate, arsenite, and their methylated metabolites, monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA), were characterized using 1H and 13C NMR under a nitrogen atmosphere. Binding to GSH through the thiol group was primarily followed by shifts in the carbon atom bonded to the sulfhydryl group of the cysteinyl residue, i.e., the CH2 carbon atom and the protons bonded to it. The methylated metabolites also showed shifts in the methyl groups attached to the arsenic atom after reaction with GSH. Sodium arsenite, As(III), bound to GSH to form an As(SG)3 complex in solution as indicated by NMR spectra. The identity of the complex was confirmed by FAB-MS after isolation of the compound. Mixtures of sodium arsenate, As(V), and GSH showed that arsenate oxidized GSH in D2O solutions at pH 7 to form oxidized glutathione (GSSG). When the molar ratio of As:GSH exceeded 1:2, evidence for the formation of As(SG)3 was observed. MMA and DMA are both As(V) species, and mixtures with GSH showed oxidation to GSSG initially followed by formation of CH3.As(SG)2 and (CH3)2.As.SG, respectively. The effects of GSH on arsenic metabolism may result from direct reactions between the two compounds.
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PMID:Reactions of arsenic(III) and arsenic(V) species with glutathione. 844 39

In mice depleted of GSH by treatment with buthionine sulfoximine (BSO), thiabendazole (TBZ) causes renal injury characterized by an increase in serum urea nitrogen (SUN) concentration and by tubular necrosis. Previous studies have shown that TBZ requires metabolic activation before it produces nephrotoxicity and that the structure contributing to the toxicity of TBZ is the thiazole moiety of the molecule. TBZ and its thiazole analogues were examined for the ability to increase SUN concentration and serum alanine aminotransferase activity in GSH-depleted mice. Unsubstituted thiazole and thiazoles with 4- and/or 5-, and no 2-, substituents caused marked increases in SUN concentration, suggesting nephrotoxicity. Furthermore, the nephrotoxic potency of these thiazoles decreased with the increasing number and bulk of the 4- and/or 5-substituents. On the other hand, the target organ (the kidney or liver) and the toxic potency of 4-methylthiazoles were markedly altered with the type of substituents at the 2-position. These observations and the known toxicity of thiono-sulfur compounds led us to the hypothesis that the nephrotoxic thiazoles, which lack 2-substituents, would undergo microsomal epoxidation of the C-4,5 double bond and, after being hydrolyzed, the resulting epoxide would then be decomposed to form thioformamide, a possibly toxic metabolite. Evidence for this hypothesis was provided by the results that thioformamide and tert-butylglyoxal as the accompanying fragment were identified as urinary metabolites in mice dosed with 4-tert-butylthiazole and that thioformamide caused a marked increase in SUN concentration when administered to mice in combination with BSO.
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PMID:Possible role of thioformamide as a proximate toxicant in the nephrotoxicity of thiabendazole and related thiazoles in glutathione-depleted mice: structure-toxicity and metabolic studies. 847 8

Glutathione (GSH) is an important factor involved in the resistance of tumor cells to anticancer agents. Buthionine sulfoximine (BSO), a specific inhibitor of GSH synthesis, effectively decreases cellular GSH concentrations both in vitro and in vivo. Depletion of GSH by BSO sensitizes a variety of cancer cells to chemotherapeutic agents. Therefore, BSO has been on clinical trial as an anticancer adjuvant. For this purpose, it is important to understand the effect of BSO treatment not only on the sensitivity of tumor cells to anticancer agents, but also on the metabolism and function of normal tissues. The present study was undertaken to determine the effect of BSO treatment on GSH concentrations in the blood, liver, and ovary, and changes in concentrations of ovarian hormones and other important components in plasma. Female Sprague-Dawley rats, 90 days of age, were treated with 2.0 mmol/kg BSO in saline by intraperitoneal injection, twice daily for 7 days. This treatment depressed GSH concentrations in the blood, liver and ovary by 95, 75, and 85%, respectively. Several blood components were measured. These included red blood cells, hemoglobin, ceruloplasmin, hematocrit, mean corpuscular volume and hemoglobin concentration, alkaline phosphatase, urea nitrogen, creatine and creatinine, glucose, cholesterol, triglycerides, triiodothyronine (T3), thyroxine (T4), and hormones including estradiol, progesterone, and prolactin. BSO treatment significantly (P < 0.05) elevated and lowered plasma concentrations of ceruloplasmin and urea nitrogen, respectively, More importantly, plasma concentrations of estradiol and progesterone were decreased markedly (P < 0.05) in the BSO-treated animals. The hormonal results suggest that investigations on the role of BSO-induced GSH depletion in the treatment of malignancies both with and without hormone dependence in women should be undertaken.
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PMID:Suppression of plasma estradiol and progesterone concentrations by buthionine sulfoximine in female rats. 861 4

