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)

Male mice were treated (i.p.) for 3 days with 15 different environmentally encountered epoxides, and the effects of these compounds on liver microsomal and cytosolic epoxide hydrolase (mEH and cEH), glutathione S-transferase (mGST and cGST) and carboxylesterase (mCE) activities were determined. The epoxides included the pesticides: heptachlor epoxide, dieldrin, tridiphane, and juvenoid R-20458; the natural products: disparlure, limonin, nomilin, and epoxymethyloleate; the endogenous steroids: lanosterol epoxide, cholesterol-alpha-epoxide, and progesterone epoxide; and the industrial or synthetic epoxides: epichlorohydrin, araldite, trans-stilbene oxide, and 4'-phenylchalcone oxide. The pesticide epoxides were the most effective inducers of liver weight, microsomal protein, and the enzyme activities measured, with mEH and cEH activities towards cis-stilbene oxide (mEHcso and cEHcso), cGST activities towards four of five substrates, and mCE towards clofibrate (mCEclof) and p-nitrophenylacetate (mCEpna) increased following treatment with most of the pesticides. The synthetic epoxides increased some of the same activities, while the natural products, except for increases in cGST activities, and endogenous steroid epoxides were generally not inductive. cEH activity towards trans-stilbene oxide (cEHtso) was increased only following treatment with the peroxisome proliferator, tridiphane, but decreased following treatment with several of the epoxides, while microsomal cholesterol epoxide hydrolase (mEHchol) was increased only moderately by disparlure. Microsomes could effectively conjugate glutathione to chlorodinitrobenzene (mGSTcdnb) and cis-stilbene oxide (mGSTcso). These two activities were differentially induced by a few of the epoxides, suggesting that they may be selective substrates for different isozymes of mGST. Correlation coefficients were determined for the relative response of liver weight, subfraction protein, and enzyme activities. A relatively high correlation was found between the response of liver weight and cytosolic hydrolysis of trans-stilbene oxide (r = 0.73) and cis-stilbene oxide (r = 0.62), and cytosolic glutathione conjugation of dichloronitrobenzene (r = 0.66) and trans-stilbene oxide (r = 0.75). In addition, relatively high correlations were found between the different cGST activities, in particular for dichloronitrobenzene with trans-stilbene oxide (r = 0.89). These studies show that there exists a wide variation in the response of xenobiotic-metabolizing enzymes to environmentally encountered epoxides and that a fairly strong correlation exists between the increases in liver size and increases in certain cytosolic enzyme activities; they also suggest further studies concerning the possibility of an additional isozyme of mGST.
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PMID:Effects of environmentally encountered epoxides on mouse liver epoxide-metabolizing enzymes. 204 52

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC) which are microsomal enzyme inducers, and methyl iodide (MeI), cobalt chloride (CoCl2) and tri-o-cresyl phosphate (TOCP) which are inhibitors of the enzymes glutathione transferase, cytochrome (cyt) P-450 and carboxylesterase, respectively, and then challenged with soman (i.p.) to know its LD50. Pretreatment with PB and MC increased and TOCP decreased, whereas MeI as well as CoCl2 did not alter the LD50 value of soman in rats. The 1/2 LD50 dose of soman did not affect the liver microsomal cyt P-450 level, but significantly lowered carboxylesterase (CaE) and cholinesterase (ChE) activities in liver microsomes and in blood plasma. Induction of plasma CaE was more important than microsomal CaE in PB-mediated protection against soman toxicity. Gel filtration of plasma into four protein fractions for their relative soman binding capacity showed that a high-molecular-weight protein fraction (180,000 daltons on SDS-PAGE) which had no CaE activity could bind soman 6 times more than the low-molecular-weight CaE-containing protein fraction (60,000 daltons on SDS-PAGE).
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PMID:Role of carboxylesterase in protection against soman toxicity. 276 74

