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)

The distributions of gamma-glutamyltransferase (GGT) and the placental form of glutathione S-transferase (GSTP) were examined in the livers of 18-month-old and 23-month-old SPF F344/DuCrj rats of both sexes. The number of the enzyme-altered foci in males was greater than in females, and it increased with age in animals of both sexes. Histologically, most of the foci in males consisted of eosinophilic or clear hepatocytes, while those in females were predominantly basophilic. More than 75% of the foci in males stained positively for GGT and GSTP. In contrast, more than 80% of the foci in females were GGT- and GSTP-negative. Thus, though both enzymes have been widely used for analysis of carcinogen-induced hepatocarcinogenesis, it appears that GGT and GSTP are inappropriate as markers of preneoplastic lesions in natural hepatocarcinogenesis in female rats.
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PMID:Sexual difference in the histochemical characteristics of "altered cell foci" in the liver of aged Fischer 344 rats. 288 43

Experiments were designed to determine whether liver cell proliferation induced by direct mitogens is as effective as compensatory cell proliferation consequent to previous cell loss, in supporting the growth of enzyme-altered islands in the liver induced by chemical carcinogens. Male Wistar rats were given injections of a single nonnecrogenic dose of N-methyl-N-nitrosourea or benzo(a)pyrene during the S phase following the administration of four different liver mitogens, namely, lead nitrate, ethylene dibromide, nafenopin, and cyproterone acetate, or during compensatory cell proliferation following partial hepatectomy or a necrogenic dose of CCl4. The carcinogen-altered hepatocytes were monitored as gamma-glutamyltransferase- or placental glutathione S-transferase-positive foci using a 2-wk promoting regimen consisting of 0.03% 2-acetylaminofluorene coupled with a necrogenic dose of CCl4. The results indicate that, unlike compensatory cell proliferation induced by partial hepatectomy or CCl4, the mitogen-induced cell proliferation did not result in a significant number of enzyme-altered islands, despite the fact that the extent of cell proliferation at the time of carcinogen administration, as monitored by the examination of labeled cells, is similar with both types of proliferative stimuli.
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PMID:Inability of mitogen-induced liver hyperplasia to support the induction of enzyme-altered islands induced by liver carcinogens. 288 25

Using immunohistochemical demonstration of glutathione S-transferase placental type (GST-P) and histochemical demonstration of gamma-glutamyltransferase (gamma-GT), the long-term development of preneoplastic and neoplastic lesions was followed in rats over a 50-week period. Rats were given a single i.p. injection of 200 mg/kg body weight of diethylnitrosamine (DEN), and then 2 weeks later were administered 0.02% 2-acetylaminofluorene (2-AAF) (group 1), 0.05% phenobarbital (PB) (group 2), 2.0% butylated hydroxyanisole (BHA) (group 3) or no supplement (group 4) in their diet for 6 weeks, all rats being subjected to partial hepatectomy at week 3. Hepatocellular proliferated lesions were classified as foci, nodules and hepatocellular carcinomas. Development of foci, nodules and hepatocellular carcinomas was enhanced strongly by 2-AAF and weakly by PB, and inhibited by BHA. Almost all foci and nodules were GST-P positive, although 5-10% of the GST-P-positive foci were gamma-GT negative. The areas of GST-P-positive foci and nodules increased with time in all groups. In contrast, while the areas of gamma-GT-positive lesions also increased with time in groups 2-4, they decreased from week 12 in group 1. As the percentage gamma-GT-positive area in GST-P-positive foci significantly decreased with time in all groups, the rate of phenotypic reversion of gamma-GT in foci in group 1 was revealed to be larger than the focus growing rate, whereas that in groups 2-4 was smaller. Gamma-GT-negative and GST-P-positive micro-nodules of altered morphology appeared within gamma-GT- and GST-P-positive nodules in later stages. All hepatocellular carcinomas found in this experiment consisted of GST-P-positive cells. In contrast, 37% (13/35) of the hepatocellular carcinomas were negative for gamma-GT. The results indicate GST-P to be the most accurate marker enzyme for detection of initiated cells during liver carcinogenesis and gamma-GT to be more appropriate for indicating changes of phenotypic expression in each lesion type.
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PMID:Stable phenotypic expression of glutathione S-transferase placental type and unstable phenotypic expression of gamma-glutamyltransferase in rat liver preneoplastic and neoplastic lesions. 289 92