It is an established fact that animals recovering from prior acute renal failure (ARF) are resistant to subsequent renal failure challenge with the same toxic agents, although the detailed mechanisms responsible for this phenomenon remain unclear. In this study, the mechanism underlying acquired resistance to gentanmicin (GM) was investigated from the viewpoint of kidney tissue enzymology. Sprague-Dawley rats (N = 40) were administered GM subcutaneously at the dose of 80mg/day consecutively for 40 days. Blood urea nitrogen (BUN) reached the maximum mean concentration of 36 mg/dl on day 14. Thereafter, it decreased to a level within the normal range on day 21. The change in fractional excretion of sodium (FENa) showed a curve virtually identical to the change in BUN. In renal tissue, the elevation of malondialdehyde (MDA) levels was transient during continued administration of GM. The shingomyelin (SPH)/phosphatidylcholine (PC) ratio significantly decreased on day 4, but there was no marked change thereafter. The levels of total phospholipids (PLs), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) increased, whereas SPH decreased mostly on day 4. The levels of phosphatidylinositol (PI) showed a continued fall during the 40 days of the experiment. On day 40, these changes in composition recovered. Phospholipase A2 (PLA2) activities decreased gradually, whereas a distinct increase in phospholipase C (PLC) activity was maintained after day 21. Furthermore, glutathione (GSH) levels also showed two distinct cycles of decrease and increase. PLs levels correlated well with PLC activities. It was concluded that accelerated lipid peroxidation occurs early in the course of GM administration and enhances changes in the phospholipid composition, which has an influence on membrane fluidity. Thus, acquired resistance to ARF induced by GM may be due to the supply of GSH and the maintenance of alteration in phospholipid composition, which are induced by PLC activities.
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PMID:[An experimental study on the pathogenetic role of acquired resistance to acute renal failure--Enzymochemical investigation]. 871 8

Effect of glutathione (GSH) depletion on paraquat (PQ) toxicity in the liver and kidneys of mice was examined. Glutamic-pyruvate transaminase (GPT) and blood urea nitrogen (BUN) levels in plasma of mice were hardly changed by treatment with 150 micro mol/kg of PQ. However, significant increases in the plasma GPT and BUN levels after PQ injection were observed in mice which were pretreated with L-buthionine-SR-sulfoximine (BSO), an inhibitor of GSH synthesis, at 4 hr prior to PQ administration. This result supports the previous observation that hepatotoxicity of PQ was enhanced in diethyl maleate-pretreated mice (Cagen and Gibson, 1977). In the present study, lipid peroxidation evaluated by thiobarbituric acid-reactive substances (TBA-RS) level in the liver of mice given PQ was elevated by pretreatment with BSO. Moreover, enhancement of PQ cytotoxicity by BSO pretreatment was also observed in cultured mouse hepatoma cell line (NCTC clone 1469). Vitamin E, an antioxidant, and Desferal, an iron chelator, significantly prevented mice from the BSO-enhanced hepato- and nephrotoxicity of PQ. These findings suggest that the tissues or cells of low GSH concentration are highly vulnerable to PQ toxicity and GSH may play a major role in diminishing the toxic action of PQ exerted through oxidative stress.
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PMID:Enhancement of paraquat toxicity by glutathione depletion in mice in vivo and in vitro. 872 Jan 62

1. Male Wistar rats were treated with either the antitumour agent nitracrine (1-nitro-9-(3'-dimethylamino-N-propylamino)-acridine; NC), 4-methoxy-NC, NC-aliphatic-N-oxide, 4-methoxy-NC-aliphatic-N-oxide, or NC-aromatic-N-oxide (30 mumol/kg, via the femoral vein) and the major biliary and urinary metabolites analysed by hplc. 2. No NC or 4-methoxy-NC were detected in bile or urine of rat treated with NC or 4-methoxy-NC respectively, whereas the aliphatic N-oxides of NC and 4-methoxy-NC were recovered largely unchanged in both bile and urine. 3. NC-aromatic-N-oxide was rapidly and extensively converted to a major polar biliary product. This product was also synthesised enzymatically from NC-aromatic-N-oxide using rat liver cytosol and has been identified by mass and 1H-nmr spectrometry as 1-(S-glutathionyl)-9-(3'-dimethylamino-N-propylamino)-acridine-N(10)-oxi de. 4. The equivalent 1-(S-glutathionyl) conjugate appears to be formed from NC, and excreted in bile as a minor product, but not from 4-methoxy-NC. Further experiments with cytosol indicate that direct displacement of the nitro group by GSH is mediated by GSH transferase. 5. Finally, the major biliary metabolite of NC has been provisionally identified as a glucuronide of 1-nitro-2-hydroxy-NC. 6. It is concluded that, for at least a significant fraction of NC, nitroreduction does not occur. Further, N-oxidation of the aliphatic (but not the aromatic ring) nitrogen, plus 4-methoxy substitution, decreases the overall metabolism of NC in the rat.
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PMID:Effect of substituents on the metabolism of nitracrine in rat. 873 66