In a chronic study by the National Toxicology Program (NTP), dimethyl hydrogen phosphite (DMHP) caused neoplastic and nonneoplastic changes in the lungs and forestomach of F344/N rats following gavage administration for 2 years. The current investigation was designed to study the effect of a short-term exposure on a series of biochemical systems in target and nontarget tissues which may be involved in the metabolism and/or the manifestation of DMHP toxicity. Rats were treated daily with a dose similar to that used in the NTP study (200 mg/kg) for 4, 5, or 6 weeks. Two groups of animals were also treated for 4 weeks and then treatment was discontinued and the rats were allowed to recover for 1 or 2 weeks. An equal number of animals was treated similarly with the vehicle and used as control. The microsomal and soluble fractions were separated from liver, lungs, kidneys, forestomach, and glandular stomach from the 6-week treatment group. Another group of rats treated for 6 weeks was prepared for pathology examination of the lungs, forestomach, and glandular stomach. There was a significant increase in the weight of the forestomach of rats treated for 4, 5, or 6 weeks relative to control animals, while no significant difference was observed in the weight of liver, lungs, kidneys, and glandular stomach. The forestomach weight of rats treated for 4 weeks returned to the control value after 1 week of recovery. Microscopic examination of the forestomach of rats treated for 6 weeks revealed a thickened stratified squamous epithelium characterized by hyperplasia, hyperkeratosis, and subepithelial inflammation and edema. There were no microscopic changes in the lungs or glandular stomach of animals treated for 6 weeks. The activity of angiotensin converting enzyme in the serum of rats treated for 4, 5, or 6 weeks was significantly increased over that of control animals. The activity of this enzyme returned to near levels seen in the control animals after 1 week of recovery following 4 weeks of treatment. No treatment-related effect was observed in the activities of the microsomal p-nitroanisole demethylase, soluble glutathione S-transferase, and soluble superoxide dismutase in the five tissues studied. There was a significant increase in the level of nonprotein soluble sulfhydryls in the forestomach but in no other tissue of rats treated for 6 weeks. Also the activity of soluble carboxylesterase was significantly reduced in the lungs and forestomach, but not in any other tissue of the 6-week-treated rats.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pathological and biochemical effects of dimethyl hydrogen phosphite in Fischer 344 rats. 283 31

The gastrointestinal tract forms the first line of defense in the body against the main load of xenobiotics. The gastrointestinal mucosa has several mechanisms through which the xenobiotics are modified. The monooxygenase activities in most species are relatively low in the mucosa as compared to the liver, but conjugation, for example, via glucuronide formation proceeds efficiently. UDP-glucuronosyltransferase activities can exceed those in the liver. Glutathione S-transferase activity is also high. The biotransformation activities are readily inducible in the mucosa and this is, at least partly, responsible for the oral-aboral gradient seen in enzyme activities. In rainbow trout glutathione S-transferase is, however, significantly higher at the aboral third than in two oral segments, although in rats the intestinal glutathione S-transferase shows a clear oral-aboral gradient. The gradient is independent of the presence of microflora at least in the case of carboxylesterase and glutathione S-transferase. A similar gradient can also be found from the gut lumen, in both germ-free and specific pathogen-free rats. The cells in the middle of the villi appear to be most responsive under the influence of inducers. The readily occurring induction in the mucosa provides a suitable model for studies on biological effects to defined compounds and mixtures.
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PMID:Role of gut in xenobiotic metabolism. 330 15

