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 modifying potential of allyl sulfide (AS), indole-3-carbinol (I3C) and carboxyethylgermanium sesquioxide (GE) on lesion development was examined in a wide-spectrum initiation model. Groups 1-4 were treated sequentially with diethylnitrosamine (DEN) (100 mg/kg, i.p., single dose), N-methylnitrosourea (MNU) (20 mg/kg, i.p., four doses at days 2, 5, 8 and 11), and N,N-dibutylnitrosamine (DBN) (0.05% in drinking water during weeks 3 and 4). Groups 5-7 received vehicles without carcinogens during the initiation period. Group 8 served as the untreated control. After this initiating procedure, groups 2-7 were administered a diet containing 0.5% AS or I3C and 0.05% GE. All surviving animals were killed 40 weeks after the beginning of the experiment and the target organs were examined. The induction of GST-P+ hepatic foci in rats treated with carcinogens was significantly inhibited by treatment with all three compounds. AS treatment significantly decreased the incidence of hepatic hyperplastic nodules, adenoma of the lung and thyroid, and papillary or nodular hyperplasia of the urinary bladder. Administration of GE also significantly inhibited the development of hepatic nodules and adenoma of the lung and thyroid. However, I3C only inhibited the hyperplastic nodules of the liver. These results demonstrated that this multi-organ initiation model could be useful in confirming organ-specific modification potential and, in addition, the inhibitory effect of AS, I3C and GE on liver, lung, thyroid and urinary bladder carcinogenesis.
Carcinogenesis 1991 Apr
PMID:Modifying responses of allyl sulfide, indole-3-carbinol and germanium in a rat multi-organ carcinogenesis model. 201 33

Epidemiologic studies suggest that the consumption of cruciferous vegetables is associated with a reduced risk for several types of cancer including cancer of colon. Experimental studies indicate that dithiolthiones, naturally occurring substances in cruciferous vegetables, possess anticarcinogenic properties. 5-(2-Pyrazinyl)-4-methyl-1,2-dithiol-3-thione (oltipraz), a substituted dithiolthione, has been tested for its chemopreventive activity. We studied the effect of dietary oltipraz on liver and colonic mucosal enzymes and DNA adducts to evaluate the modulating role of this agent during the early period of azoxymethane (AOM)-induced carcinogenesis. At 6 weeks of age, groups of animals were fed the AIN-76A diet containing 0 and 300 ppm oltipraz. At 8 weeks of age, all of the animals except vehicle-treated animals were administered a subcutaneous injection of AOM (15 mg/kg body wt/week for 2 weeks). Animals intended for vehicle treatment were administered normal saline subcutaneously. Fifteen hours after the second AOM injection, six animals each from control oltipraz diet groups were sacrificed and liver and colonic mucosa from each animal were used for DNA adduct analysis. Animals intended for liver and colonic mucosal glutathione S-transferase, tyrosine specific protein kinase (TPK), and ornithine decarboxylase (ODC) enzyme assays were killed 5 days after the second AOM or saline injection. The results of this study indicated that dietary oltipraz significantly increased liver (P less than 0.001) and colonic mucosal (P greater than 0.05) weights, but had no effect on body weights (P greater than 0.05). In saline-treated animals, feeding of oltipraz significantly increased the cytosolic glutathione S-transferase (P less than 0.001) and ODC (P less than 0.05) activities in the liver and colon when compared with those fed the control diet. Although our unpublished results indicate an inhibitory role of oltipraz when fed during the initiation and postinitiation phases of intestinal carcinogenesis, the increased ODC activity may indicate a possible role of oltipraz in colon tumor promotion. Additional studies are indicated to test the antitumor properties of oltipraz administered during the postinitiation phases. AOM treatment significantly increased the TPK (P less than 0.0001) and ODC (P less than 0.01) activities in the liver and colon of animals fed the control diet. Dietary oltipraz significantly suppressed the AOM-induced TPK (P less than 0.001) activities in liver and colon and ODC (P less than 0.01) activity of colon. Analysis of nucleic acid bases, O6-methylguanine, and 7-methylguanine revealed that dietary oltipraz significantly (P less than 0.05) inhibited the AOM-induced adduct species. These results suggest that dietary oltipraz enhances the colonic and liver glutathione S-transferase activity and reduced the formation of DNA adducts. In addition, dietary oltipraz modulates liver and colonic ODC and TPK activities that have been shown to play a role in tumor promotion.
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PMID:Effect of oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiol-3-thione] on azoxymethane-induced biochemical changes related to early colon carcinogenesis in male F344 rats. 202 Jun 72

