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)

Rats were injected intraperitoneally with phenobarbital (PB) and 3-methylcholanthrene (MC) which are microsomal enzyme inducers, and methyl iodide (MeI), cobalt chloride (CoCl2) and tri-o-cresyl phosphate (TOCP) which are inhibitors of the enzymes glutathione transferase, cytochrome (cyt) P-450 and carboxylesterase, respectively, and then challenged with soman (i.p.) to know its LD50. Pretreatment with PB and MC increased and TOCP decreased, whereas MeI as well as CoCl2 did not alter the LD50 value of soman in rats. The 1/2 LD50 dose of soman did not affect the liver microsomal cyt P-450 level, but significantly lowered carboxylesterase (CaE) and cholinesterase (ChE) activities in liver microsomes and in blood plasma. Induction of plasma CaE was more important than microsomal CaE in PB-mediated protection against soman toxicity. Gel filtration of plasma into four protein fractions for their relative soman binding capacity showed that a high-molecular-weight protein fraction (180,000 daltons on SDS-PAGE) which had no CaE activity could bind soman 6 times more than the low-molecular-weight CaE-containing protein fraction (60,000 daltons on SDS-PAGE).
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PMID:Role of carboxylesterase in protection against soman toxicity. 276 74

The effect of dietary administration of 0.5% ethoxyquin (EQ) on the in vivo induction of enzymes and effect on aflatoxin B1 (AFB1)-DNA binding in liver and the consequent in vitro metabolism of AFB1 by male Fischer F344 rat liver-derived fractions have been examined. EQ increased microsomal cytochrome P-450s, in particular those isozymes classed as phenobarbital inducible, and the in vitro rate of metabolism of AFB1. The formation of the presumed detoxified metabolites, aflatoxins M1 and Q1, was enhanced to a greater extent than was the formation of the active metabolite, aflatoxin B1-8,9 epoxide (assessed by the level of aflatoxin B1-8,9-dihydrodiol). Prolonged feeding with EQ was accompanied eventually by a reduction in the initially elevated cytochrome P-450 content, but this was not reflected in any significant decrease in the rate of AFB1 metabolism in vitro. EQ increased the glutathione S-transferase activity of the liver cytosol fractions as assessed with the model substrate 1-chloro-2,4-dinitrobenzene. The capacity of these fractions specifically to catalyze the conjugation of AFB1 with glutathione was induced to a far greater extent than was the conjugation of 1-chloro-2,4-dinitrobenzene. gamma-Glutamyl transpeptidase was induced in the periportal areas of the liver lobule. Reduced in vivo binding of [3H]AFB1 to DNA of liver and kidney was found to result from EQ treatment. It is concluded that the reduced hepatocarcinogenesis which results from feeding EQ simultaneously with AFB1 is due to the reduction in DNA-adduct formation which in turn is due at least in part to increased detoxifying metabolism in the microsomal, cytosolic, and plasma membrane compartments of the liver cells.
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PMID:Metabolic basis for the protective effect of the antioxidant ethoxyquin on aflatoxin B1 hepatocarcinogenesis in the rat. 288 84

A previously validated small mammal trauma model, hindlimb ischemia secondary to infrarenal aortic ligation in the rat, was utilized to investigate the effects of traumatic injury on two of the major hepatic enzymes of detoxification, glutathione S-transferase and epoxide hydrolase. Hepatic cytosolic glutathione S-transferase activity toward a variety of substrates showed a 26-34% decrease at 24 hr after model injury. Hepatic microsomal epoxide hydrolase activity toward 1,2-epoxy-3-(p-nitrophenoxy)propane was diminished by 53% after model trauma. Both enzymatic activities toward styrene oxide were similarly depressed. The toxicological sequelae of these derangements were illustrated by administering a dose of styrene oxide (300 mg/kg, ip) which was below the threshold dose (350 mg/kg, ip) necessary to produce hepatotoxicity in control animals. Model trauma dramatically enhanced the hepatotoxic effects of the subthreshold dose, as well as the covalent binding of labeled styrene oxide to liver proteins. These findings indicate that traumatic injury renders the animal more susceptible to agents which are detoxified by glutathione S-transferase and epoxide hydrolase. Conversely, model trauma provided almost complete protection from the hepatotoxic effects of a standard dose (200 mg/kg, ip) of bromobenzene. This protection appeared to derive from a post-traumatic alteration of cytochrome P-450 subpopulations that decreased the formation of the potentially toxic 3,4-epoxide metabolite, despite an increase in the cytochrome P-448-mediated generation of the nontoxic 2,3-epoxide. For bromobenzene, the change in cytochrome P-450-mediated activation appeared quantitatively more significant in overall toxicity than the post-traumatic depression of detoxification pathways described above, leading to decreased toxicity in vivo. For other compounds, the combination of post-traumatic influences on cytochrome P-450/P-448 activity and epoxide hydrolase/glutathione S-transferase activities could lead to markedly enhanced toxicity.
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PMID:Effects of model traumatic injury on hepatic drug metabolism in the rat. VI. Major detoxification/toxification pathways. 289 98