We studied the effects of a zinc-inducible metallothionein-ras fusion gene (MTrasT24) in cultured rat liver epithelial (RLE) cells on expression of two genes induced during liver carcinogenesis in vivo: gamma-glutamyltransferase [(5-glutamyl)-peptide:amino acid 5-glutamyltransferase, EC 2.3.2.2] and glutathione S-transferase-P (RX:glutathione R-transferase, EC 2.5.1.18). Expression of MTrasT24 increased steady-state RNA levels of gamma-glutamyltransferase and glutathione transferase-P 6- to 100-fold and 1.6- to 6-fold, respectively; in contrast, levels of alpha-tubulin RNA fell slightly or were unchanged. RNA gel blots verified that gamma-glutamyltransferase and glutathione transferase-P RNAs were of the appropriate size, and results from immunocytochemistry on transfected cells demonstrated that RLE cells carrying MTrasT24 synthesized immunoreactive, appropriately localized gamma-glutamyltransferase and glutathione transferase-P. Zinc induction studies indicated that gamma-glutamyltransferase and glutathione transferase-P RNA levels were directly dependent on MTrasT24 RNA levels. These data suggest that expression of gamma-glutamyltransferase and glutathione transferase-P expression are part of a reorientation of cellular gene expression during carcinogenesis and that activated ras expression, like chemical carcinogens, can bring about this change.
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PMID:MTrasT24, a metallothionein-ras fusion gene, modulates expression in cultured rat liver cells of two genes associated with in vivo liver cancer. 289 74

Chronic ethanol feeding increases hepatic turnover and sinusoidal efflux of glutathione in rats. The present study was performed to determine whether the observed increase in glutathione efflux was due to increased extrahepatic requirements for glutathione. The concentration and disposition of plasma glutathione were determined in rats fed liquid diets containing 36% of calories as ethanol or pair-fed an isocaloric mixture with carbohydrate replacing ethanol calories for 5 to 8 weeks. The half-life and plasma clearance of [35S]glutathione were found to be similar in ethanol-fed and control rats and in rats withdrawn 24 hr from ethanol. Uptakes of the sulfur moiety of [35S]glutathione by kidney, jejunal mucosa, liver, lung, spleen, muscle and heart were also unchanged by ethanol feeding. The plasma glutathione concentration was significantly higher in ethanol-withdrawn rats 22.30 +/- 3.06 nmoles per ml (p less than 0.05) compared to pair-fed controls (13.51 +/- 2.04), while rats continuing to drink ethanol had intermediate levels (16.96 +/- 2.22). Plasma cysteine levels were slightly, but not significantly, higher in ethanol-fed rats. These findings suggest that increased sinusoidal efflux of glutathione in ethanol-fed rats is due to a direct effect of ethanol on hepatic glutathione transport and not due to an alteration in extrahepatic disposition of glutathione. In order to characterize further the effects of ethanol feeding on glutathione-dependent detoxification, activities of glutathione S-transferase, glutathione reductase and gamma-glutamyltransferase were determined.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of ethanol feeding and withdrawal on plasma glutathione elimination in the rat. 357 Jan 60