The time courses of induction of liver cytosolic aldehyde dehydrogenases using benzaldehyde and propionaldehyde as substrates and NADP and NAD as co-factors after i.p. and intragastric (i.g.) administration of 2-acetylaminofluorene (2-AAF), 20-methylcholanthrene (20-MC), beta-naphthoflavone (beta-NF) and benzo[alpha]pyrene (B[alpha]P) were investigated in male Wistar rats. 2-AAF did not induce the aldehyde dehydrogenase activities with any substrate:co-factor combination. The other three inducers all induced the oxidation of the aldehydes in a reversible manner. With an i.p. route of administration (one daily dose for four consecutive days) (20-MC) was the most potent inducer giving a 240-fold increase of benzaldehyde: NADP activity on the ninth day. beta-NF elevated the activity 20-fold with peak activity at day 7, while B[alpha]P gave maximal induction on day 5 with a 60-fold increase in activity over the corresponding value for normal liver. The i.g. administration resulted in a weaker but coordinated induction of activity with peak activity on the sixth day for the different inducers. The activity ratio benzaldehyde:NADP/propionaldehyde:NAD, 0.78 in normal rats, was altered in all induced states to a level close to 4. The interpretation of our work supports the hypothesis that the inducers in this respect use the same mechanisms of induction. The differences noted can be explained by variations in the exposure of the liver to the administered dose and/or by differences in receptor affinity. The inducibility of benzaldehyde:NADP aldehyde dehydrogenase in rat liver exceeds by orders of magnitude the ability of the same inducers to increase the amount of the activity of other drug metabolizing enzymes such as glutathione S-transferase, cytochrome P450 and cytochrome b5. The reversible, drug-dependent induction characterized in normal rat liver in this work differs entirely from the persistent constitutive elevation of the same enzymes in preneoplastic liver nodules.
Carcinogenesis 1991 May
PMID:Kinetics of induction of cytosolic benzaldehyde: NADP and propionaldehyde: NAD aldehyde dehydrogenase activities in rat livers from male Wistar rats. 202 38

Potential synergism between five heterocyclic amines at low doses was evaluated in a medium-term liver bioassay system for carcinogens. F344 male rats were given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and then received test compound(s) in their diet for 6 weeks beginning 2 weeks later. Control groups received DEN or test compound(s) alone. All rats were subjected to two-thirds partial hepatectomy at week 3 and killed at week 8. Compounds tested and reported positive were 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1, 150 p.p.m.), 2-aminodipyrido[1,2-a:3',2'-d]imidazole (Glu-P-2, 500 p.p.m), 2-amino-3-methylimidazo[4,5-f]quinoline (MeIQ, 300 p.p.m.), 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx, 400 p.p.m.). Groups were given each chemical at the carcinogenic dose, or 1/5 or 1/25 of this. Other groups received the five chemicals in combination, each at the 1/5 or 1/25 levels. Enhancing activity was assessed by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, the numbers being significantly increased with all chemicals at the highest dose. Trp-P-1, IQ and MeIQ also exerted positive influence even at the 1/5 dose level. Similar results were obtained regarding areas of foci at the highest dose levels, with the exception of Glu-P-2. An increase was also observed for MeIQ at the 1/5 dose. Additive or synergistic effects between the chemicals were evident in the groups given the five chemicals together at both the 1/5 and 1/25 dose levels, development of GST-P positive foic being increased over the sum totals of individual data for the 1/5 or 1/25 dose groups. Thus, carcinogenicity was predicted for all five heterocyclic amines tested in dose-dependent manner in the present system of 8 weeks duration, synergistic effects being apparent especially at the low dose level.
Carcinogenesis 1991 May
PMID:Enhancement of GST-P positive liver cell foci development by combined treatment of rats with five heterocyclic amines at low doses. 202 39

