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)

The P450-catalyzed hydroxylation of tamoxifen to give alpha-hydroxytamoxifen [(E)-4-{4-[2-(dimethylamino)ethoxy]phenyl}-3,4-diphenyl-3-buten-2- ol] and subsequent formation of reactive sulfate esters which alkylate DNA has been proposed to be a potential carcinogenic pathway for tamoxifen. In the present study, the ability of alpha-hydroxytamoxifen analogs to form GSH and sulfate conjugates was investigated in order to understand the structural features influencing reactivity. The para oxo analogs 1 [1-(4-methoxyphenyl)-3-hydroxy-1-butene], 2 [1-(4-hydroxyphenyl)-3-hydroxy-1-butene], and 4 [1-(4-hydroxyphenyl)-1-phenyl-3-hydroxy-1-butene] reacted with GSH instantaneously under strong acidic conditions to yield GSH conjugates in greater than 90% yields. Interestingly, the meta phenolic analogs 3 [1-(3-hydroxyphenyl)-3-hydroxy-1-butene] and 5 [1-(3-hydroxyphenyl)-1-phenyl-3-hydroxy-1-butene] did not react with GSH to any significant extent under similar conditions. Characterization of the GSH conjugates with 1H-NMR, electrospray mass spectrometry, and UV showed that all of the conjugates resulted from attack of GSH at the alpha-position of the substrates with displacement of the hydroxyl group. The formation of a single pair of diastereomeric conjugates strongly supported adduct formation to proceed through a direct S(N)2 displacement mechanism and not through a quinone methide (4-alkyl-2,5-cyclohexadien-1-one) intermediate. At physiological pH and temperature only the para hydroxy analogs 2 and 4 gave GSH conjugates, a reaction which seems to be catalyzed by isoforms of glutathione S-transferase. Similar substituent effects were observed in the sulfotransferase-mediated formation of alpha-hydroxy sulfate esters in that only the para hydroxy analogs formed conjugates at the aliphatic hydroxyl group. Finally, the present investigation showed a remarkable difference in the reactivities of para and meta phenolic analogs of alpha-hydroxybutenylbenzenes toward GSH and sulfate conjugation reactions.
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PMID:Oxo substituents markedly alter the phase II metabolism of alpha-hydroxybutenylbenzenes: models probing the bioactivation mechanisms of tamoxifen. 928 38

Monensin, a polyether ionophore antibiotic used worldwide for its anticoccidial and growth-promoting properties, is reported to act as anin vivo inducer or inhibitor of drug-metabolizing enzyme systems in various species according to dosage regimens and duration of exposure. When incubated at a concentration up to 0.25 mM with hepatic subfractions from either untreated- (UT) or phenobarbital- (PB) induced rats, monensin did not induce appreciable changes in cytochrome P450 content and functions as well as in NADPH cytochrome c reductase or glutathione S-transferase. On the other hand, monensin concentrations ranging from 0.05 to 0.25 mM proved to increase the initial rate of NADPH oxidation up to 63% in UT-microsomes, and the in vitro addition of the ionophore to microsomes resulted in the formation of a characteristic type I binding spectrum. The rate of monensin O-demethylation was 0.34+/-0. 01 and 0.99+/-0.07 nmol min-1 per mg of protein in UT- and PB-microsomes, respectively. In the latter, this reaction was consistently depressed when NADPH was omitted or replaced with NADH, or upon the addition of 1 mM metyrapone, a known P450 inhibitor. It is concluded that monensin does not behave as a direct in vitro inhibitor of drug metabolizing enzymes and appears to be a substrate of P450-dependent monooxygenases.
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PMID:'In vitro' interactions of monensin with hepatic xenobiotic metabolizing enzymes. 936 71

