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)

1. Ethacrynic acid (EA), a phenoxyacetic acid diuretic, has similar effects to tienilic acid (TA) on rat liver glutathione S-transferase (GST) activity in vitro, using either 1-chloro-2,4-dinitrobenzene or sulphobromophthalein (BSP) as a substrate. EA inhibits the basic rat liver GST, with inhibition being greater with GST containing subunits 3 and 4 than with those containing subunits 1 and 2. 2. In vitro inhibitors of GST can inhibit biliary excretion of BSP in a perfused liver. 3. A single bolus dose of EA had no effect on BSP excretion from the isolated perfused rat liver, and this is most likely due to the rapid disappearance of EA from the perfusion media. Experiments using perfused rat liver indicated that a sustained high concentration of EA in the perfusion media has an inhibitory effect on the excretion of both unchanged and conjugated BSP. 4. A decrease in BSP excretion may not be an indicator of liver damage, but a consequence of GST inhibition.
...
PMID:Modulation of sulphobromophthalein excretion by ethacrynic acid. 149 88

Treatment of mice with a single dose of oltipraz (OPZ) at 200 mg/kg led to a significant (P less than 0.05) increase in hepatic cytosolic glutathione S-transferase (GST) activity and content. GST activity monitored with 1,2-dichloro-4-nitrobenzene was increased 3.8-fold 3 days after treatment, suggesting the induction of mu class isoenzymes. Ethacrynic acid, a marker for pi class isoforms, showed only a slight increase in GST activity while no induction was observed with cumene hydroperoxide, an indicator for the alpha class. The increase in mu class isoenzymes was further confirmed by separation of the mouse liver affinity purified GST by chromatofocusing and also by resolving the GST subunits by reverse-phase high performance liquid chromatographic procedures. Therefore, OPZ induces mainly the mu class isoenzymes in mouse hepatic tissues.
...
PMID:Induction of glutathione S-transferase isoenzymes in mouse liver by 5-(2-pyrazynl)-4-methyl-1,2-dithiole-3-thione (oltipraz). 154 Feb 41

Glutathione transferases are enzymes implied in the resistance of tumor cells to bifunctional alkylating cytostatic drugs. We have investigated the effect of the glutathione transferase inhibitor by ethacrynic acid on the cytotoxicity of melphalan to a human melanoma cell line (RPMI 8322) with a high level of glutathione transferase activity. Using 1-chloro-2,4-dinitrobenzene as substrate, ethacrynic acid was shown to inhibit the activity of purified human glutathione transferases, with 50% inhibition values of 1, 10, and 15 microM for transferase mu (class mu), transferase epsilon (class alpha) and transferase pi (class pi), respectively, all of which occur in RPMI 8322 cells. Ethacrynic acid at a concentration of 20 microM, which by itself was noncytotoxic, increased the cytotoxicity of melphalan to RPMI 8322 human melanoma cells approximately 2-fold. The induction of DNA interstrand cross-links by 40 microM melphalan was increased 1.4-fold by 30 microM ethacrynic acid. These results indicate that a potentiation of the cytotoxic effect of bifunctional alkylating agents can be achieved by inhibition of glutathione transferase and that the enhanced cytotoxicity may be caused at least in part by increased formation of drug-DNA adducts.
...
PMID:Sensitization of human melanoma cells to the cytotoxic effect of melphalan by the glutathione transferase inhibitor ethacrynic acid. 198 11

Cytosolic glutathione S-transferases were purified from human jejunal mucosa by affinity chromatography on S-hexylglutathione-Sepharose 4B. Chromatofocusing in the pH range 7-4 yielded peaks with apparent pI's of 7.2 (peak 1), 5.2 (peak 2), and 4.4 (peak 3). Each enzymatic fraction was shown to have a homodimeric structure, with subunit mass of 24.9 +/- 0.5 (P1), 27.9 +/- 0.9 (P2), and 23.4 +/- 0.8 (P3) kDa, as determined by SDS-PAGE. The substrate specificity of each peak was tested using discriminating substrates for basic, near-neutral, and acidic GSTs. With cumene hydroperoxide, the diagnostic substrate for the alpha (basic) class of GSTs, P1 showed 8- to 36-fold higher activity than P2 and P3. Ethacrynic acid, the selective substrate for the acidic enzyme (pi), gave highest activity with P3. The inhibitory potentials of sulfobromophthalein, cibacron blue, tributyltin acetate, triphenyltin chloride, and bromphenol blue were also tested. A qualitative resemblance between P1 and alpha, and P3 and pi GSTs was noted. The substrate specificity and inhibiton parameters of P2 corresponded most closely to those of mu-GST. The relative abundances of P1, P2, and P3 (based on CDNB-conjugating activity) were 35, 5, and 60%, respectively.
...
PMID:Resolution and kinetic characterization of glutathione S-transferases from human jejunal mucosa. 225 15