The effect of an antigenic challenge with sheep red blood cells (SRBC) on the activities of cytochrome P-450-dependent and -independent xenobiotic metabolizing enzymes and on lipid peroxidation in the liver was investigated. The studies were carried out using three mouse strains of C57B1/10 and three strains of C3H backgrounds which are cogenic, differing genetically at the H-2 complex. The basal levels of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxycoumarin O-deethylase (7-Ec) were different among congenic strains. The activity of 7-Ec was lower in C3H background mice than in B10 background mice. Similarly, the difference due to the strain and the H-2 locus was detected in the activities of P-450-independent enzymes such as malathion and diethyl succinate carboxylesterases, glutathione S-transferase, and epoxide hydrolases in microsomal and cytosolic fractions. The degree of immune responsiveness in these mice was determined by a plaque forming cell assay. Within the same background, the H-2b mouse strain was a high responder and the H-2k a low responder to SRBC. However, treatment with SRBC had no significant depressive effect on P-450-dependent enzyme activities except in C3H/He. Activity of AHH was suppressed in C3H/He mice. Treatment with SRBC had no effect on P-450-independent enzyme activities except for malathion carboxylesterase: the activity was increased in C3H/He and C3H.JK, whereas it was decreased in B10. The basal level of lipid peroxidation was lower in C3H/He and C3H.JK. The treatment produced a significant enhancement in lipid peroxidation in C3H/He, B10 and B10.BR (P less than 0.05) with a concomitant increase in xanthine oxidase activity (P less than 0.05). Thus, the present study revealed that a specific antigenic challenge, unlike non-specific immunostimulants (e.g. poly IC, endotoxin), does not necessarily inhibit P-450-dependent xenobiotic metabolizing enzymes even though antigen challenge increased XO activity and lipid peroxidation. The possible roles of an increase in lipid peroxidation and xanthine oxidase activity in immune response to SRBC and xenobiotic metabolizing enzymes are discussed.
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PMID:Effect of induction of T-cell-dependent antibody with sheep red blood cells on P-450-dependent and -independent xenobiotic metabolizing enzymes. 348 42

The organophosphorous pesticide malathion is metabolized by three hepatic enzyme systems: the microsomal cytochrome P-450-dependent monooxygenase system, the microsomal carboxylesterases, and the cytosolic glutathione S-transferases. We produced differential induction of these three enzyme systems in mice with phenobarbital and 2(3)-tert-butyl-4-hydroxyanisole (BHA) and examined the effects of the induction on the inhibition of acetylcholinesterases by malathion. Phenobarbital not only significantly induced hepatic microsomal cytochrome P-450 (p less than 0.05) but also increased microsomal carboxylesterase activity (p less than 0.05). BHA not only increased the activity of microsomal carboxylesterases (p less than 0.05) but also substantially increased cytosolic glutathione S-transferase activity (p less than 0.05). Despite the differential effects of phenobarbital and BHA on the three enzyme systems, neither agent protected the mice against malathion toxicity.
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PMID:The effects of differential induction of cytochrome P-450, carboxylesterase and glutathione S-transferase activities on malathion toxicity in mice. 356 13

Moderate clinical, biochemical and hematologic signs of intoxication were observed in mice after single administration of HT-2 toxin (deacetylated derivative of T-2 toxin) in LD50 of 12.75 mg/kg or in 1/5 of LD50 for 7 days. The toxin produced no toxic effect when 1/10 and 1/50 of LD50 were administered for 14 days. With the dose exceeding 1/50 of LD50 a reduction in cytochrome P-450 content, carboxylesterase activity and increased activity of UDP-glucuronosyltransferase and glutathione transferase were recorded. T-2 toxin produced a more pronounced toxic effect, inhibited UDP-glucuronosyltransferase and insignificantly stimulated glutathione transferase activity. Lower HT-2 toxin toxicity is believed to depend on its ability to activate conjugation reactions to a greater extent than T-2 toxin.
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PMID:[The enzymes of the metabolism of exogenous compounds in the comparative assessment of the toxicity of trichothecene mycotoxins]. 369 91