Micromolar concentrations of nitrogen dioxide (NO2), a key metabolite of nitric oxide (NO) and peroxynitrite (ONOO-), were observed to cause a prolonged relaxation of isolated endothelium-removed rings of bovine pulmonary arteries (BPA) precontracted with 30 mM potassium. Relaxation to NO2 was markedly inhibited by 1 microM hemoglobin (Hb), 10 microM methylene blue (MB), and 10 microM LY-83583. The response to NO2 was enhanced in the presence of 1 mM reduced glutathione (GSH) or cysteine. The addition of NO2 to Krebs bicarbonate buffer (under 95% N2-5% CO2) containing 1 mM GSH or BPA resulted in an increase in NO formation (measured in head space gas). Relaxation to NO2 and NO formation were markedly decreased after GSH depletion by pretreatment of BPA with diethyl maleate. A high-performance liquid chromatography analysis of the products formed immediately after the addition of NO2 to GSH detected a previously isolated (but not identified) potent relaxing agent formed by a reaction of GSH with ONOO-, and this material comigrated with a synthetic product thought to be S-nitro-GSH (GSNO2). Nanomolar concentrations of GSNO2 caused a potent dose-dependent relaxation that was inhibited by Hb, MB, and LY-83583. Therefore NO2 appears to cause a prolonged guanosine 3',5'-cyclic monophosphate-mediated relaxation in BPA via thiol nitration and a subsequent time-dependent release of NO. Thus NO2 (and ONOO-) may function in a tissue hormonelike regulatory role in inflammatory processes in which large amounts of these species are produced.
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PMID:Nitrogen dioxide causes pulmonary arterial relaxation via thiol nitrosation and NO formation. 878 Feb 1

The present study was designed to test the hypothesis that para-aminophenol (PAP) nephrotoxicity is due to autooxidation. We compared renal functional responses following PAP administration to female Sprague-Dawley rats and following incubation of renal proximal tubules with PAP. The concentrations of PAP selected for in vitro incubations produced cytotoxicity (for example, a decrease in oxygen consumption or adenine nucleotide concentration) in rat renal epithelial cells or rabbit proximal tubule suspensions. In rats, PAP (300 mg/kg i.p.) caused proximal tubular necrosis within 24 hr. Changes in renal function 24 hr following PAP administration included increased kidney weight and blood urea nitrogen concentration and decreased renal glutathione (GSH) content and adenine nucleotide concentrations. PAP did not cause hepatic damage. Within 2-4 hr following PAP administration, renal GSH content and adenine nucleotide concentrations were significantly decreased. In renal cortical slices prepared from PAP-treated rats, oxygen consumption and accumulation of organic ions (para-aminohippurate and tetraethylammonium) were significantly decreased compared with renal cortical slices prepared from control rats. In liver, GSH content was significantly decreased from 1 to 4 hr following PAP administration. In contrast to the effects of PAP in vivo, renal proximal tubules showed little evidence of injury when incubated with 0.1 or 0.5 mM PAP for up to 4 hr in the presence or absence of amino acids in the incubation medium. When tubules were incubated with 1 mM PAP for 4 hr in the presence of amino acids, GSH content, AMP concentration, and TEA uptake were significantly decreased. When amino acids were removed from the incubation medium, 1 mM PAP caused decreases in oxygen consumption and ATP concentration after 4 hr of incubation. Functional changes observed during incubation with PAP in vitro were not consistent with functional changes observed in vivo. The discrepancy between PAP toxicity in vivo and in vitro suggests that autooxidation is unlikely to be responsible for PAP nephrotoxicity and that nephrotoxicity in vivo is primarily mediated by extrarenal bioactivation. Further, depletion of hepatic GSH content prior to changes in renal function suggests that PAP or a PAP metabolite may conjugate with hepatic GSH. These observations suggest that PAP nephrotoxicity may be mediated by PAP-GSH conjugates rather than autooxidation of PAP in the kidney.
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PMID:Lack of correlation between para-aminophenol toxicity in vivo and in vitro in female Sprague-Dawley rats. 878 93

