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)

C57BL/6J (C57) and DBA/JBOMf (DBA) mice were used to study the role of adipose tissue as a modifier of tissue distribution, biological effects, and elimination of a lipophilic foreign chemical, 2,4,5,2',4',5'-hexachlorobiphenyl (HCB). As an indication of biological potency of the model compound, the activities of hepatic drug-metabolizing enzymes were determined. DBA mice contained twice as much body fat as C57 mice. Since the highly lipophilic HCB was primarily sequestered by the adipose tissue, DBA mice required greater doses of HCB than did C57 mice to reach similar tissue levels of the chemical. Accordingly, greater HCB doses were required by DBA mice for elevation of drug-metabolizing enzyme activities. Phenobarbital elevated enzyme activities in a similar way in both mouse strains. When the dietary intake of DBA mice was restricted, the body fat content decreased from 15% to 5% of body weight during 1 week. In these animals the tissue accumulation of HCB and enzyme induction resembled the situation in C57 mice fed ad libitum. Highest elevations were seen in the activities of 7-ethoxycoumarin-O-deethylase and arylhydrocarbon hydroxylase (EC 1.14.14.2). In addition, the activity of epoxide hydrolase (EC 3.3.2.3) was increased, whereas glutathione S-transferase as well as UDP-glucuronosyltransferase (EC 2.4.1.17) activities remained unchanged. The abundant adipose tissue content played no role in the nonresponsiveness of DBA mice to 3-methylcholanthrene since, in contrast to C57 mice, no changes in enzyme activities were detected in DBA mice deprived of food, even after large doses of 3-methylcholanthrene. The adipose tissue content also affected the rate of elimination of HCB. DBA mice excreted smaller quantities of HCB than did C57 mice after equal doses. When, however, fasted DBA mice received HCB, they excreted it at rates similar to those of C57 mice fed ad libitum. In C57 mice, concomitant to the elevation of monooxygenase activities, there was an increase in the rate of excretion of HCB. No such elevation could be seen after a dose that was too small to elevate enzyme activities.
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PMID:Adipose tissue content as a modifier of the tissue distribution, biological effects, and excretion of a hexachlorobiphenyl in C57BL/6J and DBA/JBOMf mice. 641

The effects of treating male Sprague-Dawley rats with phenobarbital, 3-methylcholanthrene or trans-stilbene oxide on cytosolic glutathione transferase and microsomal epoxide hydrolase activities in the liver, intestine, kidney, lung, testis, adrenal, spleen, heart and brain have been investigated. Studies on the time-courses of induction in liver demonstrate that these are complete after five days' treatment at the doses used. Phenobarbital induces both cytosolic glutathione transferase and microsomal epoxide hydrolase activities significantly only in liver and intestine. 3-Methylcholanthrene induces these activities in liver only. Trans-Stilbene oxide induces both of these activities in liver and kidney, and cytosolic glutathione transferase activity in adrenal as well.
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PMID:Induction of cytosolic glutathione transferase and microsomal epoxide hydrolase activities in extrahepatic organs of the rat by phenobarbital, 3-methylcholanthrene and trans-stilbene oxide. 646 99

Adult male rats were nose-only exposed to cigarette smoke for 20 min each day for 6 months. Smoke inhalation was confirmed by urinary excretion of nicotine (4.5 micrograms/rat/day) and elevated blood carboxyhemoglobin (13.3%). Phenobarbital- and 3-methylcholanthrene-treated rats were included as positive controls for assessing hepatic enzyme induction. Cigarette smoke did not induce statistically significant alterations in hepatic enzyme activity when measured in vivo (pentobarbital sleep time and zoxazolamine paralysis time) or in vitro (oxidation, hydrolysis, glucuronidation, and glutathione conjugation). In some cases, the smoke-exposed rats did exhibit higher microsomal enzyme activity than did the controls, but this increase was also evident in the sham-control group. Therefore, these increases were attributed to stress and not to smoking per se. Additional evidence of stress associated with manipulation of the animals was the smaller percentage weight gains of the smoke-exposed and sham control rats over the 6-month period as compared to the controls (12, 35, and 50%, respectively). Smoking reduced hepatic glutathione by as much as 15%, but the glutathione transferase activity was not affected. These studies showed that chronic exposure of rats to cigarette smoke did not alter hepatic biotransformation processes, but do suggest that smokers may be less efficient than nonsmokers in the deactivation of xenobiotics by glutathione conjugation mechanisms.
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PMID:Effect of cigarette smoking on hepatic biotransformations in rats. 654 Sep 1

