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)

Dihalomethanes are metabolized to carbon monoxide both in vivo and in vitro. The reaction is catalyzed by a hepatic microsomal cytochrome P-450 dependent mixed function oxidase system. Bioorganic mechanism studies suggest an initial oxygen insertion reaction followed by rearrangement to a formyl halide intermediate which in turn decomposes to yield carbon monoxide. In vitro studies show that 14C-dichloromethane becomes covalently bound to both microsomal protein and lipid. The similar characteristics of metabolism to carbon monoxide and covalent binding suggests that a common intermediate, perhaps the formyl halide, may be involved. Dihalomethanes are also metabolized to formaldehyde, formic acid, and inorganic halide. A glutathione transferase, located in hepatic cytosol fractions, appears to be involved. Reaction mechanism studies suggest that a S-hydroxymethyl glutathione intermediate may yield formaldehyde or be diverted via formaldehyde dehydrogenase/S-formyl glutathione hydrolase to yield formic acid. Haloforms are also metabolized in vitro to carbon monoxide by a hepatic microsomal cytochrome P-450 dependent mixed function oxidase system. This reaction is a markedly stimulated by sulfhydryl compounds.
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PMID:Metabolism of halogenated methanes and macromolecular binding. 9 15

Comparative studies of in vitro drug metabolism by hepatic and extrahepatic tissues have been complicated by the use of a single experimental tissue, few animal species, and variable experimental conditions. In an attempt to minimize these complications, liver, lung and kidney from rat, mouse, rabbit, hamster, and guinea pig were assayed for standard microsomal and soluble fraction enzymes involved in drug biotransformation. For all species, liver was the most active organ. Kidney and lung activities were usually 15%-40% of those found in liver, with kidney slightly more active than lung. No single species demonstrated total superiority in its drug-metabolizing ability, although hamster showed a large number of instances of greatest activity. The rat was a surprisingly poor representative of drug-metabolizing ability; it was superior to the other four species in less than 25% of the instances studied. All species appeared to N-demethylate aminopyrine equally except for high pulmonary and nearly absent renal activities in rabbit and high hepatic activity in hamster. Rat had the lowest level of cytochrome P-450 and low activity of NADPH-cytochrome c reductase. UDP-glucuronyltransferase activity toward the acceptors p-nitrophenol and o-aminophenol was higher in hamster and rabbit than other species. Guinea pig appeared to have the most active soluble fraction enzymes. Mouse lung and kidney had glutathione S-aryltransferase activities 10-fold greater than any other species and comparable to liver activity from rabbit and hamster.
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PMID:Comparison of in vitro drug metabolism by lung, liver, and kidney of several common laboratory species. 24 Jun 55

The present study describes the effects of tetraethyl lead on various drug metabolizing enzymes in different tissues of the rat. Tetraethyl lead was administered intraperitoneally to rats (250 mumol/kg) on two consecutive days. The animals were killed on day 3. Tetraethyl lead-treatment decreased the concentration of hepatic cytochrome P-450 (to 45 per cent of the control), the hepatic activity of aryl hydrocarbon hydroxylase (to 41 per cent of the control) and ethoxycoumarin deethylase (to 45 per cent of the control). Epoxide hydratase activity was enhanced in the liver (1.3-fold), kidney (3.3-fold), and small intestinal mucosa (4.7-fold). The activity of glutathione S-transferase decreased in the liver (to 69 per cent of the control) but increased in the kidney (1.5-fold) and small intestinal mucosa (1.7-fold). The glucuronidation of o-aminophenol was enhanced (2.2-fold) in the kidney of tetraethyl lead treated rats. It is concluded that exposure to tetraethyl lead brings about widespread changes in the ability of mammals to detoxify foreign compounds.
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PMID:Effects of tetraethyl lead on the activities of drug metabolizing enzymes in different tissues of the rat. 47 47

