Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thie biological effect of low dose radiation is little known. In the current study male Wistar rats were exposed monthly to a 60Co-source low dose whole body irradiation (0.25 Gy, per 18 months; total dose: 4.5 Gy). The glutathione disulphide (GSSH): total glutathione (GSH) ratio, the concentration of thiobarbituric acid-reactive substances and the activities of glutathione peroxidase and glutathione transferase in: small intestine, spleen, kidney, soleus muscle, and liver were analysed. Low dose irradiation is accompanied by distinct peroxidative changes in organs, observed in the small intestine, the spleen and in the kidneys. The current study suggests that the measurement of glutathione status and thiobarbituric acid-reactive substances can be proposed as sensitive parameters for low dose radiation induced changes.
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PMID:Effect of low dose ionizing irradiation on rat metabolism. 975 55

The metabolism of 1,2-dihaloethanes (DHEs) to glutathione-containing metabolites by freshly isolated rat hepatocytes was investigated. 1,2-Dichloroethane (DCE), 1,2-dibromoethane (DBE), and 1-bromo-2-chloroethane (BCE) were metabolized to S-(2-hydroxyethyl)glutathione (HEG), S-(carboxymethyl)glutathione (CMG), and S,S'-(1,2-ethanediyl)bis(glutathione) (GEG). The formation of these glutathione-containing metabolites was concomitant with the depletion of intracellular glutathione (GSH) and accounted for 58%, 84%, and 71% of the DCE-, BCE-, and DBE-induced loss of intracellular GSH, respectively. The covalent binding of [14C]DBE to hepatocyte protein reached 18.7 nmol/mL of cell suspension (7.8 nmol/mg of protein) within 2.0 h of incubation. Half of this covalent binding occurred within 0.5 h of incubation (4.0 nmol/mg of protein) in the presence of high levels of intracellular GSH (30% of initial GSH level at 0.5 h). Hepatocyte metabolism of 2-chloroacetic acid produced only CMG. 2-Chloroethanol metabolism gave rise to CMG and HEG in a 11.5:1.0 ratio; 2-chloroacetaldehyde produced almost equal amounts of CMG and HEG. GEG formation was increased significantly for DBE and BCE when GSH was added to the medium during treatment, suggesting that the GSH conjugates S-(2-haloethyl)glutathione are exported from the hepatocytes. These results indicate that the glutathione S-transferase-catalyzed conjugation of GSH with the DHEs is responsible for the majority of the DHE-induced GSH depletion. The S-(2-haloethyl)glutathione conjugates appear responsible for the extensive covalent binding to protein observed during [14C]DBE metabolism.
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PMID:Utilization of glutathione during 1,2-dihaloethane metabolism in rat hepatocytes. 150 62

Lead acetate (100 mg/kg) administered i.p. to male mice decreased hepatic glutathione (GSH) content and also glutathione S-transferase (GST) activity. However, the liver GSH content of mice treated with both lead and phenobarbital (80 mg/kg, i.p.) remained unchanged, whereas their GST activities were higher than the controls. Phenobarbital antagonized the Pb-induced decrease in liver adenosine triphosphate content. Additionally, phenobarbital shortened the half-life of hepatic GSH determined using buthionine sulfoximine, an inhibitor of GSH synthesis. Acceleration of hepatic GSH turnover by phenobarbital possibly diminishes the Pb-induced impairment of GSH-conjugation of xenobiotics.
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PMID:Modification by phenobarbital of decreased glutathione content and glutathione S-transferase activity in livers of lead-treated mice. 150 8

