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)

Foci of atypical acinar cells observed in male rats 1 year after a single injection of hydroxyaminoquinoline 1-oxide (HAQO) were assessed immunohistochemically for altered expression of a number of enzyme forms considered to play important roles in drug metabolism. The pancreatic lesions, classified as of either basophilic or eosinophilic type on histological appearance, demonstrated distinctive patterns of altered enzyme phenotype. On the one hand, the basophilic foci composed of enlarged cells/nuclei with very prominent nucleoli were characterized by increase in GST-P, G6PD and P450 PB1 and MC2 forms. The eosinophilic type, in contrast, comprised smaller cells demonstrating elevated P450 MC1 and PB1 but not MC2, normal G6PD and strong GST-P binding limited only to a proportion of the nuclei. Both shared decreased GGT and almost total lack of GST-B positive connective tissue and ductular elements. Apparent islet cell lesions and normal islet tissue were characterized by a distinct enzyme phenotype strongly positive for all P450 species investigated. The results indicate that HAQO-induced putative preneoplastic pancreatic lesions, like equivalent carcinogen associated with focal populations in liver, kidney and ductular pancreas, demonstrate a non-random altered expression of specific drug metabolizing enzyme species.
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PMID:Altered drug metabolizing potential of acinar cell lesions induced in rat pancreas by hydroxyaminoquinoline 1-oxide. 288 32

Effects of three different doses of endosulfan respectively designated as low, medium and high on cytochrome P450(Cyt.P450), glutathione S-transferase(GST) activity and glutathione content (GSH) of hepatic and extra hepatic tissues of rat were determined after 24 hours of treatment. Endosulfan caused induction of cyt. P450 in liver, lung and brain at all the three doses tested while in kidney, spleen and heart either induction or reduction took place and was unrelated with dosages of endosulfan. Similarly, GST activity significantly changed in extra hepatic tissues while liver GST activity did not record any significant alteration under the experimental conditions. The GSH content also showed changes (increase/decrease) unrelated to endosulfan dosages in different organs. Thus, the effects varied with organ and dosages. As these metabolic parameters are involved in biotransformation of many endogenous molecules as well, the study may throw some light on physiological disturbances due to changes in metabolizing system on one side and organ specificity in toxic action of endosulfan on the other.
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PMID:Some metabolic changes induced by endosulfan in hepatic and extra hepatic tissues of rat. 368 Aug 62

Two cytochromes P450 (PB1 and PB2) have been isolated from the livers of rats treated with phenobarbital. PB2 (mol. wt. 53 500) is novel and is the first example of a phenobarbital-inducible enzyme with a Soret peak at 447 nm. Using an enzyme-linked immunosorbent assay, some immunochemical and structural similarities were observed between these cytochromes. PB1 and PB2 were induced by phenobarbital, Aroclor 1254, trans-stilbene oxide and to a lesser extent by isosafrole. Immunohistochemical localization of these proteins in the liver of untreated rats showed PB1 to be localized in a large area and PB2 in a narrow range of cells around the central vein. This demonstrates the heterogeneity of hepatocytes even within the centrilobular area and indicates that the synthesis of these two proteins is regulated differently although both are induced by the same agent, phenobarbital. Two 3-methylcholanthrene inducible cytochromes MC1 (mol. wt. 54 500) and MC2 (mol. wt. 57 000) were present at very low levels, MC2 mostly in the periportal region but also diffusely distributed throughout the lobule including some centrilobular cells, MC1 concentrated in the centrilobular region. The localization of two major groups of glutathione transferases (GST's) was also different. 'C' type proteins (Yb Yb') and microsomal epoxide hydrolase (EH), were concentrated around the central vein, whereas the 'B' type proteins (Ya Yc) and cytochrome P450 reductase were distributed in a larger area of this region. Thus, the localization was different for some members of the same enzyme family, whilst similarities in the localization existed across the border of the families: (i) PB2, MC1, EH and GST 'C' type proteins were concentrated in a narrow area around the central vein; (ii) PB1 and GST 'B' type proteins occupied a large centrilobular area; (iii) MC2 levels were very low, predominantly periportal but also diffusely distributed throughout the lobule. Treatment of the animals with inducers increased the staining intensity and in several cases extended the areas of cells containing these proteins over the adjacent zone without fundamentally altering their distributions. However, treatment with beta-naphthoflavone led to a shift of MC1 to the periportal area. This suggests that the expression of these proteins in certain cells is not an irreversible quality of differentiation but depends on the degree of suppression and derepression of regulatory components.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Characterization, localization and regulation of a novel phenobarbital-inducible form of cytochrome P450, compared with three further P450-isoenzymes, NADPH P450-reductase, glutathione transferases and microsomal epoxide hydrolase. 643 May 87