Exposure of rats to 1% or 3% (w/w) di(2-ethylhexyl)phosphate in the diet for five days results in two- to three-fold inductions of liver cytosolic epoxide hydrolase activity and microsomal cytochrome P-450 content. Cytochromes P-450b + e were induced 20- to 35-fold, but no increase was observed in cytochrome P-450c. Considerably smaller effects were obtained on NADPH-cytochrome c reductase, microsomal epoxide hydrolase and microsomal cytochrome b5 content, and there was no effect on cytosolic glutathione transferase activity, under the same conditions. A dramatic increase in cyanide-insensitive palmitoyl-CoA oxidation and total mitochondrial protein, together with smaller increases in total catalase and cytochrome oxidase activities, were observed after treatment with di(2-ethylhexyl)phosphate, indicating that this compound causes proliferation of both peroxisomes and mitochondria. It is suggested that the induction of cytosolic epoxide hydrolase and the proliferation of peroxisomes may be related processes.
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PMID:Induction of xenobiotic-metabolizing enzymes and peroxisome proliferation in rat liver caused by dietary exposure to di(2-ethylhexyl)phosphate. 311 Nov 7

Propiconazole, a foliar fungicide used for agricultural purposes was studied for its effects on the hepatic xenobiotic biotransformation in the rat. Rats were given an intraperitoneal injection of 0.1, 1, 10 or 100 mg/kg in corn oil for seven consecutive days. Induction was seen for cytochrome P-450, ethoxyresorufin-O-deethylase, ethoxycoumarin-O-deethylase, aldrin epoxidase, aminopyrine N-demethylase and microsomal expoxide hydrolase activities. Aniline p-hydroxylase and cytosolic glutathione S-transferase activities were unchanged. All responses occurred at only 100 mg/kg, except for that of aminopyrine N-demethylase which also occurred at the 10 mg/kg dose. SDS polyacrylamide gel electrophoresis showed increased staining of a protein band of molecular weight 54,000 corresponding to cytochrome P-450b and/or P-450d. Collectively these results suggest that cytochromes P-450b and P-450d have been induced after exposure of rats to propiconazole.
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PMID:The effects of propiconazole on hepatic xenobiotic biotransformation in the rat. 319 Jul 55

By the use of the dextran-coated charcoal method the presence of a high-affinity binding site for benzo(a)pyrene in the cytosol from rat liver (R strain) has been demonstrated. This binder was saturable by ligand concentration and by time. Sucrose density gradient analysis after charcoal treatment revealed one major peak of radioactivity sedimenting at 4.4 S which was displaceable by a 100-fold molar excess of nonlabeled benzo(a)pyrene. Benzo(a)pyrene binding to liver cytosol was sensitive to protease treatment of the cytosol suggesting that the binder was a protein. Saturation and Scatchard plot analysis of benzo(a)pyrene binding indicated a high-affinity (Kd = 4.7 nmol) and a relatively low binding capacity (Bmax = 379 fmol/mg cytosolic protein), allowing, to denote this binder as a receptor for benzo(a)pyrene. Competition studies showed that this cytosolic receptor was distinct from steroid hormone receptors since benzo(a)pyrene binding was partially inhibited by aromatic carcinogens 3-methylcholanthrene and benz(a)anthracene but not by estradiol, progesterone or cortisol. R strain rats used in these experiments were sensitive to induction with 3-methylcholanthrene which produced the increase of cytochrome Pl-450 content in liver microsomes, enhanced the glutathione S-transferase activity in hepatic cytosol and produced liver hypertrophy in stimulated animals. All these effects were related to the dose of 3-methylcholanthrene used for the induction. Also, the cytosolic binding capacity for benzo(a)pyrene was increased in animals stimulated with 3-methylcholanthrene in a dose-dependent fashion. The 3-methylcholanthrene-induced binder displayed identical sedimentation velocity and kinetic parameters (Kd) to those characteristic for the benzo(a)pyrene receptor in hepatic cytosol from unstimulated animals. Conclusively, our results demonstrated that benzo(a)pyrene was bound to a receptor protein in rat liver cytosol which was inducible by the classical inducer 3-methylcholanthrene. The mechanism of induction of this receptor and its role in cell response to aromatic carcinogens still need to be elucidated.
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PMID:Inducible high-affinity binding site for benzo(a)pyrene in cytosol from rat liver. 332 Jul 70