To assess possible maternal hepatic and reproductive effects of this uncharged, low molecular weight, lipophilic chlorinated benzene 0, 100, 300 and 1000 mg/kg/day of 1,2,3,4-tetrachlorobenzene (TCB) was orally administered to pregnant rats on days 9-13 of gestation and the animals were killed on day 14 of pregnancy. Phenobarbital and beta-naphthoflavone were administered to other pregnant rats as positive hepatic controls. Maternal mortality (7/19 rats) was increased and body weight gain was greatly decreased in the 1000 mg/kg/day TCB group. Liver to body weight ratio and hepatic microsomal protein content were unaffected by any TCB treatment. On day 14 maternal NADPH-cytochrome c reductase activity was increased at 1000 mg/kg/day, while the maternal hepatic microsomal cytochrome P-450 content was significantly induced by both 300 and 1000 mg/kg/day of TCB. Microsomal N-demethylation of aminopyrine was increased from 2.6 to 4.0 and 4.5 nmol/mg protein/min at doses of 300 and 1000 mg/kg TCB, respectively. However, maternal hepatic microsomal ethoxyresorufin O-deethylase activity was not consistently increased by TCB. Hepatic glutathione S-transferase activity towards 1,2-dichloro-4-nitrobenzene was increased only by the 1000 mg/kg/day TCB treatment. The rate of microsomal p-nitrophenol and phenolphthalein glucuronidation was increased by TCB administration. Embryonic growth was adversely affected by TCB treatment. Yolk sac diameter, embryonic crown-rump length, and head length were all decreased by treatment with 300 mg/kg/day TCB. This TCB treatment did not significantly elevate the number of dead or abnormal embryos.
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PMID:Maternal hepatic and embryonic effects of 1,2,3,4-tetrachlorobenzene in the rat. 685 97

Fatty acid ethyl esters (FAEE) are formed following the administration of ethanol and have previously been associated with toxicological effects in animals and humans. It has been suggested that the enzyme responsible, FAEE synthase, has both structural and catalytic properties very similar to a glutathione S-transferase (GST). Since GSTs are inducible, their induction could be associated with enhanced FAEE formation and toxicity. In the present study, rats were administered beta-naphthoflavone, phenobarbital, ethanol, or Aroclor 1254, and hepatic FAEE synthase and GST activities were measured. beta-Naphthoflavone and ethanol did not induce either activity. Phenobarbital increased GST activity in the liver but not in lung or pancreas. Only Aroclor 1254, which increased GST activity in liver and pancreas, increased FAEE synthase activity and then only in the liver. Thus, in comparison with GST activity, FAEE synthase activity is very limited in its ability to be induced.
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PMID:Comparison of the induction of rat glutathione S-transferase and fatty acid ethyl ester synthase activities. 788 83

