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)

We investigated the expression of the genes for several antioxidant and xenobiotic-detoxifying enzymes in the multidrug-resistant variant of the human breast cancer cell line MCF-7, MCF-7/Dox. MCF-7/Dox is greater than 500-fold resistant to doxorubicin by clonogenic assay. Enzyme activity determinations in the cytoplasmic compartment of MCF-7/Dox revealed a 25-fold increase in glutathione peroxidase level compared to the parent line (mean +/- SD, 10 +/- 2.8 versus 0.4 +/- 0.24 nmol/min/mg; P less than 0.005). The activity of the other major hydrogen peroxide-detoxifying enzyme, catalase, was diminished in MCF-7/Dox (2.0 +/- 0.4 versus 4.8 +/- 1.4 mumol/min/mg; P less than 0.025 compared to MCF-7). Superoxide dismutase activity did not differ between the two cell lines. The specific activity of the xenobiotic-detoxifying enzyme DT-diaphorase was 4-fold lower in MCF-7/Dox compared to MCF-7 (DT-diaphorase, 117 +/- 45 versus 509 +/- 123 nmol/min/mg; P less than 0.005). Daunorubicinol-producing carbonyl reductase activity was equal in the two lines. Northern blot analysis demonstrated a 0.9-kilobase band of glutathione peroxidase mRNA in MCF-7/Dox; no glutathione peroxidase mRNA was detected in MCF-7. A 2.4-kilobase catalase and 0.7- and 1.4-kilobase superoxide dismutase mRNAs were detectable in MCF-7/Dox and MCF-7. When normalized to 28S RNA, no difference in the mRNA levels of catalase and superoxide dismutase in MCF-7/Dox and MCF-7 could be determined. DT-diaphorase mRNAs of 1.4 and 2.7 kilobases were found in both MCF-7/Dox and MCF-7 cells. A 1.2-kilobase mRNA homologous to the putative carbonyl reductase cDNA was also easily detectable in both MCF-7 and MCF-7/Dox. The amount of mRNA for both xenobiotic-detoxifying enzymes was decreased 2- to 4-fold in the doxorubicin-resistant cells. Southern blot analysis of PstI- and MspI-restricted genomic DNA revealed no evidence for amplification or rearrangement of the glutathione peroxidase gene. These results indicate that, in addition to the previously described overexpression of anionic glutathione S-transferase in MCF-7/Dox cells, an augmented glutathione peroxidase mRNA level is the major alteration in antioxidant and xenobiotic-detoxifying enzyme expression that could contribute to doxorubicin insensitivity in these multidrug-resistant breast cancer cells.
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PMID:Antioxidant and xenobiotic-metabolizing enzyme gene expression in doxorubicin-resistant MCF-7 breast cancer cells. 240 12

The relative rates of transcription of the rat liver glutathione S-transferase Ya-Yc and Yb genes were determined in purified liver nuclei isolated at different times after phenobarbital or 3-methylcholanthrene administration. The transcriptional rates of the Ya-Yc and Yb genes were elevated approximately fivefold 8 and 6 h, respectively, after phenobarbital administration. In contrast, the transcriptional rates of the Ya-Yc genes were elevated approximately eightfold at 16 h after 3-methylcholanthrene administration, whereas the transcriptional rates of the Yb genes were elevated approximately fivefold at 6 h after the administration of this xenobiotic. The elevation in transcriptional activity of the glutathione S-transferase genes is sufficient to account for the increase in glutathione S-transferase mRNA levels determined previously by RNA blot hybridization [C. B. Pickett, C. A. Telakowski-Hopkins, G. J-F. Ding, L. Argenbright, and A. Y. H. Lu (1984) J. Biol. Chem. 259, 5182-5188]. Therefore, it appears that phenobarbital and 3-methylcholanthrene elevate the level of the rat liver glutathione S-transferases primarily by augmenting the transcriptional rates of their respective genes.
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PMID:Transcriptional regulation of rat liver glutathione S-transferase genes by phenobarbital and 3-methylcholanthrene. 241 Dec 20

