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)

1. The inductive effect of N-benzylimidazole (NBI) on hepatic microsomal and cytosolic drug-metabolizing enzyme activities in aryl hydrocarbon (Ah)-responsive C57BL/6N (B6) and Ah-non-responsive DBA/2N (D2) mouse strains was determined and compared with that caused by beta-naphthoflavone (BNF). 2. Relative Ah-responsiveness of the two strains was confirmed by measurement of BNF-induced ethoxyresorufin deethylase (EROD) activity and ELISA immunoquantification. BNF markedly induced EROD activity only in the Ah-responsive B6 mouse strain (65-fold increase). 3. NBI (150 mg/kg per day for 3 days) increased cytochrome P450 concentration similarly in both strains (40 and 60% in B6 and D2 strains, respectively). Compared with BNF treatment of the B6 strain, increases in EROD activity following NBI treatment were only minor. In addition, EROD activity increases were greater in the Ah-nonresponsive D2 strain (300%) than in the Ah-responsive B6 strain (100%) suggesting the possibility of an induction mechanism different from that of recognized Ah receptor agonists. 4. Induction of UDP-glucuronosyltransferase activity (p-nitrophenol acceptor) by BNF was greater in the Ah-responsive B6 strain than in the Ah-non-responsive D2 strain. NBI failed to induce this activity in either strain. 5. Induction of glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene following NBI treatment occurred to the same extent (25% increase) as that seen following BNF treatment, in the Ah-responsive B6 strain. Neither xenobiotic affected this activity in the Ah-non-responsive D2 strain. 6. Although NBI is a major inducer, possessing Ah-like inducing properties in rat, it caused only minor changes in murine drug metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:N-benzylimidazole-mediated changes in hepatic drug-metabolizing enzyme activities in Ah-responsive and Ah-non-responsive mice. 149 85

Liver cytosol from mice fed on a normal diet contains Alpha-class glutathione S-transferase (GST) subunits of Mr 25,800, Mu-class GST subunits of Mr 26,400 and Pi-class GST subunits of Mr 24,800. Feeding female mice with a diet containing the anticarcinogenic antioxidant butylated hydroxyanisole (BHA) causes induction of the constitutively expressed Mu-class and Pi-class subunits. BHA also induces an Alpha-class GST comprising subunits of Mr 25,600, which is not expressed at detectable levels in normal mouse liver [McLellan & Hayes (1989) Biochem. J. 263, 393-402]. Data are now presented that show that administration of the anticarcinogen beta-naphthoflavone (BNF), like BHA, induces the Alpha-class 25,600-Mr subunits but not the constitutive Alpha-class GST with subunits of Mr 25,800. The effects of BNF on expression of hepatic GST were studied in both DBA/2 and C57BL/6 mice; these studies revealed a preferential induction of the Alpha-class 25,600-Mr subunits and of the Pi-class 24,800-Mr subunits in those mice in possession of a functional Ah receptor. The BHA/BNF-inducible Alpha-class GST can be resolved into two separate, non-interconvertible peaks by reverse-phase h.p.l.c. Automated amino acid sequence analysis of CNBr-derived peptides from each of these h.p.l.c.-purified peaks showed that the peaks contained at least two very similar subunits. These have been named Ya1 and Ya2. The amino acid sequence of the Ya1 subunit was compared with sequences deduced from a genomic clone, lambda mYa1 (Daniel, Sharon, Tichauer & Sarid (1987) DNA 6, 317-324], and a cDNA clone, pGT41 [Pearson, Reinhart, Sisk, Anderson & Adler (1988) J. Biol. Chem. 263, 13324-13332]. Our data suggest that the Ya1 subunit represents the subunit encoded by the genomic clone, lambda mYa1. Sequence analysis of the constitutive Alpha-class Ya3 subunit (Mr 25,800) shows that, although it is a member of the same gene family as the Ya1 and Ya2 subunits, it represents a distinct sub-family of Alpha-class GST, containing subunits that are more similar to rat Yc. Our data indicate that, of these Alpha-class GST subunits, the two with Mr 25,600 (Ya1 and Ya2) are selectively induced by BHA or BNF in mouse liver; neither BHA nor BNF induces significantly the GST subunit with Mr 25,800 (Ya3).
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PMID:Regulation of mouse glutathione S-transferases by chemoprotectors. Molecular evidence for the existence of three distinct alpha-class glutathione S-transferase subunits, Ya1, Ya2, and Ya3, in mouse liver. 204 74

