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)

Cytosolic glutathione S-transferase (GST) and microsomal epoxide hydrolase (EH) are important detoxification enzymes for many epoxide xenobiotics. We have developed a rapid, simple, and convenient HPLC assay which measures both of these enzyme activities toward benzo[a]pyrene-4,5-oxide (BaPO) in tissue homogenates. Tissue fractions were incubated at 37 degrees C in the presence of 5 mM glutathione. Reactions were initiated by addition of BaPO and terminated by the addition of ice-cold acetonitrile containing 2-methoxynaphthalene as an internal standard. Samples were analyzed directly on a 15-cm C18 reverse-phase column at room temperature, with a ternary solvent program which utilized 0.01% ammonium phosphate buffer (pH 3.5), acetonitrile, and water. The uv absorbance (260 nm) was monitored. Baseline resolution of BaPO, BaPO-GSH, and BaPO-diol and the internal standard was accomplished in 10 min. In rat hepatic S9, production of both BaPO-GSH and BaPO-diol was linear with time and protein up to 15 min and 500 micrograms/ml, respectively. Coefficients of variation for replicate analyses were 2.7 and 3.7% for GST and EH activities in S9, respectively. With fluorescence detection (ex, 241; em, 389 nm), this assay was sensitive enough to measure GST and EH activities in mononuclear leukocytes (MNL). GST and EH activities in 109 human MNL samples were 142 +/- 74 (mean +/- SD; range 21-435) pmol/mg/min and 19 +/- 9 (mean +/- SD; range 3-59) pmol/mg/min, respectively. These results demonstrate the simplicity, high sensitivity, and applicability of this assay for a broad range of tissues.
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PMID:Simultaneous determination of cytosolic glutathione S-transferase and microsomal epoxide hydrolase activity toward benzo[a]pyrene-4,5-oxide by high-performance liquid chromatography. 272 67

Testicular toxicants have become of increasing importance necessitating a better understanding of the possible role of testicular xenobiotic metabolism. The responsiveness of testicular microsomal epoxide hydrolase (mEH), cytosolic epoxide hydrolase (cEH), and cytosolic glutathione S-transferase (cGST) to hepatic inducers was studied in sexually mature male F344 rats and CD-1 mice. The hepatic inducers employed were phenobarbital (PB), beta-naphthoflavone (BNF), and butylated hydroxyanisole (BHA) which are known to induce cytochrome P-450, cytochrome P-448, and cGST, respectively. Hepatic mEH, cEH and cGST activities were assessed as positive controls. Measurable activities of all enzymes studied were present in the testes of both rats and mice. PB, BNF, and BHA produced the expected effects on mEH, cEH, and cGST in rat and mouse livers, whereas the testes were generally nonresponsive to the inducers. Induction of testicular cGST by PB occurred in mice but not rats and was the only testicular effect produced by the hepatic inducers in this study.
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PMID:Effects of hepatic inducers on testicular epoxide-metabolizing enzymes in the rat and mouse. 273 60

1. The effects of dietary clofibrate (0.5%, w/w, for 10 days) on seven inbred strains of mice--C57BL/6, C57BL/B10A(5R), ATL/OLA, C3H/HE/OLA, BALB/C, CBA/CA and A/J/OLA--and three strains of rats--Sprague-Dawley, Wistar and LOU/OLA--have been investigated. Liver weight, peroxisome proliferation, catalase activity, cytosolic, microsomal and mitochondrial epoxide hydrolase activities, cytochrome oxidase activity, microsomal cytochrome P-450 content and cytosolic glutathione transferase activity in liver were determined, together with cytosolic and microsomal epoxide hydrolase and cytosolic glutathione transferase activities in the kidneys. 2. In all cases peroxisome proliferation and induction of cytosolic epoxide hydrolase were observed in livers of rodents exposed to clofibrate. Thus, no non-responsive strains were found and further evidence for a coupling between these two phenomena was provided. In many cases significant increases in the liver microsomal cytochrome P-450 content and decreases in the hepatic cytosolic glutathione transferase activity were also seen. 3. High levels of cytosolic epoxide hydrolase were found in the rat kidney. In several strains of mice and rats renal cytosolic epoxide hydrolase activity was increased by clofibrate. 4. There were often considerable strain differences. However, in general mice had higher cytosolic epoxide hydrolase and glutathione transferase activities, whereas rats had higher microsomal epoxide hydrolase activities.
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PMID:Proliferation of peroxisomes and induction of cytosolic and microsomal epoxide hydrolases in different strains of mice and rats after dietary treatment with clofibrate. 281 29

