UMLS:C1260386 - FACTA Search

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Query: UMLS:C1260386 (GSH)
38,102 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A centrifugal analyzer and a spectrophotometer were compared for routine analysis of xenobiotic metabolizing enzymes glutathione (GSH) peroxidase, GSH-S transferase, and GSH reductase. Lung, liver, and kidney from 60-day-old male rats were used as the source of enzymes. Linear regression analysis was used to assess the accuracy and precision of the centrifugal analyzer method in measuring enzyme activities. Biologically and statistically, the centrifugal analyzer proved to be acceptable for routine measurement of these GSH-dependent enzymes.
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PMID:An automated analysis of glutathione peroxidase, S-transferase, and reductase activity in animal tissue. 685 9

Nitrofurantoin (NF) is a urinary antimicrobial drug which causes pulmonary injury. We measured levels of total lung glutathione (TLG), a tripeptide central to cellular antioxidant defenses and xenobiotic detoxification, and enzyme activities related to maintenance and utilization of reduced glutathione (GSH) in isolated, New Zealand white rabbit lungs perfused with a Kreb's-Ringer's bicarbonate medium containing NF (420 microM). After 30 minutes there was no net difference in the level of TLG [GSH + GSSG(oxidized) + effluent GSH-GSSG] or total nonprotein sulfhydryls in NF-perfused or control lungs. However, there was a decrease in the GSH:GSSG redox ratio to 2% of control (P less than .0005) and an 87% increase in GSH-GSSG efflux (P less than .005). This increased oxidation of GSH indicates that toxicity of NF is likely oxidative in nature, possibly via redox cycling of NF in the presence of oxygen to generate activated oxygen species. Activities of glucose-6-phosphate and 6-phosphogluconate dehydrogenases, GSH reductase, and GSH S-transferase were not significantly different due to NF perfusion. GSH peroxidase activity decreased 34% (P less than .025) in NF-perfused lungs. Because all TLG, as well as total nonprotein thiol was accounted for in NF-perfused lungs, it would appear that no GSH-NF metabolite conjugation occurred. GSH metabolic conjugation in the perfused lung is easily detected when tissue-alkylating drugs or their metabolites are present.
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PMID:Effects of nitrofurantoin on the glutathione redox status and related enzymes in the isolated, perfused rabbit lung. 732 44

Glutathione (GSH) is known to play a role in cellular sensitivity to some chemotherapeutic agents and to radiation. Depletion of cellular GSH has been demonstrated to result in enhanced toxicity of these drugs, and this approach is being explored in the clinic as a form of biochemical modulation, using the drug buthionine sulfoximine (BSO). The fact that some drug-resistant cell lines have increased glutathione levels, and that enhancing GSH concentrations in animal tissues protects against a variety of xenobiotic agents, suggest a different potential approach to improving anti-cancer therapy. We have examined the efficacy of the cysteine "pro-drug" L-2-oxothiazolidine-4-carboxylate (OTZ) at enhancing normal tissue versus tumor GSH. Animals were treated with OTZ or BSO, and the concentrations of GSH in normal tissues and tumor were measured. We found that the presence of the tumor itself decreased bone marrow GSH, but that OTZ significantly increased it in this setting. Interestingly, OTZ administration significantly depleted tumor GSH levels to the same level as did BSO. OTZ could offer a selective biochemical modulation of GSH.
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PMID:In vivo selective modulation of tissue glutathione in a rat mammary carcinoma model. 750 2