We have identified previously a xenobiotic-responsive element, which we termed the beta-naphthoflavone-responsive element, between nucleotide -722 and -682 in the 5'-flanking region of the rat glutathione S-transferase Ya subunit gene (Rushmore, T.H., King, R.G., Paulson, K.E., and Pickett, C.B. (1990) Proc. Natl. Acad. Sci. U.S.A. 87, 3826-3830). The beta-naphthoflavone-responsive element is responsible for part of the transcriptional activation of the Ya subunit gene by planar aromatic compounds but has a sequence distinct from the xenobiotic-responsive element found in multiple copies in the cytochrome P-450 IA1 gene and as a single copy in the Ya subunit gene. In the present study, we demonstrate that the beta-naphthoflavone-responsive element is required for the transcriptional activation of the Ya subunit gene by phenolic antioxidants such as t-butylhydroquinone through a mechanism that does not require functional Ah receptors. Furthermore, we present evidence that planar aromatic compounds must be metabolized before they transcriptionally activate the Ya subunit gene through the beta-naphthoflavone-responsive element. The transcriptional activation of the Ya subunit gene by planar aromatic compounds requires a functional Ah receptor. These data provide evidence that transcriptional activation of the glutathione S-transferase Ya subunit gene can be mediated by a novel xenobiotic-responsive element which is directly responsive to phenolic antioxidants such as t-butylhydroquinone. Hence we have named this new xenobiotic-responsive element the antioxidant-responsive element or ARE.
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PMID:Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. 238 73

A series of environmentally occurring nitro-polycyclic aromatic hydrocarbons (nitro-PAHs) including those containing nitro-groups oriented coplanarly to the aromatic rings, such as 1- and 3-nitrobenzo[a]pyrene (1- and 3-NBAP), 6-nitrochrysene, and 1- and 4-nitropyrene, and those with a molecular orientation of the nitro-groups perpendicular to the aromatic moieties, such as 7-nitrobenz[a]anthracene and 6-nitrobenzo[a]pyrene (6-NBAP), were used to study the induction of certain rat hepatic phase II conjugating enzymes. Effects of these two different classes of nitro-PAHs on microsomal UDP-glucuronyltransferase (UDPGT), cytosolic glutathione S-transferases (GSTs) and sulfotransferases (STs) were investigated. After three consecutive daily i.p. injections, 1- and 3-NBAP and 6-nitrochrysene significantly increased the activities of UDPGT and GST, whereas their parent PAHs did not induce UDPGT (and GST activity was also unaltered by benzo[a]pyrene). UDPGT and GST activities were also significantly increased by 1-nitropyrene. In contrast, the sulfotransferases directed to 2-naphthol were not significantly induced by any PAH or nitro-PAH when assayed at either pH 5.5 or 7.5; however, the activities of aryl STs III and IV (pH 5.5) were significantly decreased following treatment with pyrene and two nitro-compounds, 6-NBAP and 7-nitrobenz[a]anthracene, in which the nitro-group is oriented perpendicular to the aromatic moiety. These results indicate that a coplanar orientation of the nitro-group of certain nitrated PAHs facilitates the induction of hepatic phase II enzymes by these compounds in rats, and the comparable induction patterns for P450IA1, UDPGT, and GST provide further evidence supporting the coordinate regulation (through the Ah receptor) of these phase I and phase II activities.
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PMID:Effect of nitro-substitution of environmental polycyclic aromatic hydrocarbons on activities of hepatic phase II enzymes in rats. 251 57

The Ah receptor (AhR) and Ah receptor nuclear translocator (Arnt) heterodimer bind the xenobiotic-responsive element (XRE) sequence in the upstream region of the genes for some drug-metabolizing enzymes, such as P4501A1 and glutathione S-transferase Ya, to activate their transcription. This paper describes transcriptional activation domains of the AhR and Arnt as examined in vivo by DNA transfection experiments using GAL4-AhR or GAL4-Arnt chimeric plasmids and a reporter plasmid containing five GAL4 DNA binding sites. The major activation domain of Arnt was localized in a short segment of the C-terminal 34 amino acids, while the glutamine-rich domain of Arnt showed no transcriptional activity. This activation domain of Arnt could be further divided into two subdomains with some sequence similarity. Point mutation analysis of one of the subdomains revealed that bulky hydrophobic amino acids and neighboring acidic amino acids were necessary for the transcription-enhancing activity of Arnt. The C-terminal half of the AhR showed a strong transcription-stimulating activity, apparently five times as strong as that of Arnt. Further analysis of the activity revealed that the C-terminal transcriptional activity was distributed in several activation domains, one of which is rich in glutamine residues. These results indicate that the glutamine-rich domains of the AhR and Arnt function differently in the heterodimer regulatory complex. Previously, we showed that the enhancer activity of XRE was repressed by E1A proteins, especially the 12S form of E1A. Cotransfection experiments using an E1A12S expression plasmid and a GAL4-AhR or GAL4-Arnt expression plasmid demonstrated that E1A protein rather predominantly inhibited the transcriptional activity of Arnt.
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PMID:Transcriptional activation domains of the Ah receptor and Ah receptor nuclear translocator. 755 46