The principal biochemical mechanisms of resistance to insecticides involve either modified, less sensitive cholinesterase, esterase action, glutathione S-transferase action or cytochrome P-450-dependent monooxygenation. Both quantitative and qualitative differences in cytochrome P-450 isozymes are under genetic control and both are related to resistance. Recent characterization studies involving ligand binding and multiplicity of isozymes in Musca domestica (the housefly) are discussed in relation to resistance. The recent demonstration that multiple isozymes of glutathione S-transferase exist in susceptible and resistant insects is of interest, and some re-examination of their role in the mechanism of resistance is required. Esterases are a heterogeneous group of enzymes whose role in resistance has often been suggested but seldom rigorously defined. Purification studies in the green rice leafhopper, Nephotettix cincticeps, have involved an enzyme with carboxylesterase, phosphotriesterase and pyrethroid esterase activities. A similar enzyme, but without pyrethroid esterase activity, is also found in the housefly. In resistance such enzymes may serve either to catalyse hydrolysis or as binding proteins. It has been suggested, from time to time, that regulator genes, enzyme induction and gene magnification all play a part in controlling biochemical mechanisms of resistance, although clearly defined evidence has not always been brought forward. These hypotheses are re-examined.
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PMID:Biochemical mechanisms of resistance to insecticides. 655 14

Non-specific carboxylesterases (carboxylesterases) and glutathione S-transferases (GSTs) are two groups of drug metabolizing enzymes responsible for hydrolysis and glutathione conjugation of xenobiotics. This study was conducted to determine the following: (1) the distribution of carboxylesterase and GST activities in different rat liver cells, (2) the effects of vitamin A deficiency (A-) on the absolute activities and on the distribution of carboxylesterases and GSTs in rat liver. Rat livers were fractionated into parenchymal and non-parenchymal cells by means of collagenase perfusion and differential centrifugation. Non-parenchymal cells were further fractionated by means of Percoll density gradient centrifugation into a layer of Kupffer cells and another layer containing stellate and endothelial cells. Carboxylesterase and GST activities were determined in these fractions. show that: (1) both carboxylesterases and GSTs were mainly localized in the parenchymal fraction, (2) there was no significant difference between male and female rats with regard total activity or distribution of carboxylesterases and GSTs in rat liver cells, (3) A- caused a highly significant reduction in carboxylesterase and GST activities in total liver homogenates and parenchymal cells. This reduction was not ameliorated by administration of retinoic acid 18 hr before sacrifice of animals. These results open up a new era of investigations about the potential role of vitamin A in the regulation of detoxification enzymes.
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PMID:The distribution of non-specific carboxylesterases and glutathione S-transferases in different rat liver cells. Effects of vitamin A deficiency. 804 15

Effects of either a single (300 mg/kg) or a subchronic (0.3 and 0.6% for 70 days) oral administration of a dithiocarbamate fungicide (zinc ethylene-bis-dithiocarbamate, zineb) on hepatic drug metabolism and on the activity of several glutathione-dependent enzymes were investigated in male New Zealand White rabbits. While a pronounced reduction in the rate of oxidative biotransformations occurred after either single or repeated exposure, both cytochrome P450 and total haem content were lowered following acute challenge to zineb. None of the experimental protocols affected microsomal carboxylesterase but induced a marked increase in glutathione content and none of the examined glutathione-dependent enzymes was altered by the single administration of zineb, whereas the subchronically exposed rabbits showed a fall in the activities of both total glutathione S-transferase and selenium-independent glutathione peroxidase. In the 0.6% treated animals, a decrease in class mu glutathione S-transferase and glyoxalase I, and an increase in thiol-transferase activities were also recorded. It is concluded that (1) zineb is able to selectively impair oxidative drug metabolism with possible different mechanism(s) according to the duration of the exposure, (2) only the subchronic treatment affects glutathione-dependent enzymes, (3) the decrease in glutathione S-transferase activity would seem to be ascribed to a direct interaction with the fungicide.
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PMID:Inhibition of hepatic xenobiotic metabolism and of glutathione-dependent enzyme activities by zinc ethylene-bis-dithiocarbamate in the rabbit. 829 52


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