Glutathione-dependent defense against xenobiotic toxicity is a multifaceted phenomenon that has been well characterized in mammals. This study undertakes a comparison of two benthic fish species, the channel catfish and brown bullhead, in terms of characteristics of the glutathione system. The channel catfish, a species that has seldom been observed to express pollutant-mediated neoplasia in field studies, was observed to have significantly higher constitutive levels of hepatic total glutathione and reduced glutatione (GSH). Brown bullhead, a species that is often observed to express neoplasia in contaminated systems, had significantly higher hepatic levels of glutathione disulfide. Furthermore, catfish expressed higher levels of activity of the enzymes gamma-glutamylcysteine synthetase (GCS), glutathione reductase (GR), and glutathione S-transferase, whereas bullhead expressed higher hepatic glutathione peroxidase (GPOX) activity. Both species responded to treatment with the redox active quinone, menadione, by expressing elevated hepatic content of total glutathione. However, the induction response was more rapid and more extensive in catfish compared to that in bullhead. This is attributable to the observed interspecific difference in GCS activity. Following treatment with the organic peroxide, tert-butyl hydroperoxide (t-BOOH), bullhead hepatic glutathione was depleted up to 4 hr post-treatment, whereas catfish demonstrated no significant depletion of glutathione in response to t-BOOH. The differing responses to t-BOOH are attributable to interspecific differences in hepatic GPOX and GR activity. Bullhead, therefore, appear to be more susceptible to the effects of GSH arylators and oxidants based upon constitutive levels of glutathione, related enzyme activities, and the response of this system to model xenobiotics.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Glutathione-dependent defense in channel catfish (Ictalurus punctatus) and brown bullhead (Ameriurus nebulosus). 752 70

We report the results of a further study to test our hypothesis that toxic metabolite stress is germane to heightened free radical activity and hence to the genesis of chronic pancreatitis. Consecutive black South African patients with clinically quiescent chronic pancreatitis were studied, provided that the diagnosis had been made within the previous 2 years and that they did not have overt liver disease. All of them had been advised to stop drinking alcohol. Analysis of an early morning sample of urine showed a lower ratio of inorganic to ester sulphate (P < 0.001) and a higher ratio of D-glucaric acid to creatinine (P < 0.02) in the group of 14 patients than in 15 local controls, while plasma analysis showed a lower concentration of glutathione (GSH) in the patients (P < 0.001). This evidence of increased utilisation of phase II conjugative pathways of xenobiotic disposal was in keeping with on-going toxic metabolite stress from heightened phase I oxidative metabolism in the group of patients. Parallel studies of theophylline pharmacokinetics showed heightened drug clearance compatible with induced cytochrome P-4501A2 in two patients, whereas increased activity of gamma-glutamyl transferase in serum suggested persisting induction of P-4502E1, as by ethanol, in several others. The contemporaneous increases in free radical activity and utilisation of xenobiotic disposal pathways in Sowetan Africans with chronic pancreatitis is in line with the toxic metabolite concept of disease pathogenesis.
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PMID:Evidence of toxic metabolite stress in black South Africans with chronic pancreatitis. 755 81

Prevailing controversies regarding the identity and nature of S-(2,4-dinitrophenyl) glutathione (Dnp-SG) and GSSG transport system(s) led us to examine xenobiotic-SG transport from human erythrocytes and into inside-out vesicles (IOV) using N-ethyl-maleimide-glutathione conjugate (NEM-SG) as substrate. Efflux of NEM-SG from intact erythrocytes was linear over a period of 4 h, occurred against a concentration gradient, and required energy. No transport of NEM-SG was observed when endogenous ATP was exhausted by preincubation of the erythrocytes for 8 h at 37 degrees C in the absence of glucose. When cellular GSH was partially conjugated with NEM to form 1.5 and 1.0 mM NEM-SG, and the remaining GSH was oxidized with t-butylhydroperoxide to generate 0.2 and 0.4 mM GSSG, respectively, the extrusion of NEM-SG from erythrocytes was not inhibited. The kinetics of NEM-SG transport in intact erythrocytes were monophasic; the Km NEM-SG was 0.62 mM +/- 0.24. However, in IOV two components of NEM-SG transport with respect to NEM-SG and ATP were discernible. The low Km for NEM-SG was 5.6 +/- 1.51 microns with a Vmax of 7.30 +/- 0.69 nmol/mg protein/h and the high Km for NEM-SG was 1.35 +/- 0.14 mM with a Vmax of 65.1 +/- 3.5 nmol/mg protein h. With respect to ATP, the NEM-SG transport had a low Km of 0.12 +/- 0.004 mM and a high Km of 0.52 +/- 0.052 mM. Both components of NEM-SG transport were inhibited by fluoride, o-vanadate, p-hydroxymercuribenzoate and 5,5'-dithiobis(2-nitrobenzoic acid). However, NEM (1 mM) inhibited only the high Km transport. GSH stimulated the low Km transport 1.7-fold. Both low and high Km components of NEM-SG transport significantly declined when ATP was substituted with CTP, UTP, or GTP. GSSG and Dnp-SG competitively inhibited the low Km NEM-SG transport (Ki = 18.5 +/- 2.9 and 1.32 +/- 0.16 microns, respectively) whereas the high Km transport was inhibited by Dnp-SG but not by GSSG. These findings suggest that glutathione S-conjugates may be transported out of erythrocytes by both the high and the low Km mechanisms, the latter being shared by GSSG.
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PMID:ATP-dependent transport of glutathione-N-ethylmaleimide conjugate across erythrocyte membrane. 771 Jul 66

