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)

2-(Allylthio)pyrazine (2-AP), which is effective in suppressing constitutive and inducible cytochrome P450 2E1 expression, exhibits hepatoprotective and chemopreventive effects. The radioprotective effects of 2-AP were examined in animals in association with the expression of microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs). 2-AP pretreatment (100 mg/kg/day, for 2 days) prior to total body irradiation (TBI) at the dose of 8 Gy increased the 30 day survival rate of mice to 91% from 48% in TBI alone. 2-AP caused an increase in the mean survival time of mice exposed to 9 Gy of TBI. Light microscopic examinations revealed that exposure of mice to 8 Gy of gamma-ray radiation resulted in hepatocyte degeneration in the surviving animals at day 1 through day 22 with certain extents of necrosis observed at early times, whereas 2-AP pretreatment protected the liver against ionizing radiation with no hepatic necrosis being observed. Mice irradiated at the dose of 8 Gy showed time-related decreases in the counts of WBC, RBC and platelet. 2-AP treatment, however, failed to protect the peripheral blood cells against gamma-irradiation and resulted in no improvement in the ratio of myeloid to erythroid bone marrow cells, as compared to TBI alone. Northern blot analysis revealed that exposure of mice to 8 Gy of TBI plus 2-AP exhibited greater mEH and mGSTA3 mRNA levels in the liver than those with TBI alone, although mGSTP1 mRNA level failed to be altered. Studies were also extended to determine the effects of 0.5 Gy gamma-irradiation in combination with 2-AP on the expression of hepatic mEH and GST genes in rats. Whereas mEH, rGSTA2, rGSTA3 and rGSTA5 mRNA levels were elevated 2- to 2.8-fold at 24 h after 2-AP treatment at the dose of 30 mg/kg, rats exposed to both 2-AP and 0.5 Gy of irradiation showed greater relative increases in the mRNAs. 2-AP enhanced the mEH and rGSTA2 gene expression to greater extents at day 1 after irradiation than after 3-5 consecutive daily treatment. The radiation-inducible mRNA levels of rGSTA3/5 and rGSTM1/2 were affected less by 2-AP pretreatment than were those of mEH and rGSTA2. These results demonstrate that 2-AP exhibits radioprotective efficacy against gamma-ray ionizing radiation in both mice and rats, which might be associated with enhanced expression of mEH and GST genes, but not with hematological improvement.
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PMID:Radioprotective effects of 2-(allylthio)pyrazine an experimental chemopreventive agent: effects on detoxifying enzyme induction. 987 86

The naturally occurring organosulfur compounds (OSCs) diallyl sulfide (DAS), diallyl disulfide (DADS), dipropyl sulfide (DPS), and dipropyl disulfide (DPDS) were studied with respect to their effects on hepatic, intestinal, renal, and pulmonary phase II drug metabolizing enzymes, i.e., glutathione S-transferase (GST), microsomal epoxide hydrolase (mEH), quinone reductase (QR), and UDP-glucuronosyltransferase (UGT). OSCs were administered po to male SPF Wistar rats. In addition to assays of total enzyme activity, the ability of OSCs to modify the levels of mEH and rGSTA1/A2, A3/A5, M1, M2, and P1 was assessed by Western blotting. Remarkably, DADS significantly increased all Phase II enzyme activities, except the pulmonary mEH. It was noteworthy that only DADS induced QR activity. DAS, DPS, and DPDS induced mEH, GST, and UGT activities in the liver. Interestingly, DAS, DPS, and DPDS significantly decreased renal GST activity. In the same manner, DAS, DPS, and DPDS decreased rGSTA1/A2 and A3/A5 levels in the kidney. Conversely, all OSCs were able to induce GST of alpha and mu classes in the liver. In the intestine, DADS and DAS increased rGSTA1/A2, M2, and P1, while rGSTA3/A5 and M2 were only increased by DADS. In addition, DADS induced rGSTP1 dramatically in the four tissues analyzed. DADS also increased the mEH levels in the liver, intestine, and kidney, while DAS and DPS moderately induced mEH level in the liver. This study brings additional insights into the effects of OSCs on Phase II enzymes and suggests that DADS could be a promising chemopreventive agent considering its pleiotropic capacity of induction.
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PMID:Modulation of phase II enzymes by organosulfur compounds from allium vegetables in rat tissues. 988 91