Ethacrynic acid and piriprost (6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1) have been shown to potentiate the cytotoxic activity of chlorambucil in rat and human tumor cell lines. Walker 256 rat breast carcinoma cells (WS), with acquired resistance to nitrogen mustards (WR), and two human colon carcinoma cell lines, HT 29 and BE, were sensitized to chlorambucil when either ethacrynic acid or piriprost was administered at the same time as the alkylating agent. Both as single agents and in combination with chlorambucil, there was inhibition of glutathione S-transferase activity as measured with 1-chloro-2,4-dinitrobenzene as a substrate. A depletion in intracellular glutathione was also evident following ethacrynic acid alone or in combination with chlorambucil. Thus, diuretic plant phenols or prostaglandin analogues may have potential therapeutic utility in combination with alkylating agents.
...
PMID:Ethacrynic acid and piriprost as enhancers of cytotoxicity in drug resistant and sensitive cell lines. 328 31

Ethacrynic acid (EA) is a plant phenolic acid that is both an inhibitor and an inducer of glutathione S-transferase (GST) activity. To determine contributory factors in the increased GST activity caused by EA treatment, human colon carcinoma HT29 cells were compared with a cloned EA-resistant population (HT6-8) maintained in medium containing 72 microM EA. Several factors are involved in the increased expression of GST pi in HT6-8. For example, nuclear run-on experiments showed an approximately 2-fold increase in the rate of transcription of GST pi. In addition, the half-life of GST pi transcript was increased from 4.1 (wild type, HT29, HT4-1) to 8.4 hr. The half-life of GST pi protein was 1-2 hr in HT4-1 cells versus 8-9 hr in HT6-8 cells. When either human ovarian carcinoma cells (SKOV3) or human prostatic carcinoma cells (DU145) were treated with EA, the half-life of the GST pi transcript was also increased. The transcript half-lives of another thiol-metabolism enzyme, gamma-glutamylcysteine synthetase (gamma-GCS), and a phase II detoxification enzyme, dihydrodiol dehydrogenase (DDH), were also increased in HT6-8, SKOV3 and DU145 cells treated with EA. However, the half-lives of transcripts from "housekeeping genes," such as glyceraldehyde 3-phosphate dehydrogenase (G3PDH), beta-actin and beta-tubulin, were not changed in these cell lines following EA. Apparently, a number of coordinated factors are involved in EA-enhanced expression of GST pi and other detoxification enzymes.
...
PMID:Influence of ethacrynic acid on glutathione S-transferase pi transcript and protein half-lives in human colon cancer cells. 748 39

We examined whether inhibitors of the arachidonic acid cascade inhibited nitric oxide (NO) production, as measured by nitrite concentration, either in macrophages or by their cytosolic fractions. Nitrite production by peritoneal macrophages from mice receiving OK-432 treatment was significantly inhibited by phospholipase A2 inhibitors [dexamethasone and 4-bromophenacyl bromide (4-BPB)], lipoxygenase inhibitors [nordihydroguaiaretic acid (NDGA) and ketoconazole] and a glutathione S-transferase (leukotrienes LTA4-LTC4) inhibitor (ethacrynic acid). However, caffeic acid and esculetin, inhibitors of 5- and 12-lipoxygenase respectively, were not inhibitory. On the other hand, indomethacin, a cyclooxygenase inhibitor, slightly inhibited whereas another inhibitor, ibuprofen, did not. Inhibition of the nitrite production by dexamethasone, 4-BPB, NDGA and ethacrynic acid was also demonstrated when the macrophages were restimulated ex vivo with OK-432 or with lipopolysaccharide. The inhibitory activity of dexamethasone, NDGA and ethacrynic acid was significantly reduced by ex vivo restimulation with OK-432, whereas that of 4-BPB was hardly affected. Furthermore, the inhibitory activity of dexamethasone, NDGA and ethacrynic acid was much higher when the macrophages were continuously exposed to the agents than when they were pulsed. Meanwhile, inhibition by 4-BPB was almost the same with either treatment. In addition, the inhibitory activity of these agents was not blocked with L-arginine, a substrate of NO synthases, or with arachidonate metabolites (LTB4, LTC4 and LTE4). Ethacrynic acid and 4-BPB, but not dexamethasone and NDGA, also inhibited nitrite production by the cytosolic fractions from OK-432-restimulated peritoneal macrophages, and the inhibitory activity of 4-BPB was superior to that of ethacrynic acid. These agents, however, did not inhibit nitrite production from sodium nitroprusside, a spontaneous NO-releasing compound. These results indicate that dexamethasone, 4-BPB, NDGA and ethacrynic acid inhibited the production of NO by macrophages through at least two different mechanisms: one was inhibited by dexamethasone, NDGA and ethacrynic acid and the other by 4-BPB. Furthermore, 4-BPB and ethacrynic acid directly inhibited the activity of the NO synthase in macrophages, suggesting that the agents work by binding to the active site(s) of the enzyme.
...
PMID:Inhibition of macrophage nitric oxide production by arachidonate-cascade inhibitors. 769 96