The effects of the synthetic dibromo-pyrethroid insecticide deltamethrin on some hepatic phase I and II enzyme activities were studied in rat liver. The animals were treated with daily doses of 5 and 10 mg/kg of both pure insecticide or its commercial formulation (Decis), administered i.p. in corn oil for 7 days. The following enzyme activities were studied: NADPH-cytochrome-P450 reductase, aryl-hydrocarbon hydroxylase, aminopyrine N-demethylase, glutamyl cysteine synthetase, glutathione S-transferase, glutathione peroxidase, peroxisomal acyl-CoA oxidase, catalase, and urate oxidase. Both deltamethrin and its commercial formulation were effective in modifying the activities of several of these hepatic xenobiotic-metabolizing enzymes. However, some differences in enzyme modifications were found between treatment with pure or commercial deltamethrin, the latter being more active. This effect could be ascribed to additives, solvents, and chemical intermediates present in the Decis formulation. These results suggest that exposure to this deltamethrin commercial formulation could be more dangerous than exposure to deltamethrin alone, both in terms of its hepatotoxicity and/or alterations in the hepatic biotransformation of other occupational/environmental xenobiotics.
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PMID:Studies on hepatic xenobiotic-metabolizing enzymes in rats treated with insecticide deltamethrin. 747 74

Cytogenetic alterations have been associated with the occurrence of many cancers. However, limited data exist to address whether increased chromosomal changes in surrogate normal tissue are similarly associated with malignancy. As part of an ongoing case-control study of lung cancer, we have studied the factors that affect sister chromatid exchange (SCE) frequency in lymphocytes from lung cancer patients. Further, we sought to investigate whether the factors that affect SCE frequencies were comparable in lung cancer cases and controls. Cases had newly diagnosed, operable primary lung cancer. Controls were friends and spouses of cases. Detailed information on smoking, family history of cancer, medical history, and environmental and occupational exposures was obtained in an interviewer-administered questionnaire. Intake of antioxidants was also determined through the administration of a validated semiquantitative food frequency questionnaire. Metabolic traits studied included the polymorphic glutathione-S-transferase class mu (GST-mu) and variants of P450 isoenzymes CYP1A1 and CYP 2D6. Overall, 78 cases and 78 controls were included in the analysis. Although there was a small number of lung cancer patients who had never smoked in the study (9% of cases), these patients had higher SCE frequencies than current or former smokers. This suggests that factors associated with genomic instability may also play a role in the pathogenesis of lung cancer. The best fit model for SCE frequency, which had been previously generated from control data alone, included age, gender, smoking, GST-mu, and vitamin A intake. However, when this model was applied to lung cancer patients, smoking was not associated with an elevated SCE frequency. Thus, it is not clear that SCE frequency data in prevalent lung cancer cases and controls are comparable.
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PMID:Comparison of sister chromatid exchange frequency in peripheral lymphocytes in lung cancer cases and controls. 747 55

Various natural and synthetic compounds are known to protect against cancer by elevating phase II detoxification enzymes. Generally classified as monofunctional, these inducers are believed to trigger cellular signal(s) that activate gene transcription through an antioxidant or electrophile response element (ARE/EpRE) in responsive genes. In contrast, the phase I enzymes of drug metabolism (cytochrome P450s) are not believed to be induced by monofunctional inducers and P450 genes have not been found to contain functional ARE/EpREs. In this study, rats were treated with the monofunctional inducers tert-butylated hydroxyanisole, ethoxyquin, and oltipraz to study the inducibility of individual glutathione S-transferase isozymes, NADP(H):quinone oxidoreductase, gamma-glutamylcysteine synthetase, UDP-glucuronosyl transferase, and cytochrome P450 enzymes. Hepatic mRNAs were analyzed on Northern blots using gene-specific oligonucleotide probes for GST Ya1, Ya2, Yc1, Yc2, Yb1, Yb2, and Yf, for UGT 1*06, and for P450 1A1, 1A2, 2B1, 2C11, 3A2, and 4A1. NADP(H):quinone oxidoreductase and gamma-glutamylcysteine synthetase mRNAs were detected using cDNA probes. All the phase II detoxification enzymes analyzed, except GST Yf, were induced by the three monofunctional inducers, suggesting that these genes may be regulated by a mechanism involving an ARE/EpRE element in their promoter region. Interestingly, it was found that ethoxyquin was a particularly good inducer for both members of the P450 2B family, 2B1 and 2B2, and both ethoxyquin and oltipraz were also capable of modestly inducing P450 1A2 and 3A2. Oltipraz was found to slightly induce P450 2B2, but not 2B1, at the dose and time analyzed. Induction of mRNA generally correlated well with induction of protein levels determined by Western blot and/or enzyme activity measurements for selected enzymes. The results of this study suggest that many phase II enzymes may contain ARE/EpRE elements in addition to those confirmed to be regulated by a mechanism involving ARE/EpRE elements. In addition, it was found that several P450 enzymes were induced by monofunctional inducers, suggesting a possibility that some phase I enzymes may also be regulated by a mechanism involving ARE/EpRE elements.
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PMID:Induction of phase I and phase II drug-metabolizing enzyme mRNA, protein, and activity by BHA, ethoxyquin, and oltipraz. 748 39