Induction of Phase II enzymes of the [Ah] gene battery by L-buthionine (S,R)-sulfoximine (BSO) and other agents was examined in mouse hepatoma Hepa-1c1c7 cells. BSO, a nonelectrophilic inhibitor of gamma-glutamylcysteine synthetase (GCS), is routinely used to examine the toxicological implications of GSH depletion. Exposure to BSO for 24 h produced a 75-85% depletion of GSH levels, proportional to the inhibition of GCS activity, as well as small increases in the UDP-glucuronosyltransferase (UGT, 60%) and glutathione transferase (GST, 30%) enzyme activities in Hepa-1 wild-type (wt) cells. However, for the NAD(P)H:menadione oxidoreductase (NMO1) and cytosolic aldehyde dehydrogenase class 3 (AHD4) enzyme activities, BSO produced larger increases (110% and 170%, respectively). The mechanisms of NMO1 and AHD4 induction were examined further. In Hepa-1 wt cells, NMO1 and AHD4 activities were increased by the aromatic hydrocarbon inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and by the electrophile tert-butylhydroquinone (tBHQ), known inducing agents for these enzymes. However, NMO1 and AHD4 were induced in Ah receptor nuclear translocation-defective mutant (c4) cells by BSO and tBHQ, but not by TCDD, suggesting that the induction by BSO and tBHQ is not Ah receptor-mediated. In wt cells, N-acetylcysteine produced a concentration-dependent increase in intracellular cysteine levels, but not GSH levels, in the absence or presence of BSO. Furthermore, N-acetylcysteine had no effect on NMO1 activity under any conditions examined, suggesting that GSH levels per se, rather than change in overall thiol status, might be mediating increased NMO1 activity.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Enzyme induction by L-buthionine (S,R)-sulfoximine in cultured mouse hepatoma cells. 757 30

A number of genes under the control of the arylhydrocarbon (Ah) receptor were tested for the effects of glucocorticoids on their expression in cultured primary rat hepatocytes. Treatment of cultured hepatocytes with 1.0 microM dexamethasone potentiated the induction (2- to 3-fold) of cytochrome P4501A1, glutathione S-transferase Ya subunit (GSTYa), and UDP-glucuronosyltransferase gene expression by polycyclic aromatic hydrocarbons (PAH), whereas the glucocorticoid agonist suppressed PAH induction of NAD(P)H:quinone oxidoreductase (QOR) subunit and aldehyde dehydrogenase 3C gene expression by 60-80%. These results were seen at the level of enzyme activity for induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin and at the level of enzyme activity, protein, and specific mRNA for induction by 1,2-benzanthracene. Two of these rat genes, GSTYa and QOR are also induced by electrophilic agents, such as t-butylhydroquinone. In the presence of t-butylhydroquinone, dexamethasone caused a similar level of potentiation of GSTYa subunit expression and suppression of QOR subunit expression as was seen with the PAH, 1,2-benzanthracene. Studies using the glucocorticoid receptor antagonist, RU38486, demonstrated that the modulation of PAH induction by glucocorticoids of cytochrome P4501A1 and QOR activity is apparently dependent on action of the glucocorticoid receptor. These results suggest that the positive and negative changes observed are the result of specific alterations in the rates of transcription of these genes because of the action of the glucocorticoid receptor, thereby affecting regulation of GSTYa and QOR by both Ah receptor-dependent and independent mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes. 758 46

Wild-type MCF-7 human breast cancer cells were cultured for 3 months in 1 microM benzo[a]pyrene (BaP), and resistant clones were screened for inducibility of CYP1A1 gene expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). One of the BaP-resistant (BaPR) clones exhibited unique genotypic expression which distinguished it from both wild-type and drug-resistant (AdrR) variant MCF-7 cells. Glutathione levels, glutathione S-transferase activities, estrogen receptor levels, estrogen responsiveness, and expression of the multidrug-resistant MDR1 and MRP mRNA levels were similar in the wild-type and BaPR cells, whereas these parameters were reported to be altered in AdrR cells. In contrast, TCDD induced CYP1A1 gene expression and inhibited selected estrogen-induced responses in wild-type but not BaPR MCF-7 cells. Treatment of wild-type and BaPR cells with [3H]TCDD resulted in formation of the radiolabeled aryl hydrocarbon (Ah) 6 S nuclear receptor complex in both cell lines. The loss of Ah responsiveness in the BaPR variant cells correlated with the failure of the nuclear or transformed cytosolic Ah receptor complex to bind genomic dioxin-responsive elements as determined in gel retardation assays.
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PMID:Benzo[a]pyrene-resistant MCF-7 human breast cancer cells. A unique aryl hydrocarbon-nonresponsive clone. 790 15