To exclude the possibility that changes in hepatotoxicity and biotransformation were induced by diabetogen administration, the influence of long-lasting experimental insulin-dependent diabetes on the activities of benzphetamine demethylase, styrene oxide hydrolase, and UDP-glucuronosyl-transferases toward 1-naphthol, diethylstilbestrol, estrone and testosterone, and glutathione S-transferases toward 1-chloro-2,4-dinitrobenzene, ethacrynic acid, and sulfobromophthalein was studied. Adult male Sprague-Dawley rats injected with 45 mg streptozotocin/kg rapidly developed the classical symptoms of diabetes which persisted throughout the 90-day test period. Ketonemia was detectable at 6 but not at either 35 or 90 days after streptozotocin administration. After acute challenge with bromobenzene or carbon tetrachloride (CCl4), aspartate and alanine aminotransferase activities in rats diabetic for 35 and 90 days were markedly higher than those in normal rats, suggesting that diabetes potentiated the hepatotoxicity of these chemicals. Administration of 25 microliters CCl4/kg, ip, to diabetic rats decreased enzyme activities toward benzphetamine, sulfobromophthalein, 1-chloro-2,4-dinitrobenzene, and 1-naphthol. In normal rats, a dose of 400 microliters CCl4/kg, ip, was required to cause similar changes in enzyme activities. Bromobenzene (500 microliters/kg, ip) elicited opposing responses in diabetic and normal rats in N-demethylase activity, in UDP-glucuronosyltransferase activity toward 1-naphthol, estrone, and testosterone, and in glutathione S-transferase activity toward 1-chloro-2,4-dinitrobenzene. Total cytochrome P450 concentrations were reduced by both induction of diabetes and hepatotoxicant challenge. Thus, chronic uncontrolled diabetes alters the response of hepatic xenobiotic biotransformation enzymes in a non-uniform, substrate-dependent manner, independent of initial diabetogen effects. The role of cytochrome P450j in potentiating CCl4 toxicity is discussed.
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PMID:The effect of long-term streptozotocin-induced diabetes on the hepatotoxicity of bromobenzene and carbon tetrachloride and hepatic biotransformation in rats. 335 67

MCF7 human breast cancer cells selected for resistance to doxorubicin (adriamycin; DoxR) have developed the phenotype of multidrug resistance. Multidrug resistance in DoxR MCF7 cells (called AdrR MCF7 cell line in previous publications) is associated with biochemical changes similar to those induced by carcinogens in rat hyperplastic liver nodules (HNs) and associated with resistance to xenobiotics in that system. In HNs and DoxR cells, exposure to a single agent results in the selection of cells that are cross-resistant to a wide variety of structurally dissimilar toxic agents. Resistance in both systems is associated with decreases in intracellular accumulation of toxins and changes in phase I (decreased cytochrome P1-450) and phase II (increased glutathione transferase and glucuronyltransferase) drug-metabolizing activities. In HNs and DoxR cells, resistance is associated with the induction of relatively stable levels of an immunologically related anionic glutathione transferase isozyme (EC 2.5.1.18). The finding of similar biochemical changes associated with the development of resistance to various xenobiotics in HNs and to many naturally occurring antineoplastic agents and at least one carcinogen (benzo[a]pyrene) in DoxR MCF7 cells suggests that the mechanisms of resistance in these two models may be similar.
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PMID:Similar biochemical changes associated with multidrug resistance in human breast cancer cells and carcinogen-induced resistance to xenobiotics in rats. 354 Sep 35

