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

---

Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
...
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

Programmed cell death is increasingly viewed as a key component of the hypersensitive disease resistance response of plants. The generation of reactive oxygen species (ROS) such as H2O2 triggers a cell death programme in Arabidopsis suspension cultures following challenge with the bacterial elicitor harpin. Both harpin and exogenous H2O2 initiate a cell death pathway that requires gene expression, and also act as signalling molecules to induce the expression of plant defence genes encoding enzymes such as phenylalanine ammonia-lyase (PAL), glutathione S-transferase (GST) and anthranilate synthase (ASA1), an enzyme of phytoalexin biosynthesis in Arabidopsis. H2O2 induces the expression of PAL1 and GST but not that of ASA1. Harpin initiates two signalling pathways, one leading to increased ROS generation and expression of PAL1 and GST mRNA, and another leading to increased GST and ASA1 expression, independent of H2O2.
...
PMID:Harpin and hydrogen peroxide both initiate programmed cell death but have differential effects on defence gene expression in Arabidopsis suspension cultures. 946 99

1. 2-(Allylthio)pyrazine protects the liver against acetaminophen- and carbon tetrachloride-induced injury through inhibition of cytochrome P4502E1 and induction of glutathione S-transferases (GSTs). By comparison, the effects of allylthiobenzimidazole (ATB) on the levels of several hepatic cytochrome P450, microsomal epoxide hydrolase (mEH) and GST expression have been studied in the rat herein. 2. Western immunoblotting analyses revealed that ATB treatment (50 mg/kg/day for 5 days) failed to alter cytochrome P4501A2, P4502B1/2 and P4502E1 levels in the liver, whereas the expression of P4502C11 was reduced approximately 50% by ATB. 3. Treatment of rat with a single dose of ATB resulted in 2-21-fold increases in mEH mRNA levels at 24 h with an ED50 = 60 mg/kg. mEH mRNA level was elevated 9- and 21-fold at 12 and 24 h after treatment at 200 mg/kg respectively as compared with control. Western blot analysis revealed that ATB induced mEH protein levels by 2-fold relative to control. 4. ATB induced the major GST mRNA levels as a function of dose, resulting in rGSTA2, rGSTA3/5 and rGSTM1 mRNA levels elevated by 20-, 6- and 8-fold at 24 h respectively. The relative rGSTM2 mRNA level was minimally affected. Time-course studies showed that mEH, rGSTA2 and rGSTM1 mRNA levels were significantly increased at 12 and 24 h after ATB treatment, returning to control levels by 48 h. Treatment of rat with ATB (20-50 mg/kg/day for 5 days) resulted in 2-3-fold increases in mEH, rGSTA1/2, rGSTA3/5 and rGSTM1 mRNA levels with the induction of GST subunits. 5. ATB failed to block carbon tetrachloride-induced liver toxicity in rat and mouse. ATB treatment (50 mg/kg day for 3 days) prior to a lethal dose of acetaminophen significantly reduced acetaminophen-induced liver toxicity in mouse, as assessed by both plasma alanine aminotransferase activity and histopathological examination. The 30-day survival rate of mouse gamma-irradiated at 8 Gy failed to be improved by ATB pretreatment (100 mg/kg/day for 2 days). 6. These results provided evidence that ATB stimulated mEH and GST gene expression at early times and reduced the P4502C11 level in the absence of P4502E1 suppression. ATB was only partially effective in protecting the liver against toxicant-induced injury despite the presence of allylthio moiety in its chemical structure.
...
PMID:Partial hepatoprotective effects of allylthiobenzimidazole in the absence of cytochrome P4502E1 suppression: effects on epoxide hydrolase, rGSTA2, rGSTA3/5, rGSTM1 and rGSTM2 expression. 957 20

The effect of acute exposure to lead acetate on the expression of glutathione S-transferase (GST) subunits and the levels of reduced and oxidized glutathione (GSH) and malondialdehyde (MDA) in rat kidney and liver was determined. The purpose of this study was to determine if GSH depletion and/or oxidative stress were responsible for changes in the expression of some or all GSTs that followed lead exposure. In kidney, all GST subunits increased following injection of lead. The level of kidney GSH was not changed at either 0.5 or 1 h after lead exposure, but increased 3, 6, 12 and 24 h after a single injection of lead. MDA levels (a marker of lipid peroxidation) did not change in kidney following lead injection. Immunohistochemical markers of oxidative stress and nitric oxide production were also unchanged by lead administration. Therefore. we conclude that the increases in GST levels in kidney following lead exposure were not dependent on oxidative stress. In liver, lead injection caused GSH depletion (61% of control 12 h after lead treatment) and increased MDA production (2.5-fold increase 6 h after lead exposure), while GSTA1, GSTA2, GSTM1 and GSTM2 did not increase. Analysis of the effects of lead on GST mRNA and GST cellular localization were performed by Northern blot and immunohistochemical techniques. Immunoperoxidase light microscopy and immunogold electron microscopy revealed that the increase in kidney GSTM1 and GSTP1 occurred in nuclei, cytoplasm and microvilli of proximal tubules. Northern blot analysis of GSTA2 and GSTP1 mRNAs showed that their increase following lead exposure was inhibited by actinomycin D, suggesting transcriptional induction. This study demonstrates that acute lead exposure causes dramatic changes in the subcellular distribution and expression of rat kidney GSTs, and that these changes are not a result of oxidative stress.
...
PMID:Effects of lead on rat kidney and liver: GST expression and oxidative stress. 975 42