The nitrosated form of cimetidine (Tagamet), nitrosocimetidine (NC), belongs to a group of nitrosoamidines in which the mutagenic and carcinogenic properties of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-ethyl-N'-nitro-N-nitrosoguanidine (ENNG) have been studied in detail. The common mechanism of action of these compounds is that nucleophilic atoms can attack their iminocarbon, thereby leading to the formation of alkyldiazohydroxide and, subsequently of an alkylating and mutagenic diazonium ion. A competitive, non-mutagenic pathway involves denitrosation, which is strongly dependent on pH and can be enhanced by glutathione transferase. The influence of different thiols (e.g. glutathione and the L- and D-forms of N-acetylcysteine (L-NAC and D-NAC respectively] at different extra- and intracellular concentrations on the mutagenicity of these nitrosoamidines in V79 cells has been studied in the present investigation. The results demonstrate that the mutagenicity of MNNG and ENNG is highly dependent on where their reaction with thiols takes place. Thus, an increase in the intracellular glutathione level in combination with treatment with MNNG (or ENNG) in thiol-free medium elevated the mutagenicity, whereas treatment with thiols in the medium reduced mutagenicity. The mutagenicity of NC was, on the other hand, only slightly affected by increasing extra- or intracellular thiol levels. The dependence of NC-induced mutagenicity on thiols was indicated, however, by the finding that depletion of intracellular glutathione reduced this mutagenicity almost completely. The effects of treatments with thiols alone or in combination with glutathione transferases suggest that, under our assay conditions (e.g. physiological pH and thiol levels, in combination with low levels of the nitrosoamidines), no denitrosation occurs. On the contrary, our results indicate that intracellular thiols, and possibly glutathione transferases, potentiate the production of mutagenic species from these nitrosamidines.
Carcinogenesis 1991 May
PMID:Thiol-enhanced decomposition of MNNG, ENNG, and nitrosocimetidine: relationship to mutagenicity in V79 Chinese hamster cells. 202 48

In the present study, we investigated Phase I (cytochrome P450; DT-diaphorase, DTD) and Phase II (epoxide hydrolase, EH; glutathione-S-transferases, GSTs) enzymes in normal colon from patients without colorectal adenocarcinoma and in peritumoral and tumoral tissues from patients with colorectal adenocarcinoma. No significant changes in levels of cytochrome P450IIIA4 (the only P450 detectable in this tissue), EH, GSTs and DTD activity were found between normal and peritumoral tissues. In tumoral tissue, compared with peritumoral tissues, we observed significant decreases in cytochrome P450IIIA4 (-50%, P less than 0.002) and EH (-60%, P less than 0.03), no change in DTD activity and significant increases in GST pi (+40%, P less than 0.03) and total GST activity (+30%, P less than 0.01). The numerous changes observed in tumoral tissues suggest that variations in drug-metabolizing enzyme expression in colorectal adenomatous polyps could represent pretumoral markers. Moreover, a better understanding of the expression of these enzymes in tumoral tissues would help us to choose the most appropriate colon tumor cell lines for the testing of new anti-cancer drugs.
Carcinogenesis 1991 May
PMID:Drug-metabolizing enzyme expression in human normal, peritumoral and tumoral colorectal tissue samples. 202 56