Previous studies have shown that pyridazine (PD) and pyrazine (PZ) are efficacious in inducing microsomal epoxide hydrolase (mEH) in the liver with elevation of the mRNA level. The present study was designed to investigate the expression of mEH and rGSTA2 genes in response to the diazines including PD, PZ and pyrimidine (PM) and the basis for their enzyme induction. Rats treated with either PD or PZ for 3 days resulted in marked increases in mEH and rGSTA2 mRNA levels with concomitant induction of the proteins, whereas PM failed to elevate the mRNA levels. Treatment of rats with a single dose of PD or PZ showed dose-dependent increases in mEH and rGSTA2 mRNA levels at 24 h with ED50 values being approximately 10 mg/kg. Time-course studies showed that the mRNA levels were increased to maximal extents at 24-48 h after treatment. Studies were extended to assess the mechanistic basis for the enzyme induction by PD and PZ. beta-Naphthoflavone (BNF) caused a 6-fold increase of rGSTA2 mRNA in the liver (100 mg/kg per day, p.o., 3 days), as compared to control, whereas the agent failed to increase mEH mRNA level. Administration of PD or PZ (50 mg/kg) to BNF-pretreated rats resulted in no enhanced increase of the mEH mRNA as compared to the individual treatment, while the rGSTA2 mRNA level was additively elevated, suggesting the possibility that increases of the mEH and rGSTA2 mRNAs by PD or PZ might be mediated with antioxidant responsive element(s) in the genes, but not with xenobiotic responsive element. Western blot analysis revealed that cytochrome P450 2E1 was induced 3- to 4-fold by both PD and PZ, whereas PM failed to induce P450 2E1. Concomitant treatment of rats with PD or PZ in combination with acetone, a substrate for P450 2E1, caused no significant increase in the mEH and rGSTA2 mRNA levels relative to that in untreated animals, whereas PD or PZ treatment without a concomitant acetone administration resulted in marked increases of the mRNAs. Diazine-inducible mEH and rGSTA2 mRNA levels were approximately 2-fold enhanced in P450 2E1-induced starved rats, as compared to those in diazine-treated unstarved animals. These data indicate that P450 2E1-mediated bioactivation of the diazines might contribute to transcriptional activation of the mEH and GST genes. These results provide evidence that both PD and PZ efficaciously induce mEH and rGSTA2 in the liver with increases in the mRNA levels, while PM is ineffective, and that induction of mEH and rGSTA2 may be mediated through bioactivation of the diazines by P450 2E1.
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PMID:Differential induction of rat hepatic microsomal epoxide hydrolase and rGSTA2 by diazines: the role of cytochrome P450 2E1-mediated metabolic activation. 992 Apr 64

A series of organosulfur compounds were synthesized with the aim of developing chemopreventive compounds active against hepatotoxicity and chemical carcinogenesis. 2-(Allylthio) pyrazine (2-AP) was effective in inhibiting cytochrome P450 2E1-mediated catalytic activities and protein expression, and in inducing microsomal epoxide hydrolase and major glutathione S-transferases. 2-AP reduced the hepatotoxicity caused by toxicants and elevated cellular GSH content. Development of skin tumors, pulmonary adenoma and aberrant crypt foci in colon by various chemical carcinogens was inhibited by 2-AP pretreatment. Anticarcinogenic effects of 2-AP at the stage of initiation of tumors were also observed in the aflatoxin B1 (AFB1)-induced three-step medium-term hepatocarcinogenesis model. Reduction of AFB1-DNA adduct by 2-AP appeared to result from the decreased formation of AFB1-8,9-epoxide via suppression of cytochrome P450, while induction of GST by 2-AP increases the excretion of glutathione-conjugated AFB1. 2-AP was a radioprotective agent effective against the lethal dose of total body irradiation and reduced radiation-induced injury in association with the elevation of detoxifying gene expression. 2-AP produces reactive oxygen species in vivo, which is not mediated with the thiol-dependent production of oxidants and that NF-kappa B activation is not involved in the induction of the detoxifying enzymes. The mechanism of chemoprotection by 2-AP may involve inhibition of the P450-mediated metabolic activation of chemical carcinogens and enhancement of electrophilic detoxification through induction of phase II detoxification enzymes which would facilitate the clearance of activated metabolites through conjugation reaction.
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PMID:Chemopreventive effects of 2-(allylthio)pyrazine. 1023 Apr 97