Polycyclic aromatic hydrocarbons, cigarette smoke components that induce atherosclerosis in animals, require metabolic biotransformation to electrophilic intermediates to exhibit atherogenic effects. The formation of reactive metabolites depends on both rates of cytochrome P450-catalyzed oxidation and rates of detoxification through conjugation with glutathione. Thus, changes in the activity of glutathione S-transferase in vascular tissue could affect the risk of polycyclic aromatic hydrocarbon-induced atherogenesis. We compared the effects of several exogenous chemicals on levels of glutathione S-transferase in aorta and liver. Male Wistar rats were treated with 3-methylcholanthrene, a polycyclic aromatic hydrocarbon, phenobarbital and butylated hydroxytoluene, an antioxidant known to have anti-atherogenic properties. In control animals, glutathione S-transferase activity was about 20-fold greater in liver than in aorta. Subunit expression was tissue specific. GST-Yp, for example, was the most abundant subunit in aorta but was undetectable in liver. In contrast, GST-Ya was barely detectable in aorta but was abundant in liver. Each of the xenobiotics caused induction of glutathione S-transferase but the extent of induction was greater in liver than in aorta. Phenobarbital, for example, caused 300% induction in liver but only 70% induction in aorta. By western blot analysis, differences in amounts of enzyme subunits corresponded to changes in enzyme activity. Thus, exogenous chemicals differentially regulate levels of glutathione S-transferase in the aorta and liver.
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PMID:Differential induction of glutathione S-transferase in rat aorta versus liver. 820 8

Previous studies have demonstrated that ingestion of 5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione (oltipraz) during the aflatoxin B1 (AFB1) treatment phase completely prevented hepatic cancer. In this study we evaluated the effect of feeding oltipraz during the post-AFB1 treatment phase. Fifty-five male F344 rats were divided into five groups. All rats were gavaged with 25 micrograms AFB1/rat, five times a week for two successive weeks. The rats were fed the oltipraz-supplemented diet according to three different feeding regimes: during the AFB1 treatment phase (1 week prior to, during and 1 week after the last gavage with AFB1); during the post-treatment phase; or throughout the entire time of the experiment. Phenobarbital-supplemented diet was fed during post-treatment phase to one group and this was used as a positive control for the promotion of AFB1-induced focal growth. The burden of putative, preneoplastic, hepatic glutathione S-transferase P-positive foci was evaluated at 13 weeks after the AFB1 treatment phase. As seen previously, oltipraz fed during the AFB1 treatment phase significantly inhibited focal development, i.e. the volume percent of the liver occupied with foci was reduced by 87%. Oltipraz when fed during the post-treatment phase neither inhibited nor enhanced focal development.
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PMID:Evaluation of the post-initiation effects of oltipraz on aflatoxin B1-induced preneoplastic foci in a rat model of hepatic tumorigenesis. 824 75

The present study is aimed to elucidate the changes in glutathione S-transferase (GST) activity and GST subunit components in primary cultured rat hepatocytes. Enzyme activity was measured with 1-chloro-2,4-dinitrobenzene as cosubstrate. The activity decreased at 48 hr, and subsequently increased and returned to levels initially observed at 12 hr by 120 hr. Phenobarbital caused an induction of GST activity in culture at 72 and 168 hr. Immunocytochemical studies were performed using a peroxidase-anti-peroxidase technique with three polyclonal antibodies: anti-Ya, Yb1 and Yp. With anti-Ya, hepatocytes were persistently positive up to 144 hr in cell culture. With anti-Yb1, hepatocytes were positive at 24 hr, though positivity then gradually decreased. On the other hand, with anti-Yp, cells were almost negative at 48 hr and became obviously positive at 96 hr. Immunoelectron microscopy with anti-Yb1 using the avidin-biotin ferritin method revealed ferritin particles in the ribosomes on endoplasmic reticulum as well as in the free cytoplasmic space. In conclusion, the GST subunit components are in a state of dynamic change in cultured rat hepatocytes, and overall time-dependent increase in the total activity of the enzyme can be accounted for by increased expression of the Yp subunit. Finally, the intracellular localization of Yb1 subunit was clarified in the present report.
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PMID:Glutathione S-transferases in primary cultured rat hepatocytes. 844 Apr 22