The murine aromatic hydrocarbon ([Ah]) gene battery consists of at least six genes that code for two functionalizing (Phase I) enzymes and four non-functionalizing (Phase II) enzymes. These enzymes are induced by compounds such as aromatic hydrocarbons and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) that bind to the cytosolic Ah receptor protein. Studies in rodents indicate that certain enzymes of this battery, namely cytochrome P4501A1 (CYP1A1), UDP-glucuronosyltransferase (UGT1*06) and NAD(P)H: quinone acceptor oxidoreductase (NMO1) are induced by the synthetic antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII). The induction of [Ah] gene battery enzymes and the levels of reduced glutathione (GSH) were examined in mouse Hepa-1c1c7 hepatoma wild-type cells (wt), a CYP1A1 metabolism-deficient mutant (c37) and an Ah receptor nuclear translocation-defective mutant (c4). DHII and TCDD increased the activities of ethoxyresorufin O-deethylase, an indicator of CYP1A1 activity, as well as NMO1, UGT1*06, cytosolic aldehyde dehydrogenase class 3 and glutathione S-transferase form A1 in wt cells, but had little or no induction effect in c37 or c4 cells. DHII and TCDD differed in their effects on GSH levels; while DHII increased GSH levels 3-fold in wt, but not at all in c37 or c4 cells, TCDD had no effect on GSH levels in any cell type. However, GSH levels were enhanced in both wt and c4 cells by tert-butyl hydroquinone (TBHQ). L-Buthionine S,R-sulfoximine, an inhibitor of gamma-glutamylcysteine synthetase, prevented DHII-induced increases in wt cell GSH. The increase in GSH levels occurred after 8 h, while the induction of enzymes occurred within 4 h. The induction of the higher GSH levels in wt cells by DHII and TBHQ correlated with increases in intracellular levels of the GSH precursor thiol cysteine, as well as with increased activities of gamma-glutamylcysteine synthetase, the rate-limiting enzyme of GSH synthesis. However, TBHQ-mediated GSH increases in c4 cells were accompanied by increased gamma-glutamylcysteine synthetase activity with no change in intracellular cysteine concentration. The results suggest that DHII induction of [Ah] gene battery enzymes requires a functional Ah receptor, but not the functional gene product CYP1A1. Furthermore, metabolism, possibly via CYP1A1, appears to be required for DHII to enhance intracellular levels of cysteine and GCS activity that result in higher GSH levels.
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PMID:Regulation of [Ah] gene battery enzymes and glutathione levels by 5,10-dihydroindeno[1,2-b]indole in mouse hepatoma cell lines. 795 76

Aflatoxin B1 (AFB1), a metabolite of the grain mold Aspergillus flavus, is a potent hepatocarcinogen and widespread contaminant of human food supplies. AFB1-induced tumors or preneoplastic lesions in experimental animals can be inhibited by cotreatment with several compounds, including indole-3-carbinol (I3C), a component of cruciferous vegetables, and the well-known Ah receptor agonist beta-naphthoflavone (BNF). This study examines the influence of these two agents on the AFB1-glutathione detoxication pathway and AFB1-DNA adduction in rat liver. After 7 days of feeding approximately equally inhibitory doses of I3C (0.2%) or BNF (0.04%) alone or in combination, male Fischer 344 rats were administered [3H]AFB1 (0.5 mg/kg, 480 microCi/kg) intraperitoneally and killed 2 hr later. All three experimental diets inhibited in vivo AFB1-DNA adduction (BNF, 46%; I3C, 68%; combined, 51%). Based on Western blots using antibodies specific for the glutathione S-transferase (GST), subunit Yc2 (subunit 10) appeared to be substantially elevated by the diets containing I3C (I3C diet, 4.0-fold increase in band density; combined diet, 2.8-fold). The BNF diet appeared to elevate Yc2 to a lesser extent (2.2-fold increase in band density).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Indole-3-carbinol induces a rat liver glutathione transferase subunit (Yc2) with high activity toward aflatoxin B1 exo-epoxide. Association with reduced levels of hepatic aflatoxin-DNA adducts in vivo. 807 Mar 15


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