We have previously demonstrated that geniposide (GP) inhibits the aflatoxin B1 (AFB1) induced-hepatotoxicity and hepatic DNA binding in rats. To address the mechanism of action, the effects of GP on AFB1-induced DNA repair synthesis and AFB1 biotransformation in cultured rat hepatocytes were investigated. By evaluation of unscheduled DNA synthesis (UDS), GP reduced AFB1-induced DNA repair synthesis in a dose-dependent manner in hepatocyte cultures. GP elevates the metabolism of AFB1 and decreases the formation of AFM1. The enzyme activities of glutathione S-transferase (GST) and GSH-peroxidase (GSH-Px) in AFB1-treated hepatocyte cultures are enhanced in the presence of GP. GP reduces AFB1-induced DNA repair synthesis through an increased AFB1 detoxication metabolism. It provides one possible mechanism for the chemopreventive activity of GP.
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PMID:Inhibitory effect of geniposide on aflatoxin B1-induced DNA repair synthesis in primary cultured rat hepatocytes. 151 17

Glutathione metabolism was studied in cancer cells during the growth of an Ehrlich ascites tumour. GSH, but not GSSG, content decreases when cell proliferation and the rate of protein synthesis in the tumour decrease. This change correlates with a decrease in the rate of GSH synthesis and an increase in glutathione peroxidase and glutathione S-transferase activities. Glutathione efflux from tumour cells seems to co-ordinate with the rate of GSH synthesis. Cysteine, and not methionine, promotes GSH synthesis in tumour cells. However, changes in the rate of GSH synthesis are not due to limitations in the supply of blood cysteine or to changes in the intracellular amino acid pool of the cancer cells. Our data suggest that changes in protein metabolism accompanying tumour growth in vivo can modulate glutathione content in cancer cells.
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PMID:Regulation of glutathione metabolism in Ehrlich ascites tumour cells. 152 Feb 78

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

The role of the hydroxyl group of tyrosine 6 in the catalytic mechanism of isoenzyme 3-3 of rat glutathione S-transferase has been examined by x-ray crystallography and site-specific replacement of the residue with phenylalanine and evaluation of the catalytic properties of the mutant enzyme. This particuar tyrosine residue is conserved in the sequences of all of the cytosolic enzymes and is found, in crystal structures of both isoenzyme 3-3 from the mu-gene class and an isoenzyme from the pi-gene class, to be proximal to the sulfur of glutathione (GSH) or glutathione sulfonate bound at the active site. The 2.2-A structure of the binary complex of isoenzyme 3-3 and GSH indicates that the hydroxyl group of Tyr6 is located 3.2-3.5 A from the sulfur of GSH, well within hydrogen bonding distance. Removal of the hydroxyl group of Tyr6 has essentially no effect on the dissociation constant (22 +/- 3 microM) for GSH. Nevertheless the Y6F mutant exhibits a turnover number which is only about 1% that of the native enzyme when assayed at pH 6.5 with either 1-chloro-2,4-dinitrobenzene (CDNB) or 4-phenyl-3-buten-2-one. UV difference spectra of the binary enzyme-GSH complexes suggest that the predominant ionization state of GSH in the active site of the Y6F mutant is the neutral thiol (e.g. EY6F.GSH) which is in contrast to the native enzyme in which the thiol is substantially deprotonated (e.g. E.GS-). Spectrophotometric titration suggests that the pKa of the thiol is 6.9 +/- 0.3 in the E.GSH complex and greater than or equal to 8 in the EY6F.GSH binary complex. In addition, the pH dependence of kcat/KmCDNB reveals that the reactions catalyzed by the native enzyme and the Y6F mutant are dependent on a single ionization in the E.GSH and EY6F.GSH complexes with pKa = 6.2 +/- 0.1 and 7.8 +/- 0.3, respectively. The results suggest that the hydrogen bond between Tyr6 and the enzyme-bound nucleophile helps to lower the pKa of GSH in the binary enzyme-substrate complex.
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PMID:Contribution of tyrosine 6 to the catalytic mechanism of isoenzyme 3-3 of glutathione S-transferase. 153 22

