Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Glutathione transferase (GST) activity and GST isoenzyme composition have been determined for 24 human neoplasms and 6 human tumor cell lines. Substantial activity (40-1010 milliunits/mg protein) was identified in all tumor specimens examined and three of the tumor cell lines. Three tumor cell lines, the human small cell carcinoma line SW2-10S, the Burkitt's lymphoma derived cell line Raji, and the human breast carcinoma cell line MCF-7, contained minimal GST activity. Although the small size of the tumor samples precluded isoenzyme analysis by substrate specificities, analysis of GST activity following sample separation by isoelectric focusing indicated that the predominant (comprising at least 70% of the 1-chloro-2,4-dinitrobenzene-conjugating activity) GST isoenzyme in each of these primary tumor (17 of 17) and tumor cell line (3 of 3) extracts was anionic (isoelectric point, 4.5-4.8). In three tumor samples, adenocarcinomas of the lung, colon, and stomach, analysis by isoelectric focusing identified minor but detectable (10-20% of total) cationic GST. The anionic form of GST has been purified to homogeneity from three primary human tumors: a malignant melanoma; a mesothelioma; and a breast carcinoma. GST from these tumors consists of two subunits each of Mr 25,200. On Western blot analysis, antibodies raised against the anionic GST purified from mesothelioma detect protein of Mr approximately 25,000 in extracts of both normal kidney and tumors containing anionic GST activity but not in extracts of human liver that did not contain detectable anionic activity. The amino acid compositions of these proteins were quite similar to that previously described for GST-pi and the amino-terminal amino acid sequences for these tumor-derived isoenzymes are identical to one another and to that previously described for GST-pi from human placenta. GST is a major enzymatic activity in many human malignancies, comprising as much as 3% of the cytosolic protein of some tumors. Anionic GST is the predominant form of glutathione transferase activity in many human tumors and human tumor cell lines. In selected tumor samples the predominant anionic GST isoenzyme has been identified as a member of the pi class of this enzyme family. In addition, at least 3 of 17 tumor samples contained lesser but detectable amounts of cationic GST, probably of the alpha class. By conjugating glutathione with electrophilic anticancer drugs, the substantial levels of GST in human tumors may have a role in the innate or acquired resistance of these neoplasms to anticancer therapy.
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PMID:Identification of an anionic form of glutathione transferase present in many human tumors and human tumor cell lines. 327 99

We have developed a human head and neck squamous cell carcinoma cell line (SCC-25/CP) which is relatively stably resistant to cis-diamminedichloroplatinum(II) (CDDP) after repeated exposure to escalating doses of the drug. The studies reported elucidate the mechanism(s) by which the SCC-25/CP cell line is resistant to CDDP. The SCC-25/CP cell line is approximately 30-fold resistant to CDDP, approximately 10-fold resistant to carboplatin, and about 9-fold resistant to iproplatin. Using [195mPt]CDDP, we examined the levels of platinum in whole cells and cellular fractions of both the SCC-25 and SCC-25/CP cells after 1 h exposure to 100 microM drug. The SCC-25 cells took up 30 pmol of platinum/10(6) cells in 1 h; 64% of the drug was in the nucleus and 21% in the cytosol. The SCC-25/CP cells took up 7 pmol of platinum/10(6) cells; of this, 41% was in the nucleus and 33% in the cytosol. The SCC-25 cell nuclei contained 331 pmol of platinum/mg protein and the cytosol 21 pmol of platinum/mg protein, whereas the SCC-25/CP cell nuclei contained 47 pmol of platinum/mg protein and the cytosol 8.1 pmol/mg protein. The release of drug from both cell lines followed a very similar course and was most rapid over the first 6 h. There was no difference in the non-protein sulfhydryl content of the cell lines. The protein sulfhydryl content, as measured by Ellman's procedure, indicated that the SCC-25/CP cell line has approximately a 2-fold increase in protein sulfhydryl content compared to the SCC-25 cell line. The SCC-25/CP cell line is about 2-fold resistant to cadmium chloride at 50% cell kill and about 2.5-fold resistant at 1 log kill compared to the SCC-25 cell line. Glutathione transferase activity in crude cytoplasmic extracts was measured and found to be approximately 2- to 3-fold higher in the CDDP resistant cells. The isoelectric point of the glutathione transferase isozyme was 4.8 in both the sensitive and resistant cell lines, suggesting induction of the predominant isozyme present in the parent cell line. By alkaline elution there was greater cross-link formation by CDDP in the SCC-25 cell line than in the SCC-25/CP cell line at the same drug concentrations. In conclusion, the mechanism of resistance of the SCC-25/CP cell line to CDDP is multifactorial, involving plasma membrane changes, increased cytosolic binding, and decreased DNA cross-linking.
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PMID:Characterization of a human squamous carcinoma cell line resistant to cis-diamminedichloroplatinum(II). 353 21