When mice were exposed to 1% 2-ethylhexanoic acid in the diet, cytosolic and microsomal epoxide hydrolase (EC 3.3.2.3) activities were increased maximally (2-2.5- and 0.5-1-fold, respectively) after 3 days. Immunochemical quantitation of these enzymes indicated that the process involved was a true induction in both cases. Maximal levels of peroxisome proliferation (as indicated by carnitine acetyltransferase activity) were obtained after 7 days of exposure. All three of these activities returned to control levels within 4 days after termination of the treatment. The liver somatic index was slightly increased after 4 days of administration of 1% 2-ethylhexanoic acid, but the protein contents of the "mitochondrial," microsomal, and cytosolic fractions were unaffected. The activity of peroxisomal palmitoyl-CoA beta-oxidation was increased 2-fold, whereas peroxisomal catalase activity was unaffected. Exposure to 2-ethylhexanoic acid also increased cytochrome oxidase activity, suggesting an effect on mitochondria. Other parameters of detoxication--i.e. total microsomal cytochrome P-450 content, cytosolic glutathione transferase activity toward 1-chloro-2,4-dinitrobenzene, and the "cytosolic" epoxide hydrolase activity localized in the "mitochondrial" fraction--were not affected by 4 days of treatment with 1% 2-ethylhexanoic acid.
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PMID:Characterization of the induction of cytosolic and microsomal epoxide hydrolases by 2-ethylhexanoic acid in mouse liver. 288 46

A previously validated small mammal trauma model, hindlimb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on two of the major hepatic enzymes of detoxification, glutathione S-transferase and epoxide hydrolase. Hepatic cytosolic glutathione S-transferase activity toward a variety of substrates showed a 26-34% decrease at 24 hr after model injury. Hepatic microsomal epoxide hydrolase activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was diminished by 53% after model trauma. Both enzymatic activities toward styrene oxide were similarly depressed. The toxicological sequelae of these derangements were illustrated by administering a dose of styrene oxide (300 mg/kg, ip) which was below the threshold dose (350 mg/kg, ip) necessary to produce hepatotoxicity in control animals. Model trauma dramatically enhanced the hepatotoxic effects of the subthreshold dose, as well as the covalent binding of labeled styrene oxide to liver proteins. These findings indicate that traumatic injury renders the animal more susceptible to agents which are detoxified by glutathione S-transferase and epoxide hydrolase. Conversely, model trauma provided almost complete protection from the hepatotoxic effects of a standard dose (200 mg/kg, ip) of bromobenzene. This protection appeared to derive from a post-traumatic alteration of cytochrome P-450 subpopulations that decreased the formation of the potentially toxic 3,4-epoxide metabolite, despite an increase in the cytochrome P-448-mediated generation of the nontoxic 2,3-epoxide. For bromobenzene, the change in cytochrome P-450-mediated activation appeared quantitatively more significant in overall toxicity than the post-traumatic depression of detoxification pathways described above, leading to decreased toxicity in vivo. For other compounds, the combination of post-traumatic influences on cytochrome P-450/P-448 activity and epoxide hydrolase/glutathione S-transferase activities could lead to markedly enhanced toxicity.
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PMID:Effects of model traumatic injury on hepatic drug metabolism in the rat. VI. Major detoxification/toxification pathways. 289 98