Acetaminophen (APAP) produces sex-dependent nephrotoxicity and hepatotoxicity in young adult Sprague-Dawley (SD) rats and age-dependent toxicity in male rats. There is no information regarding the susceptibility of aging female SD rats to APAP toxicity. Therefore, the present studies were designed to determine if sex-dependent differences in APAP toxicity persist in aging rats and to elucidate factors contributing to sex- and age-dependent APAP hepatotoxicity and nephrotoxicity. Young adult (3 months old) and aging (18 months old) male and female rats were killed from 2 through 24 hr after receiving APAP (0-1250 mg/kg, ip) containing [ring-14C]APAP. Trunk blood was collected for determination of blood urea nitrogen (BUN) concentration, serum alanine aminotransferase (ALT) activity, and plasma APAP concentration; urine was collected for determination of glucose and protein excretion; and liver and kidneys were removed for determination of tissue glutathione (GSH) concentration, APAP concentration, and covalent binding. APAP at 1250 mg/kg induced nephrotoxicity (as indicated by elevations in BUN concentration) in 3-month-old females but not males, whereas APAP induced hepatotoxicity (as indicated by elevations in serum ALT activity) in 3-month-old males but not females. Sex differences in APAP toxicity were no longer apparent in 18-month-old rats. APAP at 750 mg/kg ip produced liver and kidney damage in 18-month-old but not 3-month-old male and female rats. No consistent sex- or age-dependent differences in serum, hepatic, and renal APAP concentrations were observed that would account for differences in APAP toxicity. No sex- or age-dependent differences in tissue GSH depletion or covalent binding of radiolabel from APAP in livers or kidneys were observed following APAP administration. Utilizing an affinity-purified polyclonal antibody raised against APAP, arylated proteins with electrophoretic mobility similar to those observed in mice were prominent in rat livers following APAP administration to 3- and 18-month-old rats of both sexes. In contrast, no arylated proteins were detected in any rat kidneys following APAP administration. Absence of immunochemically detectable proteins in rat kidney following APAP administration is in direct contrast to observations in mice and supports the hypothesis that mechanisms of APAP hepatotoxicity and nephrotoxicity in rats and mice are distinctly different. In conclusion, sex differences in APAP toxicity are observed only in young adult (3-month-old) rats and sex differences are organ-specific with males more susceptible to hepatotoxicity and females more susceptible to nephrotoxicity. Aging rats are more susceptible to APAP-induced damage to both the liver and the kidney than are 3-month-old rats but sex differences are no longer apparent in 18-month-old rats. The mechanisms contributing to sex- and age-dependent differences in APAP toxicity cannot be attributed to differences in tissue APAP concentrations, GSH depletion, or covalent binding.
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PMID:Sex- and age-dependent acetaminophen hepato- and nephrotoxicity in Sprague-Dawley rats: role of tissue accumulation, nonprotein sulfhydryl depletion, and covalent binding. 881 6

The aim of the present study is to investigate the influence of the environmental factors, smoking and alcohol, on the biotransformation of cyclophosphamide (CP) in the rat in vivo and in vitro with S9 liver fractions. The biotransformation of CP was studied by the determination of the CP metabolites, nor-nitrogen mustard (NNM), 4-ketocyclophosphamide (KCP), and carboxyphosphamide (CAR). The effect of the environmental factors, smoking and alcohol consumption, on the biotransformation enzymes was mimicked by pretreatment of rats with beta-naphthoflavone and ethanol, respectively. Rats treated with olive oil and water served as controls and rats pretreated with Aroclor 1254 and phenobarbital were used as positive controls. The influence of sex and supplementation with NAD and GSH, mimicking a biological variation in NAD and GSH levels in rat and human liver, was also studied. Pretreatment of rats with Aroclor 1254 decreased the excretion of unmetabolized CP in urine, most likely due to an enhanced biotransformation. The in vitro hepatic biotransformation of CP in rats was strongly influenced by sex, by supplementation with NAD and GSH, and by pretreatment with the enzyme-inducers, phenobarbital and Aroclor 1254. No influence of pretreatment with the enzyme-inducers, beta-naphthoflavone and ethanol, was found. The results suggest that the influence of the environmental factors, alcohol consumption and smoking, on the biotransformation of CP in man will be negligible.
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PMID:Influence of Aroclor 1254, phenobarbital, beta-naphthoflavone, and ethanol pretreatment on the biotransformation of cyclophosphamide in male and female rats. 881 43


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