The effect of changing the format of administration as well as the total dose of the promoting agent phenobarbital (PB) on the development of altered hepatic foci (AHF) was determined in an initiation-promotion protocol with female rats fed the purified AIN-76 diet. Effects on the total number of AHF and the volume percentage of liver occupied by AHF were determined for four histochemical markers, the placental form of glutathione S-transferase, gamma-glutamyl-transpeptidase canalicular ATPase, and glucose-6-phosphatase after 16 and 60 weeks of promotion with varying doses and formats of PB, as well as for a further 16-week period in which no PB was administered. At the 16-week point, animals fed 0.1% PB continuously exhibited the largest number and volume percentage of AHF, whereas rats fed 0.1% PB for 4 days followed by 10 days of no PB with continuous repetition of this pattern during the 16-week treatment period exhibited no increase in the number of AHF over control and only a slight increase in volume percentage. Rats fed a continuous repetition of 0.2% PB for 2 days followed by 12 days of no PB exhibited an intermediate increase in the number of AHF as well as the volume percentage fraction after 16 weeks of this regimen. After 60 weeks of feeding PB by these three different formats, the numbers of AHF observed in these groups were equivalent and had increased above those seen after 16 weeks of feeding. The volume percentage occupied by the AHF in these three groups was also similar, although animals receiving 0.2% PB intermittently showed a significantly lower volume percentage than animals receiving 0.1% PB continuously for 60 weeks. When animals were maintained for an additional 16 weeks without PB feeding, the numbers of AHF decreased dramatically, much more so in animals fed PB intermittently, whereas the volume percentage fraction of AHF in livers of animals receiving 0.1% PB continuously for 60 weeks almost doubled. In contrast, the volume percentage fraction of AHF in livers of animals receiving PB intermittently for 60 weeks followed by 16 weeks of no PB was slightly less. Examination of the individual size classes of AHF showed little change in their distribution at 16 and 60 weeks, but after 16 weeks of PB withdrawal (76 weeks total time), the distribution of AHF in animals that had received 0.1% PB continuously for 60 weeks exhibited a decidedly greater shift to larger AHF than animals receiving PB intermittently for the 60-week period.(ABSTRACT TRUNCATED AT 400 WORDS)
Carcinogenesis 1991 Jun
PMID:The effect of the format of administration and the total dose of phenobarbital on altered hepatic foci following initiation in female rats with diethylnitrosamine. 204 80

Dose-dependent development of pre-neoplastic liver cell foci induced by 2-acetylaminofluorene (2-AAF) was investigated in relation to cell-proliferative activity. Male F344 rats were initially given a single i.p. injection of diethylnitrosamine (DEN, 200 mg/kg) and starting 2 weeks later received diets containing 2-AAF at dose levels of 150, 100, 60, 45, 35 or 30 p.p.m., 500 p.p.m. phenobarbital (PB) or basal diet as a control for 6 weeks. Two-thirds partial hepatectomy (PH) was performed at week 3. The rats were sequentially killed from weeks 0 to 16 and liver sections were analysed by double staining for both BrdU incorporation and glutathione S-transferase placental form (GST-P) expression. 2-AAF increased numbers and areas of GST-P positive (GST-P+) foci in a dose-dependent manner, especially after PH. Proliferation of hepatocytes, as indicated by BrdU labelling indices (LI), was higher in GST-P+ foci than in surrounding hepatocytes in all 2-AAF-treated groups, even after cessation of carcinogen administration. Proliferative response of hepatocytes to PH was delayed in rats treated with the highest dose of 2-AAF in both foci and in surrounding areas possibly due to the 2-AAF toxicity. In the PB treated group, the results were similar to those for the lower dose 2-AAF-treated groups. It is concluded that the development of GST-P+ foci and cell proliferation in GST-P+ foci are directly related to 2-AAF treatment in a dose-dependent manner and the present assay system is reliable for detection of carcinogenicity of chemicals even at low doses.
Carcinogenesis 1991 Jun
PMID:Dose-dependent effects of 2-acetylaminofluorene on hepatic foci development and cell proliferation in rats. 204 5