Glutathione transferase (GST) activity in the cytosolic fractions of four renal cortex tumors was found to be lower (1.85-3.4 times) than that present in the corresponding non-tumor cytosolic fractions. Glutathione transferase of both tumor and non-tumor kidney was purified by affinity chromatography and separated into five peaks at pH 4.7, 8.0, 8.4, 8.7 and 9.0 by isoelectric focusing. In the chromatogram of tumor tissues, the activity associated with the 'acidic' peak increased significantly, whereas the activities associated with 'basic' peaks all decreased in comparison with the corresponding peaks of non-tumor tissues. The acidic GST of human kidney is immunologically identical to GST pi, confirming that it is a good marker for human tumors.
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PMID:Alteration of glutathione transferase isoenzyme concentrations in human renal carcinoma. 360 86

1. Two duplicate groups of rainbow trout (Salmo gairdneri; mean weight 27 g) were given diets of differing selenium content (deficient 0.025 mg Se/kg; supplemented 1.022 mg Se/kg) for 30 weeks. 2. There were no significant differences between treatments in weight gain but packed cell volume, liver vitamin E and liver and plasma Se concentrations were all significantly lower in the Se-deficient trout. 3. Ataxia occurred in about 10% of the Se-deficient trout and histopathologies were evident in nerve cord (damage to axon sheath) and liver (loss of integrity in endoplasmic reticulum and mitochondria with appearance of increased vesiculation). 4. Glutathione peroxidase (EC 1.11.1.9) activity was significantly reduced in liver and plasma of Se-deficient fish but there was no indication, from differential assay, of any non-Se-dependent glutathione peroxidase activity. Glutathione transferase (EC 2.5.1.18) activity was significantly increased in Se-deficient trout.
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PMID:Some effects of selenium deficiency on glutathione peroxidase (EC 1.11.1.9) activity and tissue pathology in rainbow trout (Salmo gairdneri). 367 60

Glutathione peroxidase activity with both hydrogen peroxide and cumene hydroperoxide was measured in the cytosolic fractions prepared from five human hearts obtained from post-mortem victims. In all the samples the activity with cumene hydroperoxide was higher than that obtained with hydrogen peroxide, suggesting that the selenium-independent glutathione peroxidase could also be present in this tissue. To determine its presence in heart tissue we fractionated the cardiac cytosol fraction on a column of Sephadex G-100 and measured glutathione peroxidase activity with both the substrates. Glutathione transferase activity was measured with 1-chloro-2,4-dinitrobenzene in the fractionated cytosol. The results indicated that a selenium-independent glutathione peroxidase activity was present (about 30% of total activity). Fractionation of the cytosol by gel filtration showed that peroxidase activity co-eluted with glutathione transferase activity. Subsequently the fractions containing glutathione transferase and selenium-independent glutathione peroxidase activity obtained from gel filtration experiments were passed through an affinity column and analyzed by isoelectric focusing. It was found that the selenium-independent glutathione peroxidase copurified with three isoenzymes of glutathione transferase which had a pI of 9.2, 8.9 and 8.6 respectively. In contrast the acidic isoenzymes of glutathione transferase lacked peroxidase activity. It is suggested that the selenium-independent glutathione peroxidase may play an important role in neutralizing oxygen toxicity in heart when the selenium-dependent glutathione peroxidase activity is impaired.
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PMID:Selenium independent glutathione peroxidase activity associated with cationic forms of glutathione transferase in human heart. 378 32

Glutathione transferase (GST) from human placenta was purified by affinity chromatography and anion-exchange h.p.l.c. The enzyme exhibited different chromatographic and electrophoretic behaviours according to the concentration of GSH, suggesting a possible change in the net charge of the molecule and a concomitant conformational change due to ligand binding. Two interconvertible forms were quantitatively separated into distinct catalytically active states by h.p.l.c. Depending upon the GSH concentration, polyacrylamide-gel electrophoresis revealed the presence of one or two bands. A Kd of 0.42 mM for GSH was determined fluorimetrically. The loss in intrinsic fluorescence also suggested a conformational change in the enzyme. Kinetic studies using ethacrynic acid were conducted to determine whether the presumed conformational change could effect the catalytic capability of placental GST. A biphasic response in initial velocities was observed with increasing concentrations of GSH. Two apparent Km values of 0.38 and 50.27 mM were obtained for GSH, whereas Vmax. values showed a 46-fold difference. It was concluded that the enzyme assumes a highly anionic form in the presence of a low GSH concentration, whereas it is converted into relatively weaker anionic form when its immediate environment contains a high GSH concentration. Since the average tissue concentration of total GSH was estimated at 0.11 mM for term placenta, the results suggest that the high-affinity-low-activity conformer would predominate in vivo.
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PMID:H.p.l.c. separation and study of the charge isomers of human placental glutathione transferase. 380 Sep 86