Plant foods contain numerous non-nutritive substances which exert biological activity. Most attention has been focused on the anticarcinogenic effects of these compounds. Many of the mechanisms involved include induction or inhibition of biotransformation enzymes. Each individual has its own isoenzyme pattern for the various drug-metabolizing enzymes. The multiplicity of these enzymes results in differential responses to dietary constituents. A substance may increase the level of a certain P450, and decrease the level of another. Although this complicates matters considerably, it also offers the possibility of specifically influencing biotransformation directed at a particular compound, e.g., a cytostatic agent. Using the important class of the glutathione S-transferase (GST) as an example, the various phenotypic and genetic origins of interindividual variation are described. Genetic variation is especially important for the mu and thetra class enzymes. The induction of individual isoenzymes of the GST has been studied in man rat. It was shown that the changes in the GST isoenzyme pattern induced by Brussels sprouts in rat liver and intestine were very similar to that caused by administration of ally isothiocyanate, and not to that resulting from goitrin. In man Brussels sprouts led to induction of GST alpha only. A number of naturally occurring catechols, or more likely the quinones derived from them, are effective irreversible inhibitors of GST. Eugenol, for instance, lowers GST activity in man. A second class of compounds which shows promise are alpha, beta-unsaturated aldehydes and ketones. A number of naturally occurring representatives of this class inhibit GST pi irreversibly, and ethacrynic acid, a drug with a similar reactive moiety in its structure, has already been shown to be quite useful to inhibit GST activity in cellular systems. Several approaches for future studies on the effects of dietary constituents are indicated: 1) further studies on the mechanisms of induction and inhibition of biotransformation enzymes: 2) careful studies using human volunteers, where the effects can be studied in isolation as much as possible; 3) studies of the disposition and kinetics of the dietary constituents themselves, to assess the relevance of inducing agents in food for the day-to-day human situation.
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PMID:Influence of non-nutrient plant components on biotransformation enzymes. 943 24

The effects of acriflavine (ACF), a protein kinase C inhibitor, on the expression of hepatic microsomal epoxide hydrolase (mEH), glutathione S-transferases (GSTs), and cytochrome P450 (P450) were assessed in rat hepatic tissue. Northern blot analysis revealed that treatment of rats with thiazole, allyl disulfide (ADS), oltipraz, or clotrimazole at a single dose of 100 mg/kg resulted in 7-18-fold increases in mEH mRNA levels at 24 hr, whereas concomitant ACF treatment (20 mg/kg, im) caused 50-95% inhibition of the chemical-induced increases in hepatic mEH mRNA levels. rGSTA2, rGSTA3, and rGSTM1 mRNA levels were also significantly suppressed at 24 hr in response to a single dose of ACF (20 mg/kg, im). Animals treated with both ACF and ADS showed complete blockage of mEH and GST gene expression as early as 12 hr after treatment. ADS-inducible increases in mEH and rGSTA2 mRNA levels were suppressed at 24 hr after treatment with ACF, in a dose-related manner, with 50% inhibitory dose (ID50) values of 2.0-2.3 mg/kg, whereas glyceraldehyde-3-phosphate dehydrogenase mRNA levels were not altered. Immunoblot analysis revealed that ACF (15 mg/kg/day, im, for 3 days) inhibited induction of mEH or rGSTA2 protein by ADS (100 mg/kg/day, po, for 3 days). The levels of hepatic P450 2B1/2, P450 2C11, and P450 3A1/2 were decreased in rats treated with ACF (15 mg/kg/day, im, for 3 days), whereas P450 1A2 and P450 2E1 expression was not affected. Treatment of rats with ACF in combination with gadolinium chloride, which inhibits mEH and GST expression through calcium channel blocking, shifted the dose-inhibitory response curves for ACF to the left, with 7-15-fold decreases in the ID50 values, indicating that the active site for ACF for suppression of mEH and GST mRNA levels differs from that for gadolinium chloride. Proflavine and safranine O, which are structurally related to ACF, also caused suppression of ADS-induced increases in mRNA levels, in a dose-dependent manner, with ID50 values of 4-9 mg/kg. These results demonstrate that ACF and its related compounds effectively suppress the expression of a battery of hepatic xenobiotic-metabolizing enzymes, including mEH, GSTs, and certain P450 forms.
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PMID:Suppression of xenobiotic-metabolizing enzyme expression in rats by acriflavine, a protein kinase C inhibitor. Effects on epoxide hydrolase, glutathione S-transferases, and cytochromes p450. 944 55