The glutathione (GSH)-conjugating activity of human class Pi glutathione S-transferase (GST pi) toward 1-chloro-2,4-dinitrobenzene (CDNB) was significantly lowered by reaction with N-acetylimidazole, an O-acetylating reagent for tyrosine residues. Further, the replacement of Tyr7 in GST pi, which is conserved in all cytosolic GSTs, with phenylalanine by site-directed mutagenesis also lowered the activities toward CDNB and ethacrynic acid. The Km values of the mutant for both GSH and CDNB were almost equivalent to those of the wild type, while the Vmax of the former was about 55-fold smaller than that of the latter. Therefore, Tyr7 is considered to be an essential residue for the catalytic activity of GST pi.
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PMID:Tyrosine-7 is an essential residue for the catalytic activity of human class PI glutathione S-transferase: chemical modification and site-directed mutagenesis studies. 154 Jan 59

Hepsulfam (NSC 329680, 1,7-heptanediol disulfamate) is an alkylating agent that showed excellent activity against mouse and human mammary carcinoma in preclinical studies. We therefore studied the cytotoxicity of this drug in six human breast cancer cell lines (AdrRMCF7, WTMCF7, Hs578T, MDA-MB-231, T47D, and MDA-MB-468). Clonogenic assays of these cell lines showed a range of sensitivity with the 90% inhibitory concentration ranging from 3.1 microM hepsulfam (MDA-MB-468) to 32.3 microM hepsulfam (AdrRMCF7) after 24-h exposure to the drug. To evaluate possible mechanisms responsible for this observed variation in sensitivity to hepsulfam, we have studied glutathione S-transferase (GST) activity and glutathione (GSH) in these cell lines. Total cytoplasmic GST activity correlated with sensitivity; the most sensitive cell lines had the lowest GST activity, while the two most resistant cell lines, AdrRMCF7 and Hs578T, had the highest GST levels of the six cell lines. Western blot analysis showed that the only detectable isoenzyme was GST-pi. The amount of GST-pi isoform correlated with hepsulfam sensitivity in the three most resistant cell lines and was undetectable in the three most sensitive cell lines. Cellular concentrations of GSH did not correlate with hepsulfam sensitivity. However, GSH depletion with buthionine sulfoximine increased sensitivity to hepsulfam in a dose-dependent fashion in all six cell lines. Evaluation by mass spectrometry revealed that glutathione can form conjugates with hepsulfam. We conclude that the GST/GSH detoxication system plays a role in the sensitivity of these breast cancer cell lines to hepsulfam.
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PMID:Hepsulfam sensitivity in human breast cancer cell lines: the role of glutathione and glutathione S-transferase in resistance. 154 Sep 50

Studies were undertaken to investigate the effect of t-butylated hydroxytoluene (BHT) on reduced glutathione (GSH) levels and related enzymes in rat ocular tissues. GSH levels were significantly enhanced when 1 microM BHT was included in the medium of rat lens cultures. BHT had a dose-dependent effect on GSH levels of lenses in cultures. Inclusion of 10 microM BHT in the culture medium resulted in a twofold increase in GSH levels of the lens within 24 hr. Increased gamma-glutamylcysteine synthetase activity concomitant with the increased amount of [35S]methionine incorporation in GSH strongly suggested that BHT caused enhanced levels of GSH in lenses by increasing de novo biosynthesis. A significant increase was also observed in glutathione S-transferase (GST) levels of lenses in culture containing BHT in the medium. Present studies also demonstrated that rat lens expresses only the mu and pi class GST isoenzymes and both these classes of isoenzymes were elevated by BHT. Oral administration of BHT to rats also resulted in enhanced in vivo levels of GSH in lens, retina and cornea. In addition, a significant in vivo increase in the levels of GST, GSH-peroxidase, GSH-reductase, gamma-glutamylcysteine synthetase, and glucose 6-phosphate dehydrogenase was observed in the lens, retina, and cornea of BHT-fed rats.
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PMID:t-butylated hydroxytoluene enhances intracellular levels of glutathione and related enzymes of rat lens in vitro organ culture. 154 39


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