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 S-transferases are involved in the detoxification of carcinogens and xenobiotics and are potentially associated with the development of drug-resistance. Forty-six testicular germ cell tumors and 33 adjacent normal testicular tissue specimens were analyzed at the RNA level for the expression of glutathione S-transferase alpha and pi. Glutathione S-transferase alpha was expressed in 31 of the 33 normal testicular tissues (94%) but in only three of the 46 germ cell tumors (7%). Glutathione S-transferase pi mRNA was detected in all normal and malignant testicular tissue samples. Thirteen testicular germ cell tumors and eight normal testicular tissue samples were analyzed at the protein level. The mean specific activity of total cytosolic glutathione S-transferase in tumor tissue was decreased by about 80% as compared to normal testicular tissue. Protein analysis of the glutathione S-transferase subunits of normal testicular tissue demonstrated the presence of the glutathione S-transferase classes alpha, mu and pi, with a predominance of the mu class. In testicular germ cell tumors the glutathione S-transferase subunit pattern showed a predominance of glutathione S-transferase pi representing 88% +/- 3% of total glutathione S-transferase. Since all three glutathione S-transferase isoenzyme classes contribute to the resistance to antineoplastic drugs, the altered glutathione S-transferase isoenzyme pattern and the decrease of glutathione S-transferase activity may play a role in the high inherent drug sensitivity of human testicular germ cell tumors.
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PMID:Glutathione S-transferases in human testicular germ cell tumors: changes of expression and activity. 131 14

Four independent antibodies (6A, 5F, 2H and 2F) to Glutathione S-transferase pi (GST-pi) were selected to characterize their epitopes. Amino acid analysis of 5.6 K and 7.4 K tryptic peptides appeared to suggest that the epitope recognized by antibodies 2H and 2F is located in the N-terminal 44 peptides of GST-pi, and that of 6A and 5F is located in the C-terminal 69 peptides. Reactivities of antibodies 6A and 5F with two synthetic peptides indicated that 6A recognized an epitope in the C-terminal hydrophilic fragment 176Leu-209Gln, and could be distinguished from 5F which recognized an epitope in the 141Thr-176Leu hydrophobic fragment. The differential immuno-reactivity of antibodies 6A and 5F with GST-pi itself, was characterized by the particularly high reactivity of 6A and almost no reactivity of 5F with the natural conformation of GST-pi in solution. This may be explained by differences in the hydropathic natures of their epitopes. The 6A antibody was useful for immunodetection of GST-pi in circulation, while 5F was found to be most suitable for histochemical staining of tumor tissue.
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PMID:Determination of antigenic epitopes recognized by four monoclonal antibodies to glutathione S-transferase pi (GST-pi). 169 59

Glutathione S-transferases play a central role in drug detoxification and have been implicated in the sensitivity of tumour cells to anticancer drugs. In this study, glutathione S-transferase (GST) isozyme expression in normal and tumour tissue from human lung, colon, stomach, breast, kidney and liver tissue has been quantified using sensitive and subunit specific radioimmunoassays (RIA), together with Western blot analysis and measurement of substrate metabolism. Glutathione S-transferase pi was the predominant GST in the majority of the tumours examined. The concentration of this enzyme was increased significantly in tumour tissue relative to normal lung, colon, and stomach tissue. A strong correlation was observed (r = 0.77, P less than 0.01) between GST activity and GST pi levels in those tumour samples. The concentrations of the alpha class GST, the predominant isoenzymes in normal stomach, kidney and liver, decreased dramatically in tumour tissue from these organs. Western blot analysis revealed the presence of novel polypeptides that cross-reacted with antisera raised against alpha and mu class GST. Our data demonstrates that although GST pi is the predominant GST isoenzyme in many tumours, significant levels of the other GST subunits are also present and collectively can represent a significant proportion of the GST content. Therefore the properties of all the GST isoenzymes need consideration when assessing the role of these proteins in drug resistance. Selenium-dependent glutathione peroxidase, an enzyme activity also implicated in the mode of action of certain antitumour agents, was also studied and shown to be the predominant glutathione-dependent peroxidase in all tumours except the hepatoma.
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PMID:Glutathione S-transferase and glutathione peroxidase expression in normal and tumour human tissues. 231 Nov 89

Glutathione S-transferase sub-types alpha, mu and pi were assessed by immunocytochemistry in 109 biopsies of ovarian tissue, comprising malignant epithelial tissue in 86 cases and tissue of ovarian origin considered to be normal in 23. Glutathione S-transferase pi was the most prevalent, being present in all except one malignant epithelium studied and 83% of non-malignant tissue. There were no significant differences in the overall distribution of positive staining for alpha, mu and pi in the malignant and non-malignant biopsies, although the intensity of staining was greater in the malignant epithelium. Stromal staining was in general more pronounced in the malignant biopsies, and this was particularly prominent in the case of the alpha sub-type. Positive staining was seen more frequently in the less well-differentiated tumours, and a diffuse cytoplasmic pattern was the most common observation in tumours of moderate and poor differentiation. There was no significant association between survival and the presence or absence of sub-type staining of alpha and mu sub-type. For the sub-type pi, patient survival was found to correlate with the intensity of staining (on a 0-(+++) scale). Those patients showing resistance to cytotoxic chemotherapy were found to have a higher intensity of staining for GST pi than responding patients.
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PMID:Glutathione S-transferase expression in benign and malignant ovarian tumours. 834 77