Phenobarbital is an inducer of xenobiotic-metabolizing enzymes, such as cytochrome P-450, glutathione S-transferases (GSTs) and NAD(P)H:quinone reductase, as well as being a promoter of hepatocarcinogenesis. The molecular mechanisms regulating these biological activities are, however, unknown. In this paper we show that induction by phenobarbital of GST Ya and quinone reductase gene expression is mediated by regulatory elements, EpRE and ARE respectively, which are composed of two adjacent AP-1-like binding sites. EpRE was recently found to be activated by a Fos/Jun heterodimeric complex (AP-1). Here we show that phenobarbital induces an increase in AP-1 binding activity in nuclear extracts of cultured hepatoma cells. Furthermore, we observe that the induction of chloramphenicol acetyltransferase (CAT) activity from an EpRE Ya-cat gene construct and of AP-1 binding activity by phenobarbital is inhibited by the thiol compounds N-acetyl-L-cysteine and glutathione. These results suggest that the phenobarbital induction of AP-1 activity, leading to the AP-1-mediated transcriptional activation of the GST Ya and quinone reductase genes, may involve production of reactive oxygen species and an increase in intracellular oxidant levels, which is prevented by thiol compounds. In view of the involvement of AP-1 in the control of cell proliferation and transformation, the induction by phenobarbital of AP-1 binding activity observed here provides a possible molecular mechanism for the tumour-promoting activity of this drug.
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PMID:Phenobarbital induction of AP-1 binding activity mediates activation of glutathione S-transferase and quinone reductase gene expression. 845 90

Class mu glutathione S-transferases (GSTs) are important in the detoxication of epoxides generated by oxidative metabolism. Phenobarbital, 3-methylcholanthrene, and pyridine have failed to enhance the expression of class mu GST isozymes in rabbit hepatic tissue (T. Primiano, S. G. Kim, and R. F. Novak, Toxicol. Appl. Pharmacol., 113, 64-73, 1992). Two class mu GST isozymes have been isolated from rabbit hepatic cytosol and purified to homogeneity using S-hexylglutathione-agarose, CM-Sepharose, and PBE94 chromatofocusing chromatography. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analyses showed that both isozymes possessed M(r) values of approximately 25,500 and cross-reacted with class mu-specific GST IgG. Gel filtration analysis revealed that these isozymes were dimers with molecular weights of approximately 45 kDa. The class mu GST isozymes had pIs of 7.8 and 7.2 as determined by nonequilibrium pH gel electrophoresis. The class mu GST 7.8 and 7.2 isozymes exhibited different metabolic activities toward the substrates 1-chloro-2,4-dinitrobenzene, bromosulfophthalein, 1,2-epoxy-3-(p-nitrophenoxy)propane, trans-4-phenyl-3-buten-2-one, p-nitrobenzyl chloride, and 3,4-dichloronitrobenzene. Metabolic activity of the two GSTs toward the substrate 1-chloro-2,4-dinitrobenzene was inhibited by Cibacron blue, triethyltin bromide, S-hexylglutathione, bromosulfophthalein, and indomethacin. The amino acid composition of GST mu 7.8 and 7.2 was determined and found to be very similar to those of purified rat class mu GST isozymes. N-terminal analysis of the first 21 residues of the pI 7.8 class mu GST isozyme revealed that it had 71 and 81% sequence identity with the Yb1 and Yb2 subunits, respectively. Similarly, N-terminal analysis of the first 21 residues of the pI 7.2 class mu GST isozyme revealed a 75% sequence identity with either the rat Yb1 or Yb2 subunit. Examination of class mu GST expression in rabbit hepatic cytosol following treatment with a series of known inducers including phenobarbital, 3-methylcholanthrene, isosafrole, pyrazine, trans-stilbene oxide, butylated hydroxyanisole, and tert-butylhydroquinone was accomplished. The data show that these agents not only failed to enhance class mu GST expression, but that 3-methylcholanthrene and isosafrole caused suppression of class mu GSTs. These results provide evidence for the existence of two closely related class mu GST isozymes in rabbit hepatic tissue and suggest that the molecular mechanisms regulating GST expression differ between rat and rabbit in response to these xenobiotics.
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PMID:Purification and characterization of class mu glutathione S-transferase isozymes from rabbit hepatic tissue. 846 Sep 49


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