A series of alpha,beta-unsaturated aldehydes was evaluated to determine if these compounds could mediate inducible expression of glutathione S-transferase (GST) through the 5'-flanking antioxidant response element (ARE). The ARE from rGST A1 was subcloned into a luciferase reporter construct and used to transiently transfect rat Clone 9 hepatoma cells. Transfected cells were treated with 4-hydroxy-trans-2-nonenal (4-HNE), trans-2-hexenal (t-2-HE), 2-propenal (acrolein, 2-PE), and ethacrynic acid (EA), a control compound also containing an alpha,beta-unsaturated carbonyl moiety. Each compound was evaluated for cytotoxicity to construct dosing regimens in transfection studies. IC50 values for growth inhibition were measured using 3-[4,5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide. IC50 values in Clone 9 cells were: 4-HNE, 6.3 +/- 0.7 microM; t-2-HE, 16.0 +/- 0.7 microM; 2-PE, 2.2 +/- 0.4 microM; and EA, 38.0 +/- 1.6 microM. A dose-dependent increase in luciferase activity was observed in transfected cells with all four compounds tested, indicating that alpha, beta-unsaturated aldehydes function as direct activators of the ARE. To determine whether or not the observed promoter activation led to increased transcriptional and translational induction of GST, cells were treated with the various compounds and assayed for increases in GST mRNA, protein, and enzyme activity. Studies in Clone 9 cells revealed increased steady-state message for GST A1 and A4, increased GST A4-4 protein by Western blotting, and increased GST activity toward 1-chloro-2,4-dinitrobenzene in response to treatment with all four compounds evaluated. Collectively, these studies demonstrate that EA and certain alpha,beta-unsaturated aldehydes produced as a result of cellular membrane lipid peroxidation are activators of the ARE and efficient inducers of GST A1-1 and A4-4.
...
PMID:Alpha,beta-unsaturated aldehydes increase glutathione S-transferase mRNA and protein: correlation with activation of the antioxidant response element. 979 58

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.
...
PMID:Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines. 981 87

Lipopolysaccharide (LPS) is an endotoxin involved in septic shock syndrome and potentiates toxicant-induced liver injury. The effects of LPS on the constitutive and inducible expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) genes were studied in rats. Northern blot analysis showed that treatment of rats with LPS caused suppression in mEH and GST gene expression. The mEH mRNA level was decreased in a time-dependent manner following a single dose of LPS (1 mg/kg, i.v.), resulting in levels of 52%, 22%, 17%, and 94% of those in untreated animals at 2, 6, 12, and 24 hr, respectively. The levels of rGSTA2 and rGSTA3 mRNA were suppressed in response to an LPS injection to the similar extents as observed in mEH mRNA, whereas rGSTM1 and rGSTM2 mRNA levels were less affected. LPS inhibited mEH gene expression at the doses of 1 microg or greater. Whereas treatment of rats with allyl disulfide (ADS), oltipraz (OZ) or pyrazine (PZ) at the dose of 50 mg/kg caused increases in the mEH mRNA level at 12 hr, a concomitant LPS injection (1 mg/kg) resulted in 80%-95% suppression of the inducible gene expression. The inducible rGSTA2, rGSTA3, rGSTM1, and rGSTM2 mRNA levels were also 50%-90% decreased at 12 hr after LPS treatment, with the relative change in rGSTA being greater than that in rGSTM. Three consecutive daily treatments with LPS (10 microg/kg/day) resulted in significant decreases of the constitutive and PZ (50 mg/kg/day, i.p. for 3 days)-inducible mEH and GST mRNA levels, which were consistent with those in the protein levels. Gel shift retardation analysis showed that LPS substantially activated the hepatic nuclear p65/p50 nuclear factor-kappaB (NF-kappaB) complex with the maximal effect observed at 1 hr at the doses of 1 microg/kg or greater. LPS-induced activation of nuclear NF-kappaB (1 microg/kg, i.v.) failed to be inhibited by concomitant treatment with the mEH and GST inducers, including ADS (300 mg/kg, p.o.), OZ (300 mg/kg, p.o.), and PZ (300 mg/kg, i.p.), indicating that NF-kappaB activation was not required for suppression of the gene expression by LPS. In contrast, GdCl3, an inhibitor of mEH and GST expression, inhibited LPS-induced activation of the p65/p50 NF-kappaB. These gel shift analyses provided evidence that LPS-induced activation of the NF-kappaB was not responsible for alterations in the gene expression. In summary, the results of this research demonstrate that LPS effectively inhibits constitutive and inducible mEH and GST expression with decreases in their mRNA levels, and that LPS suppression in the expression of the detoxifying enzymes is not mediated with its activation of NF-kappaB.
...
PMID:Lipopolysaccharide inhibition of rat hepatic microsomal epoxide hydrolase and glutathione S-transferase gene expression irrespective of nuclear factor-kappaB activation. 982 74

