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)

Activities of enzymes involved in the metabolic formation and catabolism of epoxides were determined in liver subcellular preparations from 11 mammalian species and various strains of mice. The most conspicuous finding was that the activities of the microsomal epoxide hydrolase were clearly lower in the mouse than in the other species. This invited the working hypothesis that epoxides may be involved in mouse liver carcinogenesis. The carcinogens may be metabolised themselves to reactive epoxides or they may modify the metabolism of epoxides formed from endogenous or other foreign compounds. To examine the former point, phenobarbital, DDT (1,1-bis(p-chlorophenyl)-2,2,2-trichloroethane), lindane and benzo(a)pyrene were investigated for mutagenicity in Salmonella typhimurium using as the carcinogen-metabolising system subcellular liver preparations from animals in which these compounds efficiently induce liver tumours and from resistant animals. Phenobarbital, DDT and lindane were not mutagenic under any conditions, including those where microsomal epoxide hydrolase was also inhibited. However, a DDT metabolite, 1,1-bis(p-chlorophenyl)-2,2-dichloroethane was mutagenic in strain TA98, when norharman was added to the metabolising system, rat liver postmitochondrial fraction. Benzo(a)pyrene, which efficiently induces liver tumours in male but not in female newborn C3HeB/FeJ X A/J mice, was similarly activated by liver preparations from male and female animals. This was true with and without pretreatment of the mice with an inducer of cytochrome P-448. Also, activities and inducibilities of monooxygenase, epoxide hydrolase and glutathione transferase (toward benzo(a)pyrene and benzo(a)pyrene 4,5-oxide, respectively) were indistinguishable between males and females. Therefore, differences in the metabolism of benzo(a)pyrene do not appear to be the reason for the sex difference in tumour susceptibility. Likewise, mouse strains with high and low frequencies of spontaneous and chemically-induced liver tumours did not appreciably differ in their hepatic microsomal epoxide hydrolase activities. The low level of this activity therefore cannot constitute the critical factor for the high tumour susceptibility of certain strains of mice. However the statement does not preclude potentiation of the susceptibility toward particular carcinogens owing to this metabolic trait of the mouse.
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PMID:Species differences in enzymes controlling reactive epoxides. 243 83

Treatments known to alter P-450 activity and glutathione levels were used to elucidate the involvement of P-450 and glutathione S-transferase metabolism in 1,2-dibromo-3-chloropropane (DBCP) organ toxicity in the rat. Phenobarbital pretreatment abolished DBCP-induced renal necrosis, whereas it had only a small effect on initial renal DNA damage. The DBCP levels in plasma and tissues were markedly reduced by phenobarbital pretreatment. Perdeuterated DBCP had much higher plasma and tissue levels than protio-DBCP in phenobarbital-pretreated animals, but perdeuteration was without effect in uninduced animals. This indicates that P-450 metabolism of DBCP is of major importance only in phenobarbital-pretreated animals. In order to study the effects of decreased glutathione levels on renal distribution and toxicity, rats were pretreated with either diethyl maleate or buthionine sulfoximine. The DBCP levels in plasma and tissues showed transitory elevations after diethyl maleate and buthionine sulfoximine pretreatment compared to the control situation. Despite the fact that diethyl maleate and buthionine sulfoximine pretreatments are known to block DBCP-induced DNA damage in vitro, these pretreatments did not significantly alter DBCP-induced renal necrosis nor DNA damage. Thus, a role for glutathione conjugation in DBCP-induced in vivo renal toxicity could not be established in the present study.
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PMID:Role of P-450 activity and glutathione levels in 1,2-dibromo-3-chloropropane tissue distribution, renal necrosis and in vivo DNA damage. 273 6

The effect of intratracheal administration of fly ash, its benzene-extracted residue and the benzene extract has been studied on the activities of hepatic mixed-function oxidases in the rat. Fly ash and its fractions significantly increased the levels of cytochrome P-450, cytochrome b5, cytochrome b5 reductase, NADPH-cytochrome c reductase, aminopyrine N-demethylase, aniline hydroxylase, and glutathione S-transferase in a dose-dependent manner. Phenobarbital or 3-methylcholanthrene treatment along with the administration of fly ash or its fractions showed an additive effect on the activities of the mixed-function oxidases. The observed effects were due to chemical component, i.e., organic and inorganic fractions of fly ash, and not due to its particulate nature. This was shown by the administration of glass beads which did not cause any alteration in the activities of hepatic mixed-function oxidases.
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PMID:Induction of hepatic drug metabolizing enzymes by coal fly ash in rats. 312