The chloditan (o.p-DDD, mitotane), which causes the destruction of the human and dog adrenal cortex, on the most essential system of xenobiotic metabolism: glutathione-S-transferase--glutathione has been studied. The effect of o,p-DDD on GSH level and activity of glutathione-S-transferase and glutathione reductase which maintain the level of reduced glutathione was analyzed in the adrenal and liver tissue of rats. This species is resistant to adrenocorticolytic action of o,p-DDD. It was shown that feeding of rats weighting 200-240 g with oil solution of o,p-DDD (75 mg daily) for 3 days causes the decrease in activity of glutathione-S-transferase and content of oxidazed glutathione in the adrenals with simultaneous increase of the content of reduced glutathione. The glutathione-S-transferase and glutathione reductase activity in the liver rises under the effect of o,p-DDD, the decrease of the GSH level being observed. The revealed changes may explain the species sensitivity of animals to o,p-DDD.
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PMID:[Effect of chloditan on the changes of activity of glutathione transferase, glutathione reductase and glutathione content in the adrenal glands and liver in rats]. 771 31

Isoenzymes 3-3 and 4-4 of the mu class glutathione S-transferases share 77% sequence identity but have distinctly different catalytic properties. Analysis of the crystal structure of isoenzyme 3-3 in complex with the diastereomeric products of the addition of GSH to phenanthrene 9,10-oxide (Ji, X., Johnson, W. W., Sesay, M. A., Dickert, L., Prasad, S. M., Ammon, H. L., Armstrong, R. N., and Gilliland, G. L. (1994) Biochemistry 33, 1043-1052) reveals that 3 residues that are in van der Waals contact with the xenobiotic portion of the product are different in the type 4 subunit. The three mutations, V9I, I111A, and S209A, have been introduced into isoenzyme 3-3 individually and in combination in an attempt to minimally reconstruct the active site of the enzyme to mimic the type 4 subunit in structure and function. The results suggest that the V9I mutation is an important determinant in the stereoselectivity of the enzyme toward enones and epoxides. The I111A mutation increases the catalytic efficiency of the enzyme toward para-substituted 4-phenyl-3-buten-2-ones (XPBO) as measured by kcat/KmXPBO but does not affect kcat. The S209A mutation has no effect on catalysis. The double and triple mutants V9I/I111A and V9I/I111A/S209A exhibit both a high stereoselectivity and high kcat/KmXPBO comparable to that of isoenzyme 4-4. Analysis of substituent effects on the kinetics and stereoselectivity of the enzyme toward the enone substrates suggests that the mechanistic bases for the catalytic behavior of the isoenzyme 4-4 and the reconstructed mutants are not identical. The results provide functional evidence for the catalytic importance of specific residues previously identified by x-ray crystallography.
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PMID:Rational reconstruction of the active site of a class mu glutathione S-transferase. 779 37