The expression of hepatic microsomal epoxide hydrolase (mEH) and glutathione S-transferases (GSTs) by 2-(allylthio)pyrazine (2-AP), an experimental chemopreventive agent, was investigated in rats. Northern blot analysis revealed that 2-AP caused increases in mEH, rGSTA2/3/5, and rGSTM1/2 mRNA levels. mEH and rGSTA2 proteins were also induced. Molecular basis of the enzyme induction by 2-AP was studied in comparison with oltipraz (Olt). Rats exposed to buthionine sulfoximine, a GSH-depleting agent, before treatment with either 2-AP or Olt exhibited greater increases in the mRNA levels than the individual treatment. Conversely, increases of the mRNAs were prevented by cysteine treatment, indicating that metabolic intermediates or reactive oxygens produced from the agents could be reduced by cysteine. Gel shift analysis revealed that nuclear factor-kappaB, which is associated with the altered cellular redox state, was not activated by the agents. Effects of these agents on the breakage of phix-174 DNA were compared in vitro. 2-AP effectively reduced the conversion of supercoiled DNA to the open circular form induced by benzenetriol and prevented benzenetriol- and iron-catalyzed degradation of DNA, whereas Olt failed to prevent strand breakage of DNA. These results provided evidence that: 1) 2-AP was effective in elevating the hepatic mEH and GST gene expression in rats, which might be mediated with the production of reactive oxygen species; 2) nuclear factor-kappaB activation was not involved in the induction of the detoxifying enzymes by either 2-AP or Olt in spite of their production of reactive oxygens in vivo; and 3) the antioxidant effect of 2-AP in vitro differed from that of Olt.
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PMID:Molecular basis for hepatic detoxifying enzyme induction by 2-(allylthio)pyrazine in rats in comparison with oltipraz: effects on prooxidant production and DNA degradation. 1034 95

Inter-individual variation in metabolism of environmental toxicants, which is attributed to genetic polymorphism, may be a major risk factor in determining who will develop adverse health effects. This priority research area is the focus of many laboratories, and new techniques need to be developed to enhance the efficiency in generating data. We have developed and validated a new multiplex-polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) procedure for simultaneous genotyping of cytochrome P450 II E1 (CYP2E1), microsomal epoxide hydrolase (mEH), and glutathione S-transferase mu (GSTM1). Enzymes from these three polymorphic genes are involved with the phase I and II metabolism of a variety of environmental toxicants. Therefore, simultaneous characterization of these genes will not only reduce costs but will increase the efficiency of data collection, thereby contributing to health risk assessment efforts.
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PMID:A multiplex-PCR/RFLP procedure for simultaneous CYP2E1, mEH and GSTM1 genotyping. 1046 37

Tissue expression of drug-metabolizing enzymes influences susceptibility to drugs and carcinogens. Because the biliary epithelium, exposed to bile-borne chemicals, may give rise to drug-induced cholangiopathies and to cholangiocarcinomas, we determined the pattern of expression of drug-metabolizing enzymes in this epithelium. We first demonstrated by blot analyses that biliary epithelial cells (BEC) isolated from human gallbladders display cytochrome P450 (CYP) 1A, 2E1, and 3A, microsomal epoxide hydrolase (mEH), alpha, mu, and pi glutathione S-transferase (GST), transcripts and proteins. We also identified CYP-associated steroid 6beta-hydroxylase activity in BEC. CYP and mEH expression was 5- to 20-fold lower in BEC than in autologous hepatocytes, and further differed by a higher ratio of CYP3A5/CYP3A4, and by CYP1A1 predominance over CYP1A2. alphaGST was highly expressed in both hepatocytes and BEC, while piGST was restricted to BEC. In approximately 50% of individuals, muGST was expressed in hepatocytes and at lower levels in BEC. By using the same antibodies as those used in immunoblots, we could show by immunohistochemistry that CYP2E1, CYP3A, mEH, alpha, mu, and piGST immunoreactivities are expressed and display a heterogeneous distribution in the epithelium lining the entire biliary tract except for small intrahepatic bile ducts that were devoid of CYP3A and alphaGST immunoreactivities. In conclusion, BEC contribute to phase II, and although to a lesser extent than hepatocytes, to phase I biotransformation. The distribution of drug-metabolizing enzymes in BEC suggest that they are heterogeneous in their ability to generate and detoxicate reactive metabolites, which may contribute to specific distributions of cholangiopathies.
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PMID:Phase I and phase II drug-metabolizing enzymes are expressed and heterogeneously distributed in the biliary epithelium. 1057 30