Changes in body weight gain and in biochemical parameters of blood and liver were assessed in Sprague-Dawley rats after multiple oral administration of three test doses of an Alberta crude oil (ACO). Rats treated with ACO (1.25-5 ml/kg) did not show statistically significant (p greater than .05) differences from control, corn-oil treated (5 ml/kg) rats, in body weight gains, liver weight, and blood biochemical indicators of liver (alanine aminotransferase, gamma glutamyltransferase), kidney (blood urea nitrogen, creatinine), and erythrocyte (adenosine 5'-triphosphate, 2,3-diphosphoglyceric acid, reduced glutathione) cytotoxicity. Treatment with ACO, however, caused statistically significant (p less than .05) and dose-related increases from control in (1) microsomal protein and cytochrome P-450 content, and NADPH-cytochrome c reductase, aryl hydrocarbon hydroxylase (AHH), and 7-ethoxycoumarin-O-deethylase (7-ECOD) activities, and (2) cytosolic glutathione transferase activity of liver. The induction of hepatic cytochrome P-450 and xenobiotic-metabolizing enzymes in microsomes of ACO-treated rats was probably associated with dose-related changes in isozymic forms of cytochrome P-450, as evidenced by (1) appearance of a 448-nm spectral peak in microsomes of ACO-treated rats and (2) differences in the inhibition pattern of AHH and 7-ECOD activities in microsomes of control and ACO-treated rats upon treatment with metyrapone and 7,8-benzoflavone.
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PMID:Induction of hepatic cytochrome P-450 and xenobiotic metabolizing enzymes in rats gavaged with an Alberta crude oil. 257 35

1. The effect of 4,4'-methylene bis(2-chloroaniline) (MOCA), 4,4'-methylene dianiline (MDA) and 4,4'-sulphonyldianiline (Dapsone) in vivo on xenobiotic biotransformation in male rat liver was studied. 2. Treatment with MOCA or MDA but not Dapsone caused a dose-dependent increase in ethoxyresorufin O-deethylase activity and a concomitant decrease in aldrin epoxidase activity in male rats. 3. Treatment with MOCA or MDA resulted in dose-dependent increases in ethoxycoumarin O-deethylation and epoxide hydrolation, while only MOCA induced cytosolic glutathione S-transferase activity. 4. Treatment with Dapsone resulted in no changes in xenobiotic biotransformation except for the induction of aniline hydroxylation. 5. The results are consistent with the contention that there is a relationship between carcinogenic chemicals and particular alterations in the activities of biotransformation enzymes.
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PMID:Effects of mutagenic and non-mutagenic aniline derivatives on rat liver drug-metabolizing enzymes. 261 80

Female BALB/c mice were fed diets containing equimolar amounts of quercetin or its glycoside, rutin, for 5 weeks. These mice were used either in host-mediated bacterial mutation assays or as sources of hepatic microsomes. In host-mediated bacterial mutation assays using radiolabelled mutagens, the heterocyclic amines 2-amino-3,5-dimethyl[4,5-f]imidazoquinoline (MeIQ) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2) induced greater numbers of revertants in mice fed either of the flavonoid diets compared with control. Experiments using hepatic microsomes revealed that although feeding mice either flavonoid produced slight changes in some parameters of hepatic xenobiotic metabolism (mixed function oxidase and glutathione transferase activities), microsomes from quercetin-fed mice were more potent activators of both MeIQ and Trp-P-2 compared with microsomes from control or rutin-fed mice. This difference in microsomal ability may be due to the different biological availability of the two flavonoids within the gastrointestinal tract.
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PMID:Modification of in vivo heterocyclic amine genotoxicity by dietary flavonoids. 268 31

The effects of dietary Brussels sprouts and indole-3-carbinol (I3C) on xenobiotic-metabolizing enzyme activities and hepatic aflatoxin B1 (AFB1)-DNA binding were determined in rats. Animals were dosed intraperitoneally (i.p.) or intragastrically (i.g.) with [3H]AFB1 and killed 2 (i.p.) or 3 (i.g.) h later. Brussels sprouts caused a significant (P less than 0.01) 50-60% decrease in hepatic AFB1-DNA binding, and increased hepatic and intestinal glutathione S-transferase (GST) activities. Hepatic mono-oxygenase (AHH and ECD) activities were not altered in sprouts-fed rats, but greater than 2-fold increases in intestinal AHH and ECD activities were found. Although I3C increased intestinal AHH and ECD activities similarly to Brussels sprouts, I3C did not significantly decrease AFB1 binding, nor did it increase hepatic or intestinal GST activity. Route of administration did not alter the percentage inhibition of binding in comparison to control rats in either treatment group, suggesting that the small intestine may not play a significant role in the metabolism of AFB1. In a second experiment, rats were dosed either i.p. or i.g. with [3H]AFB1 and killed 2, 6, 12, 24 or 48 h later. Hepatic AFB1-DNA binding and tissue radioactivity levels were determined. Brussels sprouts once again significantly (P less than 0.001) decreased hepatic AFB1-DNA binding. Route of administration of the carcinogen did not affect DNA binding over time in sprouts-fed animals, confirming our previous results.
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PMID:Effect of diet and route of administration on the DNA binding of aflatoxin B1 in the rat. 270 10