Slow reacting substances (leukotrienes C4, D4, E4) are synthesized in vivo by a combination of two previously unrelated pathways: lipoxygenase oxygenation of arachidonic acid and the glutathione detoxification pathway. Enzymes involved in the latter pathway (glutathione transferase [RX: glutathione R-transferase, EC 2.5.1.18]; gamma-glutamyltransferase [(5-glutamyl)-peptide: amino acid 5-glutamyltransferase, EC 2.3.2.2] ) have been investigated in guinea pig lung and rat basophilic leukemia (RBL-1) cells. We report data on levels of enzymic activity both before and during the release of slow reacting substances. Both glutathione transferase and gamma-glutamyltransferase are present in significant quantities in guinea pig lung and RBL-1 cells. A model for the changes in gamma-glutamyltransferase during leukotriene release is proposed for the cell line, and differences from the guinea pig lung system are reported. Leukotriene C4 is converted to the more potent leukotriene D4 by the action of gamma-glutamyltransferase on guinea pig ileum during bioassay. gamma-Glutamyltransferase may represent a control feature in the biosynthesis of leukotriene D4, and thus be involved in leukotriene-induced bronchoconstriction in the lung.
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PMID:Slow reacting substances (leukotrienes): enzymes involved in their biosynthesis. 612 78

A method is described for the isolation of endoplasmic reticulum and Golgi apparatus from hyperplastic liver nodules produced by discontinuous feeding of 2-acetylaminofluorene to male Wistar rats. The procedure involves three centrifugation steps and permits the separation of these cell components and their subfractions from the same sample of liver tissue as little as 1 g, wet weight. The fractions have been characterized by chemical, enzymatic, and morphological techniques and were found to be as pure as preparations from normal tissue. Furthermore, some of the characteristic histochemical features of hyperplastic liver nodules have been quantitated by biochemical methods in the fractions. Glucose-6-phosphatase activity in the endoplasmic reticulum subfractions of nodules is approximately 15% of the corresponding value in normal livers, whereas the activity of reduced nicotinamide adenine dinucleotide phosphate: cytochrome c reductase is reduced to 85% of the normal activity. The amount of cytochrome P-450 in nodular membranes as measured by differential spectroscopy is 25% of the control, indicating a decreased Phase I activity in drug metabolism. A 5-fold increase in cytosolic glutathione S-transferase activity without change in the corresponding microsomal activity was detected in hepatocyte nodules in rat liver. The activity of gamma-glutamyltransferase is increased more than 20-fold in all membrane fractions prepared from nodular tissue. The cytosolic activity, which is very low in the normal liver, is similarly increased more than 20-fold. The membrane-associated gamma-glutamyltransferase seems to be an integral membrane protein which cannot be washed away from the membranes. Chemically, membranes from nodules have phospholipid and cholesterol:protein ratios as found in membranes from normal liver tissue. However, the composition of individual phospholipids is changed with a 2-fold increase in nodular phosphatidylinositol and a slight decrease in phosphatidylcholine content in nodular membranes. The amount of endoplasmic reticulum membranes is of the same magnitude as in normal liver, although the smooth-surfaced component constitutes almost 60% of the isolated endoplasmic reticulum marker enzymes in nodules, compared with only 32% in preparations from normal tissue. The albumin contents of nodular and normal microsomal and Golgi membrane preparations are similar, indicating a normal synthesis of albumin by nodular tissue.
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PMID:Isolation and characterization of endoplasmic reticulum and Golgi apparatus from hepatocyte nodules in male wistar rats. 618 97