Our laboratory has been involved in the study of Glutathione S-transferase pi (GST pi) for many years, both in terms of regulation of gene expression and in trying to understand the endogenous function(s) of this enzyme and also what role it may play in the carcinogenic process [1]. Over-expression of GST pi has been associated with carcinogenesis and the development of many different human tumours, for example testis [2], ovarian [3] and colorectal [4] and is often inversely correlated with prognosis or patient survival [5,6]. In addition, GST Pi has been implicated in the acquisition of antineoplastic drug resistance [7-9]. In order to study the transcriptional regulation of this gene, we have utilised a multi-drug resistant derivative (VCREMS) of the human mammary carcinoma cell line, MCF7, in which GST P1 mRNA and protein are significantly elevated in the absence of gene amplification [10-13]. Interestingly, we have recently reported the discovery of polymorphisms at the GSTP1 locus, resulting in two alleles GSTP1a and GSTP1b. In the study, the GSTP1b allele was found with increased frequency in bladder and testicular cancer, while the GSTP1a allele was significantly decreased in cases of prostate cancer [14]. In an attempt to elucidate the endogenous role(s) of GST pi, we have used homologous recombination in embryonic stem (ES) cells to inactivate both murine GST Pi genes and create a mouse strain completely deficient in the expression of this enzyme. This provides us with a unique animal model with which to study the effects of the absence of GST pi expression on the metabolism and pharmacokinetics of xenobiotics.
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PMID:Pi-class glutathione S-transferase: regulation and function. 967 44

Glutathione S-transferase pi (GST-pi) is a phase II detoxification enzyme whose expression is increased in estrogen receptor (ER)-poor breast cancers and in breast cancers resistant to certain chemotherapeutic agents. The aim of this study was to investigate the immunohistochemical expression of GST-pi in invasive breast carcinoma and to correlate the findings with those of nuclear morphometry. Formalin-fixed paraffin-embedded tissue specimens obtained from 21 invasive breast cancers and 16 adjacent (benign) tissues were immunohistochemically stained using polyclonal anti-human GST-pi antibody. There was positive (defined as >10% immunoreactive tumor cells) but variable expression of GST-pi in 10 (48%) cases. Nuclear morphometry in these 10 tumors revealed immunoreactive malignant cells to be larger (mean area 41.7+/-1.0 microm2) and more rounded in form when compared with non-staining cancer cells (mean area 28.7+/-0.7 microm2). It was also observed that GST-pi immunonegative tumor cells in GST-pi expressing tumors had different morphologies from malignant cells in the remaining 11 (52%) cancers that were regarded as GST-pi negative. Increased GST-pi expression determined by the percentage of positively staining tumor cells, was found to be significantly correlated with increased variability in nuclear area and perimeter (Spearman's rho=0.821, p=0.044 for both) in the subset of node-positive tumors. Our findings suggest that there exists two sub-populations of cancer cells with distinct nuclear morphologies in GST-pi positive tumors; factors other than GST-pi expression are likely to have a phenotypic effect on breast cancer cells; and there may be a special significance of this enzyme in axillary node-positive breast tumors.
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PMID:Nuclear morphometry and glutathione S-transferase pi expression in breast cancer. 1076 77

There is increasing evidence that oxidative stress plays a role in the pathogenesis of acute irritant contact dermatitis. As part of on-going studies into the effect of irritant chemicals on the anti-oxidant enzyme systems in the skin, we have examined the changing levels of two classes of glutathione S-transferase in patch test reactions to dithranol and sodium lauryl sulphate, using quantitative immunocytochemistry. Although no changes were evident after 6 hrs, significant reductions in the density of staining for glutathione S-transferase alpha were seen with both irritants after 48 hrs and 96 hrs. Glutathione S-transferase pi levels were reduced to a lesser degree, reaching significance for dithranol at the 96 hrs time point only, and for sodium lauryl sulphate at 48 hrs only. The results support the hypothesis that oxidative stress plays a role in chemically-induced inflammation, not only in the case of irritants such as dithranol which are known to directly generate reactive oxygen species, but also with chemicals not generally associated with free radical generation.
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PMID:Reduced levels of glutathione S-transferases in patch test reactions to dithranol and sodium lauryl sulphate as demonstrated by quantitative immunocytochemistry: evidence for oxidative stress in acute irritant contact dermatitis. 1127 2