The expression of A and P forms of glutathione S-transferase (GST-A and P), two cytochrome P-450 isoenzymes (P-450 PB3a and P-450 MC2), microsomal epoxide hydrolase (mEHb), glucose-6-phosphate dehydrogenase (G6PD) and gamma-glutamyltranspeptidase (gamma-GT) was compared in preneoplastic liver lesions and background parenchyma of F344 rats post-treated with butylated hydroxyanisole (BHA), ethoxyquin (EQ) or acetaminophen (AAP). These latter three compounds have been shown to inhibit hepatocarcinogenesis after initial treatment with N-ethyl-N-hydroxyethylnitrosamine (EHEN) and a significant decrease in the number of enzyme-altered foci and nodules positive for GST-P, GST-A, G6PD and gamma-GT and negative for P-450 PB3a, P-450 MC2 was associated with their administration. Whereas in the foci case the decrease was most prominent for non-discrete (heterogeneous) type lesions, the results of quantitation of nodules revealed a most significant alteration in the discrete homogeneously staining population. This indicates that BHA, EQ and AAP have the potential to inhibit the growth of the phenotypically stable lesions thought most likely to be the immediate precursors of hepatocellular carcinomas. The two anti-oxidants were associated with periportal increase of all enzymes investigated, whereas AAP induced GST species and mEHb in the perivenular zone. Irrespective of slightly elevated enzyme levels in surrounding parenchyma, mEHb antibody binding levels within lesions showed a reciprocal shift from positive to negative in rats treated with BHA, EQ and AAP.
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PMID:Effect of modifying agents on the phenotypic expression of cytochrome P-450, glutathione S-transferase molecular forms, microsomal epoxide hydrolase, glucose-6-phosphate dehydrogenase and gamma-glutamyltranspeptidase in rat liver preneoplastic lesions. 289 90

The nonparenchymal cells (NPC) of the liver are primarily located along the sinusoids and therefore are the first cells to encounter blood-borne xenobiotics. To study the possible role of the NPC in the metabolism of xenobiotics, populations of NPC and parenchymal cells (PC) were prepared from rats and various xenobiotic metabolizing enzyme activities investigated. The specific activity of every enzyme studied (ethoxyresorufin deethylase, benzphetamine demethylase, glutathione transferase, UDP glucuronosyltransferase, and microsomal epoxide hydrolase) was 12 to 1000% higher in the PC than in the NPC populations and the patterns of activities between the two populations were remarkably different. The NPC demonstrated a more dramatic induction of enzyme activities in Aroclor 1254-pretreated animals than did the PC. Moreover, despite the generally lower enzyme activities, even after induction, the NPC were damaged by biologically inert xenobiotics which can be metabolized to reactive intermediates. With some compounds, the concentrations required for producing similar damage was much higher in NPC compared with PC, while with other compounds, the NPC were affected by concentrations similar to those required for cytotoxicity in PC. Therefore, the NPC may contribute to the hepatic disposition of xenobiotics and may be adversely affected by reactive intermediates formed. Because of the distinctly different pattern of xenobiotic metabolizing enzymes in the two cell populations, the exact role of the NPC in the control of reactive metabolites and the toxicity produced by them will depend on the structural elements of the xenobiotic in question.
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PMID:Xenobiotic metabolizing enzymes of rat liver nonparenchymal cells. 308 73