Yoshida rat ascites hepatoma (AH) has several cell lines with a characteristic sensitivity to antitumor drugs. AH66 cells overexpressed 160-170 kDa P-glycoprotein (P-gp) in the membrane and glutathione-S-transferase placental form (GST-P) in the cytosol. AH44 cells did not express P-gp but contained GST-P isozyme, while normal rat liver had GST-(1,2) and-(3,4) classes. AH44 and AH66 cells were more resistant to chlorambucil (CLB) than AH66F cells, which are a variant cell line derived from AH66 cells and lacked both proteins. CLB-resistant AH44 and AH66 cells contained a high amount of glutathione (GSH) and higher GST activity than AH66F cells. Ethacrynic acid, a GST-P inhibitor, and buthionine sulfoximine, a GSH biosynthesis inhibitor, significantly decreased the CBL resistance of AH44 and AH66 cells without influencing the sensitivity of AH66F cells. The CLB resistance of these cell lines were hardly influenced by verapamil, a calcium channel blocker with P-gp antagonistic action, which significantly decreased the vinblastine resistance of AH66 cells. This study indicates that AH66 cells showed multiple drug resistance dependent on P-gp and GST-P isozyme and that the AH44 cell line was CLB resistant through the GSH/GST-P detoxification system. These hepatomas are useful for investigation of the drug resistance of hepatic carcinomas and development of counteracting drugs.
...
PMID:Glutathione-S-transferase P-form dependent chlorambucil resistance in Yoshida rat ascites hepatoma cell lines. 791 Jan 11

We evaluated the reversing activity of ethacrynic acid in a B-CLL patient resistant to chlorambucil. The glutathione S-transferase (GST) activity, measured in peripheral blood lymphocytes, resulted extremely elevated. Ethacrynic acid, at pharmacological concentrations, partially reversed chlorambucil resistance and this result appeared related to the increased GST levels.
...
PMID:Reversing of chlorambucil resistance by ethacrynic acid in a B-CLL patient. 828 Jun 15

Ethacrynic acid, a diuretic drug known to be an inhibitor of glutathione S-transferases (GSTs), has been shown to enhance the cytotoxicity of the alkylating agent class of chemotherapeutic drugs in cultured cancer cells resistant to alkylating agents. This action of ethacrynic acid is presumably mediated by inhibition of GSTs which are implicated in detoxification of alkylating agents. In addition to being an inhibitor of GSTs, ethacrynic acid also interacts with GSTs as a substrate for conjugation with GSH to yield an ethacrynic acid-GSH conjugate. This conjugate is formed both enzymatically and non-enzymatically and itself is a GST inhibitor. Since ethacrynic acid-GSH conjugate is itself likely to be able to mediate reversal of alkylating agents through GST inhibition, we have synthesized and purified the ethacrynic acid-GSH conjugate, studied the kinetics of inhibition of human lung pi-class GST by ethacrynic acid and the conjugate, and compared the kinetics of the enzymatic and non-enzymatic formation of the conjugate using an HPLC method. Results of our studies showed that the ethacrynic acid-GSH conjugate was a more potent inhibitor of human lung GST-pi than ethacrynic acid (Ki = 1.5 vs. 11.5 microM, respectively) and that their mechanisms for GST inhibition were distinct (competitive and non-competitive, respectively). Comparison of enzymatic and non-enzymatic rates of conjugate formation in vitro indicated that GST-pi catalyzed a rapid conjugation of ethacrynic acid with GSH at a concentration of ethacrynic acid an order of magnitude above that required to nearly completely inhibit GST catalyzed conjugation of 1-chloro-2,4-dinitrobenzene. However, because of the rapid non-enzymatic reaction, and the inhibition of GST-pi with the accumulation of the conjugate in the reaction mixture, the overall quantity of the conjugate formed after 150 min was nearly identical in the presence or absence of GST-pi. Results of these studies suggest that inhibition of GSTs by ethacrynic acid-GSH conjugate may be the main mechanism through which ethacrynic acid reverses alkylating agent resistance.
...
PMID:Interactions of glutathione S-transferase-pi with ethacrynic acid and its glutathione conjugate. 832 48


1 2 3 Next >>

---