Glutathione S-transferase pi (GSTP1) is involved in the metabolism of carcinogens. We assessed the association of GSTP1 genetic polymorphisms and the susceptibility to childhood acute lymphoblastic leukaemia (ALL) by conducting a case-control study on 278 ALL patients and 303 healthy controls, both of French-Canadian origin. The carriers of the GSTP1*B variant (only the Val105 substitution) were found to be associated with an increased risk of ALL [odds ratio (OR) = 1.5, 95% confidence interval (CI) 1.1-2.0], whereas the GSTP1*C variant (both Val105 and Val114) was underrepresented in cases. Thus, genetic variants of GSTP1 that are expressed at the protein level appear to contribute differently to the risk of ALL, probably because of distinct substrate specificities. When combined with other GST genotypes, we found that the combination of GSTP1*B and GSTM1 null genotypes further increased the risk of ALL (OR = 2.1; 95% CI-1.3-3.4). These findings suggest that GSTP1 variants (alone or combined with other GSTs) represent significant genetic determinants of childhood ALL.
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PMID:Glutathione S-transferase P1 genetic polymorphisms and susceptibility to childhood acute lymphoblastic leukaemia. 1243 26

Glutathione S-transferase pi (GSTpi; EC 2.5.1.18) has been shown recently to be a regulator of mitogen-activated protein kinases (MAPK). We have developed, by chronic exposure of HL60 cells to increasing concentrations of a peptidomimetic GSTpi inhibitor TLK199, a 10-fold resistant cell line (HL60/TLK199). Among the cellular adaptations observed in this cell line was an increase in extracellular signal-regulated kinase (ERK) activity without modification of basal expression levels. Phorbol 12-myristate 13-acetate (PMA) induced monocyte/macrophage cytodifferentiation in both HL60 wild-type (WT) and HL60/TLK199 cells. In contrast, PMA induced a pronounced cell growth inhibition and G(0)/G(1) cell cycle arrest in HL60 WT cells, while this differentiating agent had only a mild effect on cell growth without G(0)/G(1) cell cycle arrest in HL60/TLK199. This effect was associated with a rapid and sustained activation of ERK (up to 6hr) in HL60 WT cells but only a transient induction of these kinases (between 30 and 60min) in HL60/TLK199. Furthermore, treatment of both cell lines with PMA in combination with the protein tyrosine phosphatase inhibitors sodium orthovanadate (OV) or 3,4-dephostatin (DPN) circumvented the resistance to cell growth arrest and potentiated differentiation in HL60/TLK199 but had no effect on HL60 WT cells. The circumvention of the resistance to PMA was associated with a sustained activation of ERK. These data suggest that chronic exposure of HL60 cells to TLK199 alters cellular ERK activation by PMA, which may contribute to the differential response of the WT and resistant cells to PMA.
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PMID:Resistance to phorbol 12-myristate 13-acetate-induced cell growth arrest in an HL60 cell line chronically exposed to a glutathione S-transferase pi inhibitor. 1275 97

Glutathione S-transferase pi (GST-pi), a Phase II detoxification enzyme, has recently been implicated in protection against apoptosis. Expression of GST-pi and Bcl-2 protein, an established apoptosis marker, was analyzed by immunohistochemistry in 116 cases of infiltrative ductal breast carcinomas in Singapore women. The markers were correlated with apoptosis detected by the TUNEL method and clinico-pathological parameters. There were 67 (58%) GST-pi-positive breast tumors and 43 (37%) Bcl-2-positive tumors. In a large proportion of GST-pi-positive/Bcl-2-positive tumors, there was a distinct accumulation of the GST-pi enzyme within the nucleus of cancer cells when examined by double immunofluorescence labeling under confocal microscopy. GST-pi immunoreactivity was not significantly correlated with any of the traditional histologic factors known to influence prognosis, whereas Bcl-2 overexpression was associated with reduced size of primary tumor (P =.021) and positive estrogen receptor status (P =.001). Univariate analysis revealed that GST-pi-positive, Bcl-2-positive, and lower histological grade tumors had decreased levels of apoptosis (P =.024, P =.011, and P =.029, respectively). However, multivariate analysis showed that histological grade and Bcl-2, but not GST-pi, immunoreactivity were correlated with apoptotic status. The Kaplan-Meier disease-free survival curves showed a significant difference between GST-pi-positive and GST-pi-negative breast cancer cases (P =.002). Disease-free survival in patients with GST-pi-positive tumors was also worse than that in patients with GST-pi-negative tumors in the group who had adjuvant chemotherapy (P =.04). In patients who were lymph node positive, GST-pi immunopositivity was found to influence disease-free survival. Recurrence of tumors was also significantly affected by GST-pi immunoreactivity (relative risk of 8.1). The findings indicate that GST-pi-positive tumors are more aggressive and have a poorer prognosis than do corresponding GST-pi-negative breast cancers.
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PMID:Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. 1280 61


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