Hexachloro-1,3-butadiene (HCBD) is nephrotoxic in rats. Its toxicity is due to a multistep bioactivation pathway involving glutathione conjugation. N-Acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine resulting from further processing of the GSH conjugate of HCBD is oxidized in vitro and in vivo to the corresponding sulfoxide diastereomers by cytochromes P450 3A. N-Acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide diastereomers represent vinyl sulfoxides which are electrophiles. They are analogous to alpha,beta-unsaturated carbonyl compounds and may be conjugated with glutathione. This study presents experimental data for the different reactivity of the two diastereomers of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide with glutathione S-transferases in vitro. The structures of the individual diastereomers were assigned by stereoselective oxidation of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine with sodium periodate in the presence of chloroperoxidase. The two isolated diastereomers were incubated with rat liver and kidney cytosol in the presence of glutathione. In incubations with rat liver cytosol, the formation of a glutathione conjugate, which was identified as (R)-N-acetyl-S-(4-glutathion-S-yl-1,2,3,4-tetrachlorobutadienyl )-L-cysteine sulfoxide, was observed with the (R)-sulfoxide diastereomer. The enzymatic reaction of the (S)-sulfoxide diastereomer with glutathione resulted in two GSH conjugates identified as (S)-N-acetyl-S-(4-glutathion-S-yl-1,2,3,4-tetrachlorobutadienyl )-L-cysteine sulfoxide and (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide. In rat kidney cytosol only the S-diastereomer of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide is transformed to (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide, while transformation of the R-diastereomer to glutathione conjugates was not observed. In rat kidney cytosol, the rates of formation of (S)-N-acetyl-S-(2-glutathion-S-yl-1,3,4,4-tetrachlorobutadienyl )-L-cysteine sulfoxide from conjugation of the S-diastereomer were comparable to those in rat liver cytosol. Incubation of (S)-N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide with purified rat and human glutathione S-transferases indicates that both R- and S-diastereomers were conjugated to the corresponding 1,4-disubstituted compounds by mu-glutathione S-transferases. Formation of the 1,2-disubstituted conjugation product of N-acetyl-S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine sulfoxide was catalyzed exclusively by alpha-glutathione S-transferases. These results are one of the first examples for differences in regio- and stereospecificity in reactions catalyzed by different glutathione S-transferase enzymes.
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PMID:Stereo- and regioselective conjugation of S-halovinyl mercapturic acid sulfoxides by glutathione S-transferases. 947 21

Protein deficiency was produced by feeding synthetic 8%-protein diet. Lithium carbonate at the dose level of 1.1g/kg diet was administered to normal and protein-deficient rats for a period of one mo. A significant inhibition in the levels of cytochrome (cyt) P450, cyt b5, glutathione (GSH), glutathione S-transferase (GST) and glutathione peroxidase (GPx), but an increase in gamma-glutamyl transpeptidase (gamma-GT), was observed in low-protein LP-fed rats. Lithium treatment to normal rats caused no significant change in the activities of cyt P450, cyt b5, GST, and GSH levels, whereas there was elevation in the activities of gamma-GT and GPx and suppression in glutathione reductase (GRd) activity. Lithium administration to LP-fed rats resulted in significant increases in the hepatic gamma-GT and GPx activities.
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PMID:Effect of lithium on hepatic drug-metabolizing enzymes of protein-deficient rats. 952 58

Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study investigated the metabolism of the tobacco carcinogens N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples from China than the USA. All microsomal samples activated NDMA. However, most of the microsomal samples did not activate NNK. Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formation of NNN-derived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic-metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.
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PMID:Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus. 960 Mar 53