The effect of fly ash inhalation on xenobiotic metabolizing enzymes and heme metabolism in lung and liver has been studied in rats. Fly ash inhalation induced pulmonary and hepatic cytochrome P-450 content, aryl hydrocarbon hydroxylase and glutathione S-transferase activity. Induction of cytochrome P-450 was accompanied by induction of delta-amino levulinic acid synthetase in lung and inhibition of heme oxygenase in both lung and liver. Fly ash inhalation induced those species of cytochrome P-450 which closely resembled cytochrome P-448 in spectral properties and electrophoretic mobility.
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PMID:Induction of pulmonary and hepatic cytochrome P-450 species by coal fly ash inhalation in rats. 272 10

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

Nonoxidative alcohol metabolism to form fatty acid ethyl esters contributes to alcohol-related end-organ damage, and these products are formed by two synthase enzymes. We recently purified the major (pI 4.9) synthase from human myocardium. The N-terminal sequence (A P Y T V V Y F P V R G R X K A L R M L X A D) is greater than 73% identical with that of a neutral (pI 6.7) detoxification enzyme, glutathione transferase P from rat hepatocellular carcinoma (P P Y T I V Y F P V R G R C E A T R M L L A D). Moreover, both the major human fatty acid ethyl ester synthase and bovine liver glutathione transferase catalyze the formation of fatty acid ethyl esters (Vmax 105 and 98 nmol per hr per mg, respectively). In addition, both enzymes catalyze the formation of glutathione-xenobiotic conjugates (Vmax 67 and 335 mol per hr per mol of enzyme, respectively). Physiological concentrations of glutathione increase the rate of formation of fatty acid ethyl esters up to 5-fold, and the glutathione transferase substrate 1-chloro-2,4-dinitrobenzene is a potent inhibitor of human myocardial fatty acid ethyl ester synthase. Thus, the identification of the major form of human myocardial fatty acid ethyl ester synthase as an acidic glutathione transferase links alcohol and xenobiotic metabolism and may relate the enhancement of tumorigenesis by alcohol abuse with carcinogen-conjugation reactions.
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PMID:Metabolism of ethanol and carcinogens by glutathione transferases. 273 99

There is a varied distribution of airway epithelia throughout the respiratory tract that may explain the apparent differential susceptibility of respiratory tract tissues to carcinogens. The objective of this research was to characterize the distribution of xenobiotic metabolizing enzymes in the respiratory tract of the dog and to determine if regional variances in metabolic capability are associated with morphologic differences of surface epithelium among airways. Specific regions from one-half of the nasal, tracheal, bronchial, and pulmonary airways were excised and analyzed for the presence of xenobiotic metabolizing enzymes. Complementary halves of airways were fixed and processed for light microscopy. Substrates for different isozymes of cytochrome P-450, including benzo(a)pyrene, nitropyrene, ethoxycoumarin, and ethoxyresorufin and select Phase II enzymes were measured. The data for benzo(a)pyrene and nitropyrene were qualitatively similar in that there was high metabolic activity in certain regions of the nasal tissue (e.g. ethmoid turbinates) and in the intrapulmonary airway generations 3-18 compared with the major conducting airways (e.g. larynx, trachea, and bronchi). Most ethoxycoumarin O-deethylase activity was in the nasal region with much less activity observed in the major airways or the pulmonary airways. The specific activity of ethoxycoumarin O-deethylase in the ethmoid turbinates was, in general, 5-10 times that observed for the other portions of the nasal cavity sampled. Only the ethmoid turbinates showed evidence of ethoxyresorufin metabolism. Both epoxide hydrolase and glutathione transferase activity was higher in the various tissues of the nasal cavity and in the pulmonary airways compared with the major conducting airways. UDP-glucuronyltransferase was relatively evenly distributed throughout the respiratory tract.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regional distribution of xenobiotic metabolizing enzymes in respiratory airways of dogs. 289 39


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