An in vitro assay for the determination of the activity of disopyramide-N-dealkylation was developed. This reaction was concluded to be catalyzed by the liver microsomal, cytochrome P-450 centered monooxygenase system. Phenobarbital enhanced the N-dealkylation of disopyramide four fold, and disopyramide itself 1.6 fold, whereas methylcholanthrene was without effect. Disopyramide also increased ethoxycoumarin deethylation 1.6 fold, and had a slight increasing effect on the activity of epoxide hydratase, but did not affect the activities of glutathione S-transferase or UDPglucuronosyltransferase.
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PMID:Induction of disopyramide N-dealkylation by phenobarbital and disopyramide in rat liver. 48 13

The effects of inhalation and cutaneous exposure to styrene on the drug metabolizing enzymes were studied in the rat. Rats were exposed eight hours per day, for seven successive days to 450 ppm concentration of styrene or received one cutaneous dose of styrene daily for seven consecutive days (0.5 and 3.0 g/kg). The animals were killed one day after the last dose. Styrene inhalation increased the activities of epoxide hydrase and UDPglucuronosyltransferase (4-methylumbelliferone as substrate) in liver (1.5- and 1.7-fold, respectively). Ethoxycoumarin deethylation was enhanced 1.7-fold in the kidney. The content of cytochrome P-450 in the liver and the activities of NADPH cytochrome c-reductase, benzpyrene hydroxylase and glutathione S-transferase in the liver and kidney were not altered. No changes in the enzyme activities were detected in the lung. Styrene depressed the epoxide hydrase activity in liver when administered cutaneously. No signs of enzyme induction could be seen after cutaneous administration.
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PMID:Effects of inhalation and cutaneous exposure to styrene on drug metabolizing enzymes in the rat. 62 79

The administration of trans-stilbene oxide to rats resulted in increased hepatic microsomal and nuclear epoxide hydrase (with styrene oxide (SO), benzo[a]pyrene 4,5-oxide (4,5-BP) as substrates) and aryl hydrocarbon hydroxylase (AHH) activities. Hepatic microsomal aminopyrine N-demethylase, benzphetamine N-demethylase, and ethylmorphine N-demethylase activities were also increased. These increases in microsomal enzyme activity were dose- and time-dependent (about 100% at 200 mg/kg body weight, administered for 2 consecutive days). However, only marginal increases in hepatic microsomal NADPH-cytochrome c reductase activity and cytochrome P-450 content were observed. No apparent proliferation of hepatic endoplasmic reticulum occurred in trans-stilbene oxide pretreated rats. The administration of trans-stilbene oxide has no effect on hepatic glutathione S-transferase activities (with SO or 4,5-BPO as substrates). None of the parameters were affected in pulmonary microsomes from treated rats. The in vitro addition of trans-stilbene oxide (10(-6)--10(-2) M) did not affect hepatic epoxide hydrase or glutathione S-transferase activities.
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PMID:trans-Stilbene oxide: an inducer of rat hepatic microsomal and nuclear epoxide hydrase and mixed-function oxidase activities. 69 68

Potential chemopreventive role of an Indian food additive-garam masala has been assessed through its impact on the hepatic levels of detoxication enzymes like glutathione S-transferase (GST), cytochrome b5 (cyt. b5) and cytochrome P-450 (cyt. P-450), and acid soluble sulfhydryl (-SH) content in 8-9 weeks old Swiss albino mice of either sex fed on the 0.5%, 1.0% and 1.5% (w/w) garam masala in the diet for 10 days. The data from this short term study revealed the significant but dose-independent alteration in the levels of detoxication system enzymes. The results suggest the possible chemopreventive potency of this widely used food additive by being a bifunctional inducer of detoxication system.
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PMID:Evaluation of the modulatory influence of food additive-garam masala on hepatic detoxication system. 129 78