Oxidative desulfuration of diethyldithiocarbamate methyl ester (DDTC-Me), a thione xenobiotic and a metabolite of disulfiram, was studied. Using a rat liver microsomal incubation system, DDTC-Me was oxidized at the thionosulfur group, forming DDTC-Me sulfine. Only minimal desulfuration of DDTC-Me to S-methyl-N,N-diethylthiolcarbamate (DETC-Me) occurred. Desulfuration of DDTC-Me increased 4-fold when the microsomal incubation was supplemented with reduced glutathione (GSH) and increased 8-fold when both GSH and glutathione-S-transferase (EC 2.5.1.18) were added. Similar results were obtained using a simplified system containing DDTC-Me sulfine, GSH, and glutathione-S-transferase. This suggested that DDTC-Me sulfine is a stable intermediate formed before DDTC-Me is desulfurated to DETC-Me. This unprecedented desulfuration process can be explained as follows. GSH attacks the oxithiirane isomer of DDTC-Me sulfine, resulting in ring opening followed by loss of glutathione hydrodisulfide, which is reduced by GSH to oxidized glutathione and H2S. GSH can also reduce DDTC-Me sulfine to DDTC-Me. This mechanism is supported by in vitro studies. An approximately 1:1 stoichiometry was observed for the formation of H2S and DETC-Me. A 1:1 stoichiometry was also observed for the consumption of DDTC-Me sulfine, formation of DETC-Me plus DDTC-Me, and formation of oxidized glutathione. Glutathione hydrodisulfide was trapped by derivatization in situ using 4-vinylpyridine. Oxidative desulfuration of a series of dithiocarbamate esters also followed a similar mechanism.
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PMID:Glutathione- and glutathione-S-transferase-dependent oxidative desulfuration of the thione xenobiotic diethyldithiocarbamate methyl ester. 780 45

The three-dimensional structures of isoenzyme 3-3 of glutathione (GSH) transferase complexed with (9R,10R)- and (9S,10S)-9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene [(9R,10R)-2 and (9S,10S)-2], which are the products of the addition of GSH to phenanthrene 9,10-oxide, have been determined at resolutions of 1.9 and 1.8 A, respectively. The structures indicate that the xenobiotic substrate binding site is a hydrophobic cavity defined by the side chains of Y6, W7, V9, and L12 from domain I (the GSH binding domain) and I111, Y115, F208, and S209 in domain II of the protein. All of these residues are located in variable-sequence regions of the primary structure of class mu isoenzymes. Three of the eight residues (V9, I111, and S209) of isoenzyme 3-3 that are in direct van der Waals contact with the dihydrophenanthrenyl portion of the products are mutated (V9I, I111A, and S209A) in the related isoenzyme 4-4. These three residues are implicated in control of the stereoselectivity of the class mu isoenzymes. The hydroxyl group of Y115 is found to be hydrogen-bonded to the 10-hydroxyl group of (9S,10S)-2, a fact suggesting that this residue could act as an electrophile to stabilize the transition state for the addition of GSH to epoxides. The Y115F mutant isoenzyme 3-3 is about 100-fold less efficient than the native enzyme in catalyzing the addition of GSH to phenanthrene 9,10-oxide and about 50-fold less efficient in the Michael addition of GSH to 4-phenyl-3-buten-2-one. The side chain of Y115 is positioned so as to act as a general-acid catalytic group for two types of reactions that would benefit from electrophilic assistance. The results are consistent with the notion that domain II, which harbors most of the variability in primary structure, plays a crucial role in defining the substrate specificity of class mu isoenzymes.
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PMID:Structure and function of the xenobiotic substrate binding site of a glutathione S-transferase as revealed by X-ray crystallographic analysis of product complexes with the diastereomers of 9-(S-glutathionyl)-10-hydroxy-9,10-dihydrophenanthrene. 811 Jul 35

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