Paclitaxel and carboplatin chemotherapy is reported to be a platelet-sparing drug combination. This study investigated potential mechanisms for this observation by studying the effects of paclitaxel and carboplatin on (1) normal donor and chemotherapy patient-derived erythroid (burst-forming units-erythroid [BFU-E]), myeloid (colony-forming units-granulocyte/macrophage [CFU-GM]), and megakaryocyte (CFU-Meg) progenitor cell growth; (2) P-glycoprotein (P-gp) protein and glutathione S-transferase (GST) messenger RNA (mRNA) expression; (3) serum thrombopoietin (Tpo), stem cell factor (SCF), interleukin-6 (IL-6), IL-11, IL-1beta, IL-8, and tumor necrosis factor-alpha levels in patients treated with paclitaxel and carboplatin; and (4) stromal cell production of Tpo and SCF after paclitaxel and carboplatin exposure. CFU-Meg were more resistant to paclitaxel alone, or in combination with carboplatin, than CFU-GM and BFU-E. Although all progenitors expressed P-gp protein and GST mRNA, verapamil treatment significantly, and selectively, increased the toxicity of paclitaxel and carboplatin to CFU-Meg, suggesting an important role for P-gp in megakaryocyte drug resistance. Compared to normal controls, serum Tpo levels in patients receiving paclitaxel and carboplatin were significantly elevated 5 hours after infusion and remained elevated at day 7 (287% +/- 63% increase, P <.001). Marrow stroma was shown to be the likely source of this Tpo. It is concluded here that P-gp-mediated efflux of paclitaxel, and perhaps GST-mediated detoxification of carboplatin, results in relative sparing of CFU-Meg, which may then respond to locally high levels of stromal cell-derived Tpo. The confluence of these events might lead to the platelet-sparing phenomenon observed in patients treated with paclitaxel and carboplatin chemotherapy.
...
PMID:Investigating the platelet-sparing mechanism of paclitaxel/carboplatin combination chemotherapy. 1115 79

When the cultured cells of Glycine max (soybean) were treated with 5 mM geraniol as a chemical stress, an mRNA level was elevated in a rapid but transient increase. The mRNA was cloned and sequenced, and found to correspond to the mRNA encoding glutathione S-transferase (GST). The GST mRNA level and GST activity were elevated to maxima at 4-6 h and 8 h, respectively, after treatment of the cultures with geraniol. These indicate that GST is one of the geraniol-responsive factors in soybean cells.
...
PMID:Geraniol-inducible glutathione S-transferase in cultured soybean cells. 1186

Previous studies have shown that induction of microsomal epoxide hydrolase (mEH) and glutathione S-transferase (GST) by oltipraz correlated with the radioprotective effect. The present study was designed to investigate the expression of the antioxidant enzymes and the radioprotective effect by imidazole (IM). Northern blot analysis revealed that IM increased the mEH and GST mRNA levels in the rat liver in a dose-dependent manner. Rats irradiated with 3 Gy of gamma-rays in combination with IM showed enhanced increases in mEH and rGSTA2 mRNAs, as compared to either IM or irradiation alone. IM prevented elevations in the hepatic GSH content by gamma-irradiation. In contrast to IM, cysteine blocked radiation-inducible increases in the mRNAs with no suppression of the GSH content. The radioprotective effect by IM was greater than that by cysteine, as assessed by the 30-day survival rate of mice (i.e. 80% and 69%, respectively, vs. 48% in control). These results demonstrated that IM enhanced radiation-inducible mEH and GST expression with prevention of the increase in GSH content, which correlated with the radioprotective effect, and that the mechanistic basis of radioprotection by IM differed from that by cysteine.
...
PMID:Enhanced expression of microsomal epoxide hydrolase and glutathione S-transferase by imidazole correlates with the radioprotective effect. 1191 8


<< Previous 1 2 3 4 5 Next >>

---