Transport of reduced glutathione (GSH) was studied in isolated rat liver canalicular membrane vesicles by a rapid filtration technique. The membrane vesicles exhibit uptake of [2-3H]glycine--labeled GSH into an osmotically reactive intravesicular space. Although the canalicular membrane vesicles possess gamma-glutamyltransferase and aminopeptidase M, enzymes that hydrolyze glutathione into component amino acids, inactivation of the vesicle-associated transferase by affinity labeling with L-(alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (AT-125) had no effect on the initial rate of GSH transport. Chemical analysis revealed that intact GSH accounted for most of vesicle-associated radioactivity. The initial rate of transport followed saturation kinetics with respect to GSH concentration; an apparent Km of 0.33 mM and V of 1.47 nmol/mg protein in 20 s were calculated. These results indicate that transport of GSH across the canalicular membranes is a carrier-mediated process. Replacement of NaCl in the transport medium by KCl, LiCl or choline chloride had no effect on the transport activity of the vesicles. The rate of GSH uptake by the vesicles was enhanced by valinomycin-induced K+-diffusion potential (vesicle inside-positive) and was inhibited by probenecid, indicating that GSH transport across the canalicular membranes is electrogenic and involves the transfer of negative charge. The transport of GSH was inhibited by oxidized glutathione or S-benzyl-glutathione. This transport system in canalicular plasma membranes may function in biliary secretion of GSH and its derivatives which are synthesized in hepatocytes by oxidative processes or glutathione S-transferase.
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PMID:The mechanism of biliary secretion of reduced glutathione. Analysis of transport process in isolated rat-liver canalicular membrane vesicles. 688 44

alpha-Glutathione S-transferase (alpha-GST; EC 2.5.1.18) has been advocated as a better marker of hepatocellular damage than the transaminases in toxic and autoimmune hepatitis. We have assessed the potential interest of plasma alpha-GST determination in 94 anti-hepatitis C virus-positive patients with histologically proven chronic hepatitis C (34 women, 60 men, ages 40.0 +/- 11.9 years). Blood samples were assayed for aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase, alkaline phosphatase, and alpha-GST on the same day a liver biopsy was performed. alpha-GST concentrations were significantly above reference values in 64% of patients (compared with 58% for AST, 68% for ALT), and this increase was seen in 52% of patients with normal values for transaminases and a Knodell score > 3. Furthermore, there was a significant correlation between alpha-GST and lobular necrosis score (r = 0.31; P < 0.01). Our findings suggest that association of plasma alpha-GST with ALT may improve the biochemical assessment of liver damage in patients with chronic hepatitis C.
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PMID:Plasma alpha-glutathione S-transferase assessed as a marker of liver damage in patients with chronic hepatitis C. 749 11

The toxicity of most drugs and chemicals is associated with their enzymatic conversion to toxic metabolites. Bioactivation reactions occur in a range of organs and organelles, including mitochondria. The toxicity of haloalkene-derived cysteine S-conjugates and related 4-thiaalkanoates is associated with their mitochondrial bioactivation. Toxic cysteine S-conjugates are formed by the glutathione S-transferase-catalyzed addition of glutathione to haloalkenes to give glutathione S-conjugates, which are hydrolyzed by gamma-glutamyltransferase and dipeptidases. Mitochondrial cysteine conjugate beta-lyase-catalyzed bioactivation of cysteine S-conjugates affords unstable alpha-halothiolates. Haloalkene-derived 4-thiaalkanoates, which are analogs of cysteine S-conjugates that lack an alpha-amino group, undergo bioactivation by the enzymes of fatty acid beta-oxidation to give 3-hydroxy-4-thiaalkanoates that eliminate alpha-halothiolates. alpha-Halothiolates yield alkylating and acylating agents that interact with cellular macromolecules and thereby cause cell damage. Mitochondrial dysfunction is the hallmark of cysteine S-conjugate-induced cytotoxicity: decreased respiration, decreased ATP and total adenine nucleotide concentrations, depletion of the mitochondrial glutathione content, perturbations in cellular Ca2+ homeostasis, and damage to the mitochondrial genome are seen with cysteine S-conjugates. Similar changes are observed with cytotoxic 4-thiaalkanoates, but inhibition of the medium-chain acyl-CoA dehydrogenase and hypoglycemia are also observed.
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PMID:Mitochondrial bioactivation of cysteine S-conjugates and 4-thiaalkanoates: implications for mitochondrial dysfunction and mitochondrial diseases. 759 25


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