The inducibility of the freshwater crayfish (Astacus astacus) biotransformation enzymes with model inducers (Aroclor 1254, beta-Naphthoflavone, Phenobarbital) were investigated three days after intra cephalothoracic injection in the fasting crayfish at 5 degrees C. Of the monooxygenase activities, 7-ethoxycoumar in O-deethylase increased in the hepatopancreas significantly (p less than 0.05) after beta-naphthoflavone administration. Benzo(a)pyrene hydroxylase did not change. Aroclor 1254 and phenobarbital injection elevated hepatopancreatic glutathione S-transferase activity (p less than 0.05).
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PMID:Induction of cytochrome P-450 mediated mono-oxygenase reactions and conjugation activities in freshwater crayfish (Astacus astacus). 346 18

The organophosphorous pesticide malathion is metabolized by three hepatic enzyme systems: the microsomal cytochrome P-450-dependent monooxygenase system, the microsomal carboxylesterases, and the cytosolic glutathione S-transferases. We produced differential induction of these three enzyme systems in mice with phenobarbital and 2(3)-tert-butyl-4-hydroxyanisole (BHA) and examined the effects of the induction on the inhibition of acetylcholinesterases by malathion. Phenobarbital not only significantly induced hepatic microsomal cytochrome P-450 (p less than 0.05) but also increased microsomal carboxylesterase activity (p less than 0.05). BHA not only increased the activity of microsomal carboxylesterases (p less than 0.05) but also substantially increased cytosolic glutathione S-transferase activity (p less than 0.05). Despite the differential effects of phenobarbital and BHA on the three enzyme systems, neither agent protected the mice against malathion toxicity.
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PMID:The effects of differential induction of cytochrome P-450, carboxylesterase and glutathione S-transferase activities on malathion toxicity in mice. 356 13

To characterize the distribution and inducibility of drug metabolizing enzymes within different hepatic cell populations, the activities of aminopyrine N-demethylase, ethoxyresorufin O-deethylase, microsomal epoxide hydrolase and cytosolic glutathione transferase were measured in liver parenchymal, Kupffer, and endothelial cells isolated from untreated rats or rats pretreated with phenobarbital, 3-methylcholanthrene, or Aroclor 1254. Enzyme activities, measurable in all cases, were 2.3- to 5.7-fold higher in parenchymal cells than in Kupffer and endothelial cells. Phenobarbital increased aminopyrine N-demethylase, microsomal epoxide hydrolase, and cytosolic glutathione transferase activities, whereas 3-methylcholanthrene enhanced ethoxyresorufin O-deethylase, epoxide hydrolase, and glutathione transferase activities in the three cell populations. Aroclor 1254 consistently induced each of the enzyme activities in parenchymal, Kupffer, and endothelial cells. Western blot analyses revealed clear differences in the expression of proteins immunologically related to cytochrome P-450 PB-1, and glutathione transferases B and X in parenchymal cells compared with the corresponding Kupffer and endothelial cells. In contrast, only minor differences between the cell types were apparent in the expression of cytochromes P-450 PB-4, P-450 MC1a, P-450 MC1b and microsomal epoxide hydrolase. These studies establish that oxidative and postoxidative drug metabolizing enzymes are not restricted to parenchymal cells: similar but distinguishable complements of these enzymes are also found in Kupffer and endothelial cells.
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PMID:Xenobiotic metabolizing enzymes are not restricted to parenchymal cells in rat liver. 367 Feb 81