Several classes of compounds are able to induce a spectrum of drug-metabolizing enzymes without inducing cytochrome P450s. Examples include antioxidants such as tert-butyl-4-hydroxyanisole and its metabolite tert-butylhydroquinone, dithiolthiones such as oltipraz, and N-heterocycles such as 1,7-phenanthroline. The events associated with induction of UDP-glucuronosyltransferases (UGT), glutathione S-transferases, and microsomal epoxide hydrolase after a single oral dose of these agents have been compared. No agent significantly elevated any of these enzyme activities within 24 h, but oltipraz and 1,7-phenanthroline significantly increased glutathione S-transferase and UGT activities by 48 h. 1, 7-Phenanthroline and oltipraz showed generally similar time-course responses of drug-metabolizing enzyme mRNAs; little change from control at 6 h followed by significant and maximal increases 12 to 18 h after treatment. Maximal mRNA changes for 1,7-phenanthroline and oltipraz were of similar magnitude and clustered around 4-fold for most enzymes. With the exception of one UGT isozyme (UGT1A1), the elevations in mRNA were blocked by prior administration of actinomycin D, indicative of a transcription-dependent response. Neither tert-butyl-4-hydroxyanisole nor tert-butylhydroquinone caused a statistically significant increase in any mRNA examined at any time point.
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PMID:Early events in the induction of rat hepatic UDP-glucuronosyltransferases, glutathione S-transferase, and microsomal epoxide hydrolase by 1,7-phenanthroline: comparison with oltipraz, tert-butyl-4-hydroxyanisole, and tert-butylhydroquinone. 1095 Aug 43

Glutathione S-transferases (GSTs) and epoxide hydrolases (EHs) protect cells from exogenous insult by detoxifying electrophilic compounds. Little is known about these enzyme systems during postnatal lung development. This study was designed to help establish whether the heightened neonatal susceptibility of the lung to bioactivated cytotoxicants is the result of inadequate ability to detoxify reactive intermediates. We compared the distribution of immunoreactive protein and enzymatic activity of GSTs and EHs in isolated distal airways during pre- and postnatal development in lungs of mice from 16 days gestation to 9 weeks postnatal age (adult). GST alpha, mu, and pi class protein expression in fetal and postnatal lung varied by isozyme and age. Isozymes alpha and mu are expressed at low levels before birth, high levels on postnatal day 7, low levels between postnatal days 14 and 21, high levels at postnatal day 28, and slightly lower levels in adults. Immunoreactive protein of isozyme pi has a peak expression on gestational day 18 and again on postnatal day 4, is undetectable at postnatal day 21, and is at peak levels in the adult mouse lung. GST activity in distal airways increased with age. Microsomal EH protein expression increased in intensity with age, while activity was similar in airways from all ages. We conclude that in the mouse lung (1) cellular expression of glutathione S-transferase varies by age and isozyme and does not increase with increasing age, (2) airway glutathione S-transferase activity increases with increasing age and does not correlate with immunoreactive protein expression, and (3) airway microsomal epoxide hydrolase activity does not increase, even though immunoreactive protein expression does increase with age.
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PMID:Development of phase II xenobiotic metabolizing enzymes in differentiating murine clara cells. 1104 98

Expression of drug-metabolizing enzymes including cytochrome P450 (CYP) and flavin-containing monooxygenase (FMO) in various tissues of Suncus murinus (Suncus) were examined. Northern blot analysis showed that mRNAs hybridizable with cDNAs for rat CYP1A2, human CYP2A6, rat CYP2B1, human CYP2C8, human CYP2D6, rat CYP2E1, human CYP3A4 and rat CYP4A1 were expressed in various tissues from Suncus. The mRNA level of CYP2A in the Suncus lung was very high. Furthermore, it was found that the level of CYP2A mRNA in the Suncus lung was higher compared to the Suncus liver. The expression level of mRNA hybridizable with cDNA for human CYP3A4 was very low. The presence of CYP3A gene in Suncus was proven by the induction of the CYP with dexamethasone. Very low expression levels of mRNAs hybridizable with cDNAs for rat FMO1, rat FMO2, rat FMO3 and rat FMO5 were also seen in Suncus liver. No apparent hybridization band appeared when human FMO4 cDNA was used as a probe. The hepatic expression of mRNAs hybridizable with cDNAs for UDP-glucuronosyltransferase 1*6, aryl sulfotransferase, glutathione S-transferase 1, carboxyesterase and microsomal epoxide hydrolase in the Suncus were observed. These results indicate that the Suncus is a unique animal species in that mRNAs for CYP3A and FMO are expressed at very low levels.
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PMID:The house musk shrew (Suncus murinus): a unique animal with extremely low level of expression of mRNAs for CYP3A and flavin-containing monooxygenase. 1104 72


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