Male and female Sprague-Dawley rats were fed diets incorporating lyophilized chinook salmon obtained from Lake Ontario and Lake Huron. After 70 days, females were bred and the progeny (F1) were reared on the same fish-based diets as the adults (F0). After 78-133 days on the diets, males and females of both generations were sacrificed and hepatic microsomal enzyme activities determined, along with glutathione S-transferase-placental form (GSTP) expression and hepatic cellular proliferation. Hepatic P450 enzyme activities (MROD, EROD, PROD, BROD, and aminopyrine) were increased significantly by fish diets from both sources. Increases in hepatic enzyme activity were greatest for fish caught from Lake Ontario and reflected the total levels of organochlorine contaminants in the fish. GSTP and cell proliferation rates did not show any diet-related or dose-related changes. Vitamin A stores were analyzed as the concentration of liver retinyl palmitate. In rats receiving the highest TEQ dose (i.e., 20% Lake Ontario fish diet), vitamin A stores were significantly lower in F0 adults, F1 weanlings, and F1 adult females.
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PMID:Microsomal enzyme activity, glutathione S-transferase-placental form expression, cell proliferation, and vitamin A stores in livers of rats consuming Great Lakes salmon. 961 36

Most carcinogens and xenobiotics are metabolized primarily by the mixed function oxidase system which includes cytochrome P450, cytochrome b5, NADPH-cytochrome c reductase and aryl hydrocarbon [benzo(a)pyrene] hydroxylase. The present study investigates the influence of infection with different levels of Schistosoma mansoni cercariae on the hepatic levels of reduced glutathione, glutathione S-transferase and glutathione reductase in addition to the enzymes of mixed function oxidase. Cercariae infection levels of 60, 120, 180, 300 and 600 per mouse increased: (i) the hepatic content of cytochrome P450 by 27%, 38%, 72%, 57%, 48% respectively; (ii) the aryl hydrocarbon hydroxylase activity by 44%, 64%, 76%, 90%, 51% respectively; and (iii) the hepatic level of reduced glutathione by 67%, 83%, 103%, 60%, 38% respectively. The cytochrome b5 content did not change at the lowest level of infection but increased at the other four levels by 45%, 76%, 49% and 38% respectively. The activity of glutathione S-transferase increased at the first three levels by 42%, 40%, 27% respectively and decreased at the last two levels by 28% and 52% respectively. On the other hand, the activity of glutathione reductase did not change at any level, whereas, NADPH-cytochrome c reductase activity decreased at the last two levels by 44% and 54%. The alterations in the activities of phase I & II of drug-metabolizing enzymes as a result of infection with different levels of S. mansoni may thus change the liver's capacity to detoxify many endogenous compounds and may also potentiate the deleterious effects of aromatic hydrocarbons, e.g. benzo(a)pyrene, upon the liver and probably other organs. Such alterations may also change the therapeutic actions of drugs that are primarily metabolized by the P450 system, when administered to patients with schistosomiasis.
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PMID:Different levels of Schistosoma mansoni infection induce changes in drug-metabolizing enzymes. 963 5

Induction mode of the hepatic drug-metabolizing enzymes was studied in Corn snake (Elaphe guttata emoryi). Treatment of snakes with 3-methylcholanthrene or phenobarbital produced no effects on liver weight and total content of cytochromes P450 and b5. Treatment with 3-methylcholanthrene significantly induced the activities of arylhydrocarbon hydroxylase, 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-dealkylase, whereas those of ethoxycoumarin O-deethylase, benzphetamine N-demethylase, erythromycin N-demethylase and testosterone hydroxylases were not affected. 3-Methylcholanthrene-induced activities of 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-dealkylase were inhibited by 20 microM alpha-naphthoflavone by 98% and 73%, respectively. Phenobarbital-treatment caused a significant induction of the activities of erythromycin N-demethylase and testosterone 6 beta-hydroxylase, but did not affect those of the other phase I enzymes and the other testosterone hydroxylases. The activities of UDP-glucuronyltransferase and glutathione S-transferase were not affected by either 3-methylcholanthrene or phenobarbital administration. Immunoblotting showed that 3-methylcholanthrene-treatment induced a protein band related to hamster CYP1A2, and decreased the intensity of the two bands detected with anti-rat CYP2B1. Phenobarbital-treatment did not affect the intensity of CYP2B-related proteins. The results suggest that snake liver has multiple forms of cytochrome P450, notably those inducible by 3-methylcholanthrene.
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PMID:Modulation of snake hepatic cytochrome P450 by 3-methylcholanthrene and phenobarbital. 966 83


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