For assessment of the carcinogenic potential and the mutagenicity of dipyrone, an antipyretic anodyne, -[(2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazol-4-yl) methylamino]-methanesulfonic acid sodium salt monohydrate, three experiments were conducted using dipyrone A produced in Japan and/or dipyrone B obtained from the Federal Republic of Germany. (i) Carcinogenic potential of dipyrone A for rat liver: 8 week old male F344 rats were pretreated with 0.01% diethylnitrosamine (DEN) in drinking water for 2 weeks and, after 1 week of resting, administered 0.4% dipyrone in drinking water, 5 days a week, for 72 weeks. After an 8 week recovery period, all surviving rats were killed at 83 weeks. Hepatocellular carcinomas developed at a higher incidence in the DEN + dipyrone group (18 of 29 rats, 62%) than in the DEN alone group (9 of 29 rats, 31%), the difference being statistically significant (P less than 0.05). No carcinogenic activity of dipyrone was demonstrated in the groups given 0.4% dipyrone for 72 weeks or 0.4% dipyrone for 25 weeks, followed by 0.05% phenobarbital (PB) for 50 weeks. However, glutathione S-transferase P positive (GST-P+) preneoplastic hepatic foci in these groups were observed at a higher incidence than in the untreated control group (P less than 0.01). (ii) Effect of dipyrone A and dipyrone B on induction of DEN-initiated GST-P+ hepatic foci in a medium-term bioassay system: 0.4% dipyrone A in drinking water and 0.57% dipyrone A or dipyrone B in powdered diet after DEN initiation had similar enhancing effects on the development of GST-P+ foci (P less than 0.001). (iii) The Ames mutation test in Salmonella: both dipyrone A and dipyrone B proved weakly mutagenic for strain TA100 in the presence or absence of S9 fraction.
Carcinogenesis 1991 Jul
PMID:Tumor promoting potential in male F344 rats and mutagenicity in Salmonella typhimurium of dipyrone. 207 Apr 86

The induction of oxidation and conjugation enzymes, the scavenging of carcinogen electrophiles, and the inhibition of aflatoxin B1 (AFB1) activation were examined as possible mechanisms of anti-carcinogenesis by indole-3-carbinol (I3C). Liver microsomal 7-ethoxycoumarin O-deethylase and 7-ethoxyresorufin O-deethylase activities were not induced significantly in rainbow trout fed diets containing 500-2000 ppm I3C for 8 days compared to trout fed the control diet. Furthermore, no detectable changes in the specific contents of cytochrome P-450 isozymes LM2 and LM4b, as measured by Western-blotting and immunoquantitation, were found in liver microsomes following dietary I3C administration. Dietary I3C had no significant effect on liver microsomal uridine diphosphate-glucuronyl-transferase activity, measured using the substrates 1-naphthol and testosterone, or on cytosolic glutathione S-transferase activity, measured using the substrate styrene oxide. The ability of I3C or its acid reaction products (RXM; generated by the reaction of I3C with HCl) to act as scavengers for the direct alkylating agent AFB1-8,9-Cl2 was examined. Addition of I3C or RXM to in vitro incubations did not inhibit the covalent binding of AFB1-8,9-Cl2 to calf thymus DNA. Kinetic analyses of microsome-mediated binding of AFB1 to DNA in vitro indicated that RXM inhibited the metabolic activation of AFB1. RXM increased the apparent Km for the AFB1-DNA binding reaction without changing the associated Vmax; the apparent Km values at 0, 3.5, 35, and 350 microM RXM were 35, 38, 66, and 86 microM for trout liver microsomes. RXM also inhibited the activation of AFB1 by rat liver microsomes, but I3C was not an effective inhibitor against AFB1-DNA binding mediated by either rat or trout liver microsomes. The results of the present study indicate that inhibition of microsome-activated AFB1 binding to DNA by I3C products may be of significant importance in I3C inhibition of hepatocarcinogenesis in trout and other species. The inhibition of carcinogen activation by I3C is contrasted with the mechanism of anti-carcinogenesis by beta-naphthoflavone, which involves induction of xenobiotic metabolizing enzymes.
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PMID:Mechanisms of anti-carcinogenesis by indole-3-carbinol. Studies of enzyme induction, electrophile-scavenging, and inhibition of aflatoxin B1 activation. 210 94


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