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)

Inducibility of oxidative stress in rat liver in vivo by menadione-associated redox cycling activation under redox enzyme modulating conditions was examined by monitoring hepatocyte injury and 8-hydroxydeoxyguanosine (8-OHdG) levels of liver DNA. In addition, the treatment-associated liver tumor initiating activity was assessed in terms of development of gamma-glutamyl-transpeptidase (GGT)- and glutathione S-transferase placental form (GST-P)-positive foci and hyperplastic nodules. With or without following menadione treatment (50 mg/kg, i.g.), redox enzyme modulations of increased cytochrome P450 reductase activity induced by phenobarbital (PB)-Na (100 mg/kg, i.p. for 5 days), inhibition of DT-diaphorase by dicumarol (25 mg/kg, i.p.) and depletion of glutathione by phorone (200 mg/kg, i.p.), with or without further supplement of iron EDTA-Na-Fe(III) (70 mg/kg, i.p.), caused both substantial hepatocyte necrosis and 8-OHdG production in Fischer 344 male rats. Subsequent feeding with a 0.05% PB diet for 64 weeks resulted in slightly increased development of GGT-positive foci but not GST-P positive lesions or hyperplastic nodules, suggesting a lack of tumor-initiating activity of the oxidative DNA damage associated with redox enzyme modulations with or without menadione.
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PMID:Induction of 8-hydroxydeoxyguanosine but not initiation of carcinogenesis by redox enzyme modulations with or without menadione in rat liver. 170 52

The drug-metabolizing enzymes of olfactory and respiratory epithelium of cattle were determined. The data of nasal tissues were compared to those of bovine liver. Both oxidative and nonoxidative enzyme activities were investigated. Many compounds including testosterone were used as substrates for the P450-dependent monooxygenase activities. The results demonstrated that the P450 content and all the activities assayed including reduced nicotinamide adenine dinucleotide phosphate (NADPH)-cytochrome P450 reductase were much higher in the olfactory than in the respiratory mucosa and for some activities (hexamethyl-phosphoramide and dimethylnitrosamine N-demethylase, aniline hydroxylase, and ethoxycoumarin O-deethylase) the values in the olfactory tissue were even markedly higher than those of liver. Also the activities of some nonoxidative enzymes such as glutathione S-transferase, uridine 5'-diphosphate (UDP)-glucuronyl-transferase, and epoxide hydrolase were higher in the olfactory than in the respiratory mucosa but lower than in liver. The results taken together suggest that the olfactory and respiratory epithelium of cattle, which contain in addition to a wide array of nonoxidative enzymes multiple forms of P450, can be useful and easily available tissues to study the biotransformation processes of odorants.
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PMID:Drug-metabolizing enzymes in liver, olfactory, and respiratory epithelium of cattle. 194 98

Activities of various xenobiotic-metabolizing enzymes were determined in 18 cell lines. Activities of cytochrome P450 reductase, microsomal epoxide hydrolase and glutathione transferase were detectable in all lines. The highest values were similar to the activities found in freshly isolated rat hepatocytes. Catalase activity was also present in all 12 investigated cell lines. Activity of UDP-glucuronosyl transferase was high in some lines, but low or undetectable in others. Activity of cytosolic epoxide hydrolase was not measurable in most lines, and was low in the others. Metabolism of benzo[a]pyrene was observed in eight out of nine examined lines, no activity being found in V79 cells. V79 and three epithelial cell lines were then used as target cells in a genotoxicity assay in which the frequency of micronucleated cells was determined. In V79 cells, 7,12-dimethyl- benz[a]anthracene, benzo[a]pyrene, benzo[a]pyrene-trans-7,8-dihydrodiol, aflatoxin B1, N-nitrosomorpholine and 2-acetylaminofluorene showed negative responses, whereas N-methyl-N'-nitro-N-nitrosoguanidine, 9-hydroxybenzo[a]pyrene, 2-nitrofluorene, dibenz[a,h]anthracene 1,2-catechol, dibenz[a,h]anthracene, 1,2-quinone hydroquinone and p-benzoquinone proved positive in the test. All 13 compounds, however, induced micronuclei in rat intestinal cells (IEC-17 and IEC-18) and in embryonal human liver cells (HuFoe-15). Thus, these epithelial cell lines are capable of activating and detecting a broad spectrum of chemically diverse genotoxic compounds. They may also be useful for the detection of hazardous compounds whose active metabolites are not able to penetrate from the extracellular space into the indicator cell.
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PMID:Expression of xenobiotic-metabolizing enzymes in propagatable cell cultures and induction of micronuclei by 13 compounds. 238 78