Intoxication of male and female mice with a single dose (300 or 600 mg/kg) of 1,1,2,2-tetrachloroethane (TTCE) resulted in significant decreases in cytochrome P-450 (to 58-73% of the control) and NADPH-cytochrome (P-450) c-reductase (to 29-35% of the control) in hepatic microsomes. This was accompanied by an alteration of mixed function monooxygenases stemming from the marked reduction (to 20-64% of the control) of several oxidative activities to selected substrates towards different P-450 isozymes (classes IA1, IA2, IIB1, IIE1 and IIIA). As phase II markers, epoxide hydrolase (approximately 35% loss), UDP-glucuronosyl transferase (approximately 42% loss) and to a lesser extent glutathione S-transferase (approximately 17% loss) were all affected. Also, the activity of delta-aminolevulinic (ALA) synthetase was decreased (approximately 57% of the control). On the contrary, heme oxygenase activity was increased (up to 35%) at the maximal dose tested. The decrease of P-450-function may be explained in terms of an alteration in the rate of heme biosynthesis and degradation, provoking a loss of heme content (approximately 33%) as well as of the direct inactivation of both P-450 and reductase. Because of increasing evidence on the involvement of free radical intermediates in the case of toxicity of haloalkanes, electron spin resonance spectroscopy (ESR) spin-trapping in vivo techniques were used to characterize the possible free radical species involved in the observed liver damage. The results obtained with the spin-trap N-benzylidene-2-methylpropylamine N-oxide (phenyl t-butylnitrone, PBN) provide evidence for the formation and trapping of the CHCl2CHCl free radicals. The detection of conjugated diene signals by means of second-derivative spectrophotometry, have enabled us to show that in vivo lipid peroxidation may be one of the main mechanisms responsible for TTCE hepatotoxicity.
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PMID:On the hepatotoxicity of 1,1,2,2-tetrachloroethane. 131 68

The present study examines the effect of butylated hydroxyanisole (BHA) exposure through mother's milk on some of the hepatic xenobiotic metabolizing enzymes in the F1 offspring. Lactating Swiss albino mice received either a 0.5 or 1% BHA diet during the lactation period. The acid-soluble sulfhydryl content and activities of glutathione S-transferase and glutathione reductase increased significantly (p < 0.01) whereas the activity of glutathione peroxidase decreased significantly (p < 0.01) in the liver of pups exposed to BHA via milk. The hepatic content of cytochrome b5 increased (p < 0.01) while that of cytochrome P-450 decreased (p < 0.01) in the pups of dams which received a 1% BHA diet during lactation.
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PMID:Neonatal modulation of hepatic acid soluble sulfhydryls and xenobiotic metabolizing enzymes in suckling mice exposed translactationally to butylated hydroxyanisole. 134 Apr 32

Cytotoxicity of Adriamycin on human colon adenocarcinoma cell lines was investigated. Concentrations of Adriamycin producing 50% inhibition were very similar in HT29, Sw480, Sw620, and Sw1116 cells, whereas Caco-2 cells were relatively insensitive. As compared to the Sw1116 cell line, Caco-2 cells were also insensitive to mitoxantrone. Sensitivity to cisplatin, 5-fluorouracil, or ethacrynic acid was comparable in both cell lines. To find the mechanism for this mitoxantrone and Adriamycin resistance, several potential Adriamycin-detoxifying systems were characterized and quantified in both Sw1116 and Caco-2 cells. No dramatic differences in glutathione content and expression of both selenium dependent- and independent glutathione peroxidase, UDP-glucuronyltransferase, and cytochrome P-450 were found. However, highly significant differences in glutathione S-transferase activity were present, the expression of both class pi and class alpha glutathione S-transferases being much higher in the Caco-2 cell line. In addition, a slightly higher content of P-170 glycoprotein was present in the Caco-2 cells. These findings suggest that glutathione S-transferases, and to a lesser extent the P-170 glycoprotein, may be involved in mitoxantrone and Adriamycin resistance of Caco-2 colon carcinoma cells.
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PMID:Biochemical characterization of resistance to mitoxantrone and adriamycin in Caco-2 human colon adenocarcinoma cells: a possible role for glutathione S-transferases. 134 15


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