Transfection of murine NIH3T3 fibroblasts and human MCF7 breast carcinoma cells with a pSV2-derived eukaryotic expression vector for human cytosolic glutathione peroxidase resulted in clones with increased glutathione peroxidase activity. This heterologous expression indicates that murine cells recognize the human "selenocysteine insertion sequence" in the 3' untranslated region of the mRNA which facilitates insertion of selenocysteine directed by the opal codon. Though most clones from both cell lines eventually lost their enhanced glutathione peroxidase activity despite continuous selection on G418, some NIH3T3 clones retained enhanced enzyme activity without continuous G418 exposure. Transfection of MCF7 cells with an Epstein-Barr virus (EBV)-derived episomally replicating expression vector carrying the glutathione peroxidase gene also revealed increased glutathione peroxidase activity. These MCF7 cells, however, all required exposure to G418 to maintain enhanced glutathione peroxidase activity. Detailed biochemical analysis of a stably expressing NIH3T3 clone and MCF7 expressing cells revealed no alterations in activities of copper-zinc superoxide dismutase, manganese superoxide dismutase, catalase, phospholipid-glutathione peroxidase, glutathione reductase, glutathione transferase, or NADPH-P450 reductase. Both pSV2- and EBV-derived glutathione peroxidase-expressing clones exhibited enhanced resistance to paraquat as well as to peroxides.
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PMID:Heterologous expression of selenium-dependent glutathione peroxidase affords cellular resistance to paraquat. 748 71

The major groups of enzymes involved in activating and detoxifying therapeutic drugs, not least several anti-cancer drugs, include the cytochromes P450 (P450s), epoxide hydrolase, and glutathione S-transferases (GSTs). The expression of these enzymes in malignant tumours is one possible mechanism of anti-cancer drug resistance. This study has investigated the presence, cellular localization, and distribution of drug-metabolizing enzymes in prostate cancer. The P450 subfamilies CYP1A, CYP2C, and CYP3A were present in 63, 25, and 61 per cent of tumours, respectively. Epoxide hydrolase was identified in 96 per cent of tumours. GST-alpha and GST-mu were expressed in 29 and 41 per cent of tumours, respectively, while there was no immunoreactivity for the pi form of GST. The absence of GST-pi in prostate cancer contrasts with the frequent expression of GST-pi observed in other types of malignant tumour. In non-neoplastic prostatic epithelium, there was expression of CYP1A, CYP2C, epoxide hydrolase, and the different forms of GST, while there was no apparent immunoreactivity for CYP3A.
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PMID:The immunohistochemical localization of drug-metabolizing enzymes in prostate cancer. 749 Jun 81

Patients with idiopathic Addison's disease are characterized by cytoplasmic adrenal autoantibodies, detectable by indirect immunofluorescence of cryocut sections of human adrenal cortex. Recently, autoantibodies that bind a 55-kilodalton protein in the microsomal fraction of adrenal gland extracts identified to be the cytochrome P450 enzyme 21-hydroxylase have been found in Addisonian patient sera. We confirm the finding and report here the autoantigenic epitopes involved in the autoantibody reactivity using recombinant DNA technology. Six cDNA fragments spanning different regions of the 21-hydroxylase gene were expressed as fusion proteins with glutathione S-transferase in Escherichia coli. Immunoblot analyses were used to evaluate the reactivity of the recombinant proteins with patients' sera to determine the autoepitopes involved. We found that a conserved region (amino acids 164-356) reacted with 25 of 30 adrenal autoantibody-positive sera tested. One serum sample reacted only with the amino portion of the 21-hydroxylase (amino acids 1-162). In addition, 4 other enzymes important to steroid hormone biosynthesis, 11 beta-hydroxylase, 17 alpha-hydroxylase, side-chain cleavage enzyme P450, and 3 beta-hydroxysteroid dehydrogenase, were expressed in E. coli, but none of them gave positive autoantibody reactions by Western blot assays, even using sera from 5 patients with type I autoimmune polyglandular syndrome. The availability of recombinant antigens has permitted structural analysis of the autoepitopes involved in the autoimmune response to 21-hydroxylase in Addison's disease. Our findings should lead to the development of a simple and specific tool for immunodiagnosis of the disease.
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PMID:Autoantibody epitope mapping of the 21-hydroxylase antigen in autoimmune Addison's disease. 751 15

The cytochromes P450, epoxide hydrolase and glutathione S-transferases are several of the major groups of enzymes involved in the metabolism of xenobiotics and these enzymes may have a role in influencing the response of tumours to anti-cancer drugs. In this study the cell specific expression of individual xenobiotic metabolizing enzymes has been investigated using immunohistochemistry in primary transitional cell tumours of the urinary bladder. The cytochromes P450 CYP1A, CYP2C and CYP3A, were present in 68, 28 and 68% of tumours respectively and the expression of CYP1A correlated with bladder tumour grade (P = 0.03). Epoxide hydrolase was identified in 84% of tumours while the alpha, mu and pi forms of glutathione S-transferase were expressed in 56, 72 and 52% of tumours respectively. In normal bladder epoxide hydrolase and glutathione S-transferase pi were the main enzymes expressed while there was no expression of CYP2C.
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PMID:Expression of xenobiotic metabolizing enzymes in tumours of the urinary bladder. 754 41


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