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

Aldehyde dehydrogenase (ALDH) is well known for its involvement in the resistance of tumor cells to cyclophosphamide (CPA) and its activated derivatives, such as 4-hydroperoxy-CPA (4HC). The role of other drug-metabolizing enzymes such as glutathione S-transferase (GST) in CPA resistance is, however, less certain. In the present study of a human breast cancer cell line (MCF-7) exhibiting about 6-fold resistance to 4HC (MCF/HC), cellular levels of glutathione (GSH) were increased 1.4-fold, while cytosolic GST and ALDH activities were increased 2.7- and 7.2-fold, respectively, relative to the MCF-7 parental line. No significant changes in glutathione peroxidase and NADPH cytochrome P450 reductase activity, and no increase in microsomal GST and GST pi mRNAs were found in the resistant cells. Treatment with the ALDH substrate octanal sensitized the cells to the cytotoxic effects of 4HC to a modest extent in both MCF-7 and MCF/HC cells [dose modification factor (DMF) of 1.4 and 1.6, respectively]. Depletion of GSH by treatment with the GSH synthesis inhibitor buthionine sulfoximine (BSO) enhanced the cytotoxic effect of 4HC to a similar extent in both cell lines. By contrast, ethacrynic acid, which inhibited GST activity by > 85% in MCF-7 and MCF/HC cell extracts without depletion of GSH, sensitized the resistant but not the parental cells to 4HC cytotoxicity, indicating the importance of GST as a determinant of 4HC resistance in these cells. This conclusion is supported by the observation that in MCF/HC cells, ethacrynic acid in combination with BSO increased the DMF 3-fold higher than did BSO or EA alone, while in the parental MCF-7 cells ethacrynic acid with BSO had no significant chemosensitization effect over BSO alone. These studies establish that in addition to ALDH, GST overexpression can contribute to acquired resistance of tumor cells to 4HC and, furthermore, suggest that modulators that target the GSH/GST system could be useful in overcoming CPA resistance in the clinic.
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PMID:Identification of glutathione S-transferase as a determinant of 4-hydroperoxycyclophosphamide resistance in human breast cancer cells. 778 10

The development of drug resistance is an important factor contributing to failure of chemotherapy in cancer patients. Cyclophosphamide (CP) is a cytostatic drug widely used in the treatment of haematological malignancies and solid tumours. Because CP requires bioactivation to become cytotoxic, an in vivo approach was chosen to generate a subline of the Brown Norway rat acute myelocytic leukaemia (BNML/CPR) highly resistant to CP to serve as a model to investigate the molecular mechanism(s) of cyclophosphamide resistance. The role of the CP-detoxifying enzyme aldehyde dehydrogenase (ALDH) in the molecular mechanism of CP resistance in this subline of the BNML has been investigated. Compared to the parent BNML cell line, the BNML/CPR cell line displayed an approximately 6-fold higher level of ALDH enzyme activity. Pretreatment of leukaemic rats with the ALDH inhibitor disulfiram resulted in a restoration of CP sensitivity of animals carrying the BNML/CPR cells. Furthermore, in vitro incubation of BNML/CPR cells with disulfiram prior to incubation with the activated CP derivative mafosfamide resulted in an extra 2-3 log cell kill as indicated by the survival time of rats which were injected with disulfiram pretreated BNML/CPR cells compared to non-pretreated BNML/CPR cells. Data on the glutathione S-transferases (GSTs) isozyme profiles of cytoplasmic liver and spleen extracts of BNML- and BNML/CPR-carrying leukaemic rats indicated that the total GST enzyme amount was lower in BNML/CPR cells than in parent BNML cells. Furthermore, the BNML/CPR subline proved to be sensitive to phosphoramide mustard, both in vivo and in vitro.
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PMID:Aldehyde dehydrogenase involvement in a variant of the brown Norway rat acute myelocytic leukaemia (BNML) that acquired cyclophosphamide resistance in vivo. 785 14

Male C57 BL/6 mice were exposed to 1.0% (w/w) acetylsalicylic acid (ASA) in their diet for 10 days and effects related to peroxisome proliferation were subsequently examined. A 2.2-fold increase in mitochondrial protein content was obtained. The activities of the peroxisomal enzymes, lauroyl-CoA oxidase, palmitoyl-CoA oxidation and catalase, were enhanced 4.5-, 4.0- and 2.1-fold, respectively. There was a dramatic increase (9.1-fold) in microsomal cytochrome P450 IVA-catalysed activity, a 1.6-fold induction of total microsomal P450 content and a 2-fold induction of microsomal cytochrome P450 reductase activity (measured as NADPH-cytochrome c reductase). Catalase activity in the cytosol was induced 5.2-fold and DT-diaphorase activity was increased 3.5- and 3.2-fold in the cytosol and mitochondria, respectively. There was a significant increase in the susceptibility of microsomes to lipid peroxidation. Smaller increases in superoxide dismutase, glutathione transferase and glutathione peroxidase activities were also observed. The possible relevance of these effects to the pharmacology of ASA is discussed.
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PMID:Effects of acetylsalicylic acid on parameters related to peroxisome proliferation in mouse liver. 803 14