After administration of beta-naphthoflavone and Clophen A50 to juvenile rainbow trout, activities of hepatic cytochrome P-450-dependent deethylation of 7-ethoxyresorufin was increased 172- and 49-fold, respectively. Glutathione transferase activity towards 1-chloro 2,4 dinitrobenzene and UDP glucuronosyltransferase activities towards p-nitrophenol, 1-naphthol and testosterone were increased 1.4 to 3.0-fold by beta-naphthoflavone or Clophen A50. However, significant increases of the rate of glucuronidation of 1-naphthol by Clophen A50 and of testosterone by both Clophen A50 and beta-naphthoflavone were only determined when the activities were measured in digitonin activated microsomes. Epoxide hydrolase activity was not affected by beta-naphthoflavone or Clophen A50. The time course of induction of the various xenobiotic metabolizing enzymes exhibited different patterns. 7-Ethoxyresorufin-O-deethylase activity reached peak values 3 and 7 days after the administration of beta-naphthoflavone and Clophen A50, respectively. The rate of induction of glutathione transferase activity and UDP glucuronosyltransferase activities towards p-nitrophenol and 1-naphthol were relatively slow and did not reach distinct peak levels. These activities were still on maximum levels 4-6 weeks after the treatment. Glucuronidation of testosterone reached peak values 1 week after treatment with both beta-naphthoflavone and Clophen A50. The dissimilar patterns of induction of the cytochrome P-450-dependent activities and the various conjugation activities may indicate that these xenobiotic metabolizing enzymes are differently regulated in the rainbow trout liver.
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PMID:Differential induction of cytochrome P-450-dependent monooxygenase, epoxide hydrolase, glutathione transferase and UDP glucuronosyl transferase activities in the liver of the rainbow trout by beta-naphthoflavone or Clophen A50. 392 91

The mouse bone marrow has been used as a model for the investigation of the response of cells to cytotoxins and carcinogens. The effects of cyclophosphamide, 1-beta-D-arabinofuranosylcytosine, and X-irradiation on the levels of glutathione and glutathione transferases have been studied. A high dose of cyclophosphamide (500 mg/kg) caused a significant depletion of glutathione levels in marrow, liver, and blood. A lower dose, 75 mg/kg, caused a similar depletion but only in marrow and liver. In this case, 5 to 7 days following treatment, the glutathione content of surviving cells was 1.8- to 3-fold higher than in controls. Glutathione transferase activity was also increased at this time (2- to 3-fold). 1-beta-D-Arabinofuranosylcytosine and X-irradiation also caused a depletion of marrow glutathione and glutathione transferase levels followed increased cellular levels (approximately 2-fold) 3 to 4 days later. Animals given cyclophosphamide (75 mg/kg) survived an otherwise lethal dose of this compound administered 5 to 7 days later. The time course of this effect closely paralleled the higher glutathione and glutathione transferase levels, suggesting a correlation between these effects.
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PMID:Altered mouse bone marrow glutathione and glutathione transferase levels in response to cytotoxins. 397 35

The effects of reduced glutathione on the development of choleragenic diarrhea and the activity of glutathione transferase (GT), glutathione peroxidase (GP-GTB and GP-H2O2), superoxide dismutase (SOD), glutathione reductase (GR) in the small intestine and liver of rats with experimentally ligated jejunal loop have been studied. Diarrhea syndrome was found to decrease markedly after glutathione administration in a dose of 1 g/kg bw. GR activity in the jejunum and liver of rats treated with toxin and the following glutathione administration rose by 210 and 186%, respectively, and then reached the control level. Glutathione transferase activity in the jejunum increased by 150% (P less than 0.05), remaining, however, lower than the control values. The activity of other enzymes tested was unchanged. Polyfunctional cellular activity of glutathione suggests that antidiarrhea effect should be considered as an element of pathogenetic therapy.
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PMID:[Effect of glutathione on choleragenic diarrhea and disorders of the antioxidant system of rat intestinal and liver cells]. 405 13

Glutathione transferase activity in the soluble fraction of resting human mononuclear leukocytes was measured and characterized using [3H] trans-stilbene oxide as a substrate. Because of the low activity of this enzyme in these cells, a published assay procedure developed for rodent liver was slightly modified to improve its sensitivity: the substrate was highly radiolabeled (2 Ci/mmole) and carefully purified, and the incubation time was extended to 30-60 min. The activity measured was linear with cell density up to at least 6 million cells. Soluble glutathione transferase activity measured in this manner has a pH optimum around 7.4 and an optimal temperature of 40 degrees. This activity could be measured in lymphocytes, monocytes, granulocytes, erythrocytes and platelets, but not in plasma. From these measurements it could be calculated that lymphocytes account for somewhat more than half of the total activity in the mononuclear leukocyte fraction and that monocytes account for the rest. The intraindividual variation in soluble glutathione transferase activity towards trans-stilbene oxide in the mononuclear leukocyte fraction from different subjects was only about 10%, whereas the interindividual variation in this same activity was 15-fold. An explanation for this relatively large interindividual variation is now being sought.
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PMID:Characterization of soluble glutathione transferase activity in resting mononuclear leukocytes from human blood. 648 57


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