Hepatic microsomes from rats starved 48 hours and refed diets containing zero, 3 or 20% corn oil metabolized benzo(a)pyrene, aniline and N-nitrosodimethylamine in proportion to the quantity of corn oil in the diet. No diet-related changes in apparent Km for these reactions were evident. The content of microsomal cytochrome P-450 was also clearly dependent upon the content of corn oil in the refed diets. When metabolism of these three substrates is expressed as product formed per unit of cytochrome P-450, the activities are least in microsomes from rats fed the 20% corn oil diet, suggesting that P-450 species responsible for metabolizing substrates other than these are enhanced preferentially. Cytosolic glutathione S-transferase activities are also increased with increasing corn oil in the diet. The administration of 3-MC increased cytochrome P-448 content of microsomes from all rats, regardless of diet, however highest content was present in microsomes from rats fed the 20% corn oil diet. Induction of benzo(a)pyrene hydroxylase was not influenced by dietary corn oil and, as anticipated, 3-MC caused significant repression of DMN N-demethylase in microsomes from rats fed the 20% corn oil diet. In like manner, 3-MC induced glutathione S-transferase only in cytosol from rats fed the fat-free diet.
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PMID:Role of dietary corn oil in the function of hepatic drug and carcinogen metabolizing enzymes of starved-refed rats: response to the mixed function oxidase inducer, 3-methylcholanthrene. 355 14

A cDNA clone for the Ya subunit of glutathione transferase from rat liver was constructed in E. coli. The clone hybridized to Ya and Yc subunit messenger RNAs. On the basis of experiments involving cell-free translation and hybridization to the cloned probe, it was shown that prototype inducers of cytochrome P-450 such as phenobarbitone and 3-methylcholanthrene as well as inhibitors such as CoCl2 and 3-amino-1,2,4-triazole enhanced the glutathione transferase (Ya+Yc) messenger RNA contents in rat liver. A comparative study with the induction of cytochrome P-450 (b+e) by phenobarbitone revealed that the drug manifested a striking increase in the nuclear pre-messenger RNAs for the cytochrome at 12 hr, but did not significantly affect the same in the case of glutathione transferase (Ya+Yc). 3-Amino-1,2,4-triazole and CoCl2 blocked the phenobarbitone mediated increase in cytochrome P-450 (b+e) nuclear pre-messenger RNAs. These compounds did not significantly affect the glutathione transferase (Ya+Yc) nuclear pre-messenger RNA levels. The polysomal, poly (A)- containing messenger RNAs for cytochrome P-450 (b+e) increased by 12-15 fold after phenobarbitone administration, reached a maximum around 16 hr and then decreased sharply. In comparison, the increase in the case a glutathione transferase (Ya+Yc) messenger RNAs was sluggish and steady and a value of 3-4 fold was reached around 24 hr. Run-off transcription rates for cytochrome P-450 (b+e) increased by nearly 15 fold in 4 hr after phenobarbitone administration, whereas the increase for glutathione transferase (Ya+Yc) was only 2.0 fold. At 12 hr after the drug administration, the glutathione transferase (Ya+Yc) transcription rates were near normal. Administration of 3-amino-1,2,4-triazole and CoCl2 blocked the phenobarbitone-mediated increase in the transcription of cytochrome P-450 (b+e) messenger RNAs. These compounds at best had only marginal effects on the transcription of glutathione transferase (Ya+Yc) messenger RNAs. The half-life of cytochrome P-450 (b+e) messenger RNA was estimated to be 3-4 hr, whereas that for glutathione transferase (Ya+Yc) was found to be 8-9 hr. Administration of phenobarbitone enhanced the half-life of glutathione transferase (Ya+Yc) messenger RNA by nearly two fold. It is suggested that while transcription activation may play a primary role in the induction of cytochrome P-450 (b+e), the induction of glutathione transferase (Ya+Yc) may essentially involve stabilization of the messenger RNAs.
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PMID:A comparative study of the regulation of cytochrome P-450 and glutathione transferase gene expression in rat liver. 375 27


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