Xenobiotics previously characterized as selective inducers of drug-metabolizing enzymes were chosen to probe possible relationships between enzyme induction and vitamin A metabolism. Liver, kidney and serum retinol and retinyl palmitate levels were investigated in male Sprague--Dawley rats receiving a single i.p. injection of the polychlorinated biphenyls (PCBs), 2,2',5,5'-tetrachlorobiphenyl, 3,3',4,4'-tetrachlorobiphenyl or 2,2',4,4',5,5'-hexachlorobiphenyl (300 mumol/kg) or 1,1,1-trichloro-2,2-bis-(4-chlorophenyl)-ethane (DDT) (150 mumol/kg). While 2,2',5,5'-tetrachlorobiphenyl, a weak or non-inducer, and 2,2',4,4',5,5'-hexaclorobiphenyl and DDT, phenobarbital-type inducers of cytochrome P-450, led to no reduction in total vitamin A content of liver or kidney during the 7 day time-course, administration of 3,3',4,4'-tetrachlorobiphenyl, a toxic PCB and a potent 3-methylcholanthrene-type inducer of cytochrome P-450, resulted in progressively lowered liver vitamin A levels (to 40% of control values by day 7). During this time, kidney total vitamin A content increased 3-fold. The increase in kidney vitamin A (due primarily to increased retinol content) was only equal to 1/40 of total vitamin A which had disappeared from the liver. Although 3,3',4,4'-tetrachlorobiphenyl specifically induced certain drug-metabolizing enzyme activities, e.g. aryl hydrocarbon hydroxylase and UDP-glucuronosyltransferase (toward 4-nitrophenol), no highly significant correlations were found among the vitamin A levels and drug-metabolizing enzyme activities in the liver (aminopyrine N-demethylase, aryl hydrocarbon hydroxylase, aldrin epoxidase, microsomal epoxide hydrolase, UDP-glucuronosyltransferase toward 4-nitrophenol, glutathione transferase toward 1-chloro-2,4-dinitrobenzene and cytochrome P-450 content) as determined by multiple linear regression analysis.
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PMID:A time-course investigation of vitamin A levels and drug metabolizing enzyme activities in rats following a single treatment with prototypic polychlorinated biphenyls and DDT. 310 67

Exposure of rats to 1% or 3% (w/w) di(2-ethylhexyl)phosphate in the diet for five days results in two- to three-fold inductions of liver cytosolic epoxide hydrolase activity and microsomal cytochrome P-450 content. Cytochromes P-450b + e were induced 20- to 35-fold, but no increase was observed in cytochrome P-450c. Considerably smaller effects were obtained on NADPH-cytochrome c reductase, microsomal epoxide hydrolase and microsomal cytochrome b5 content, and there was no effect on cytosolic glutathione transferase activity, under the same conditions. A dramatic increase in cyanide-insensitive palmitoyl-CoA oxidation and total mitochondrial protein, together with smaller increases in total catalase and cytochrome oxidase activities, were observed after treatment with di(2-ethylhexyl)phosphate, indicating that this compound causes proliferation of both peroxisomes and mitochondria. It is suggested that the induction of cytosolic epoxide hydrolase and the proliferation of peroxisomes may be related processes.
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PMID:Induction of xenobiotic-metabolizing enzymes and peroxisome proliferation in rat liver caused by dietary exposure to di(2-ethylhexyl)phosphate. 311 Nov 7

The effect of dietary cabbage (Brassica oleracea) on the binding of aflatoxin B1 (AFB1) to hepatic DNA and on the activities of liver and intestinal microsomal and cytosolic enzymes was studied in weanling male Fischer 344 rats. Freeze-dried cabbage was fed to rats at a level of 25% in the diet for 21 days, while others received a basal diet. In the cabbage-fed group there was an 87% (P less than 0.01) reduction in the binding of AFB1 to hepatic DNA 2 hr after the ip injection of [3H]AFB1 (3 micrograms/kg). There was also a 41% (P less than 0.05) increase in liver weight expressed relative to body weight. Hepatic and intestinal glutathione S-transferase activities were significantly increased (2.1- and 2.3-fold, respectively) over those in rats fed the basal diet. Hepatic and intestinal microsomal epoxide hydrolase activities were significantly increased (2.6- and 1.4-fold, respectively) over the basal group. Intestinal aryl hydrocarbon hydroxylase (AHH) and ethoxycoumarin O-deethylase (ECD) activities were significantly increased (2.3- and 2.5-fold, respectively), over the basal group but dietary cabbage had no significant effect on hepatic AHH or ECD activities.
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PMID:The effects of dietary cabbage on xenobiotic-metabolizing enzymes and the binding of aflatoxin B1 to hepatic DNA in rats. 311 6


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