In this report we describe the heterologous expression of glutathione S-transferase (GST) and cytochrome P450 reductase (Red) in E. coli and Salmonella typhimurium. The same expression vectors could be applied to both systems and high levels of catalytically active GST and Red were obtained. Interestingly the level of expression was invariably higher in S. typhimurium. The level of the alpha class GST being up to 20% of the total bacterial protein. A further advantage of the salmonella system is that strains were used which can be applied to mutagenicity tests. This system was validated by demonstrating increasing mutation frequency of halogenated hydrocarbons in strains expressing the GST and increased cytotoxicity of mitomycin C in cells expressing P450 reductase.
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PMID:Heterologous expression of drug-metabolizing enzymes in cellular and whole animal models. 823 79

Female F344 rats received an i.p. injection of iron-dextran (600 mg Fe/kg) and then after 1 week were fed a diet containing 0.02% hexachlorobenzene (HCB) for up to 65 weeks. All rats (8/8) which received HCB after iron overload developed multiple hepatic nodules whereas only 3/8 rats administered HCB alone had nodules (average of one per positive liver). These hyperplastic regions were depleted of iron and were often positive for gamma-glutamyl transpeptidase (GGT) and glutathione S-transferase P (GST-P). Telangiectasis and peliosis were prominent features in the lesions. Short-term experiments (5-15 weeks of iron/HCB treatments) showed that GGT and GST-P were induced early in the neoplastic process but not in discrete focal areas. Iron alone also caused some induction of these enzymes. Some cells with induced GST-P in either short or long term experiments also stained positively for this enzyme in the nucleus. Studies of cytochrome P450 mediated activities showed that at 5 and 15 weeks HCB had induced EROD (an estimate of CYP1A1), PROD (CYP2B1 activity) and BROD activities (CYP2B1 but also other isoenzymes). Under the influence of iron overload EROD was significantly depressed from HCB alone, but not the others or cytochrome P450 reductase. Cytosolic glutathione S-transferase activities were also induced by HCB, but, unlike microsomal EROD, preloading with iron enhanced the effects. In contrast, although cytosolic diaphorase activity was induced by HCB, this response was depressed in combination with iron. Glutathione peroxidase (with H2O2 as substrate) was depressed by both iron and HCB. Clearly, iron overload potentiates the neoplastic process induced by HCB in rats, with both enhancing and depressing effects on various enzyme activities induced by this chemical.
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PMID:Enhancement by iron of hepatic neoplasia in rats caused by hexachlorobenzene. 833 Mar 54

Malignant astrocytomas are frequently resistant to cytotoxic chemotherapy. A possible mechanism of chemoresistance is drug inactivation within malignant astrocytes by detoxifying enzymes (glutathione transferases (GST) and cytochrome P450's). The aim of this study was to assess whether there was differential expression of these detoxifying enzymes in the central nervous system and any relationship to histological grade (WHO) of the tumours. Immunostaining was performed in 30 consecutive glioma samples, using class specific polyclonal antibodies to subtypes of GST (pi, alpha, mu) and to human cytochrome P450 reductase. GST immunostaining was evident in astrocytes and endothelium but not neurones or oligodendrocytes in normal brain. Immunostaining for GST increased in intensity from well differentiated tumours to glioblastoma. Staining was least evident in surrounding normal brain, strong in reactive astrocytes and astrocytic tumour cells and very intense in gemistocytic and giant tumour cells. Small anaplastic tumour cells had very little GST staining. Where endothelial proliferation was evident, GST staining in endothelial cells was increased. Pi was always the predominant subclass, although GST alpha and mu were also expressed in some tumours. Cytochrome P450 reductase immunostaining was present in normal neurones and malignant astrocytes. Gemistocytic astrocytic tumour cells stained intensely. Further work is necessary to see if there is any correlation between immunostaining intensity survival or response to chemotherapy.
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PMID:Glutathione S-transferases and cytochrome P450 detoxifying enzyme distribution in human cerebral glioma. 852 85


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