Dietary polyunsaturated fatty acids enhance activation of constitutive and induced forms of enzymes of endoplasmic reticulum responsible for drug and carcinogen metabolism. The current report demonstrates that diets containing 10% or 20% refined menhaden fish oil that contains high concentrations of omega-3 fatty acids also supports these enzymes in a manner similar to that of oils that contain high concentrations of the omega-6 fatty acid linoleate. Cytosolic glutathione S-transferase was unaffected by dietary menhaden oil. However, ingestion of increasing concentrations of menhaden oil increased hepatic microsomal cytochrome P-450 content and the apparent Vmax for ethylmorphine N-demethylase, N-nitrosodimethylamine (DMN) N-demethylase, and benzo(a)pyrene [B(a)P] hydroxylase. Feeding menhaden oil increased the Km for ethylmorphine N-demethylase, and decreased Km's for DMN N-demethylase and B(a)P hydroxylase. Phenobarbital induced glutathione S-transferase activity only in rats fed 10% or 20% menhaden oil. Ethylmorphine N-demethylase was induced by only 25% by phenobarbital in rats refed the fat-free diet compared to 128% in rats refed the 20% menhaden oil. In contrast, DMN N-demethylase was induced only in rats fed the fat-free diet. B(a)P hydroxylase was induced in all rats regardless of the level of dietary fat. The specific activity of cytochrome P-450 for the metabolism of DMN and B(a)P, however, was significantly reduced in menhaden oil-fed animals by phenobarbital. This coupled with the increased Km for these reactions may have significant effects on the in vivo activation of these carcinogens in animals fed menhaden oil and subjected to dietary inducers of the mixed function oxidases.
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PMID:Influence of dietary menhaden oil on the enzymes metabolizing drugs and carcinogens. 379 15

The effect of intratracheal administration of fly ash, benzene extracted fly ash residue and benzene extract of fly ash has been studied on the activity of pulmonary mixed function oxidase. Fly ash, its benzene extract and benzene extracted residue significantly increased the levels of cytochrome P-450, cytochrome b5 and the activities of NADPH-cytochrome c reductase, NADH cytochrome b5 reductase, aminopyrine N-demethylase and glutathione S-transferase in a dose dependent manner. Phenobarbital or 3-methylcholanthrene treatment along with administration of fly ash, its benzene extracted residue and benzene extract of fly ash showed a synergistic effect on the activity of mixed function oxidase. The observed effects were due to chemical causes, i.e. organic and inorganic fractions of fly ash and not, due to its particulate nature. This was shown by the administration of glass beads which caused no alteration in the activity of pulmonary mixed function oxidase.
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PMID:Induction of pulmonary drug metabolizing enzymes by coal fly ash in rats. 404 29

Messenger RNA extracted from the livers of normal, phenobarbital-treated, and trans-stilbene oxide-treated rats was translated in a mRNA-dependent protein-synthesizing system. Immunoprecipitation of the translation products by antibodies against the Ya and Yc subunits of glutathione S-transferase detected two polypeptides of molecular weights 23,500 and 25,000. Subsequently, a clone containing glutathione S-transferase sequences was identified from a rat liver double-stranded cDNA library that had been prepared by homopolymeric tailing and cloning into the Pst I site of pBR322. Confirmation of the identity of the clone was obtained by recloning the 550-bp insert DNA into the phage vector M13 and utilizing the single strand recombinant phage DNA in specific hybrid selection of mRNA followed by translation and immunoprecipitation with antibodies to the Ya and Yc subunits. This recombinant phage, M13GST94, was also utilized in a new technique to synthesize 32P-labeled cDNA specific to the glutathione S-transferase insert DNA that was used subsequently in RNA excess solution hybridization to determine the relative concentration of glutathione S-transferase mRNA. Phenobarbital treatment resulted in a 3.2-fold increase in glutathione S-transferase mRNA over levels found in control rats, while trans-stilbene oxide increased glutathione S-transferase mRNA levels 5.7-fold. The DNA sequence of the clone was determined and utilized to propose a partial amino acid sequence.
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PMID:Rat glutathione S-transferase. Cloning of double-stranded cDNA and induction of its mRNA. 627 41

Respiratory tract biotransformation of many xenobiotics found in inhaled environmental pollutants is generally considered essential for the mutagenic, carcinogenic, and/or toxic response of lung tissue to these xenobiotics. Typical environmental pollutants contain known carcinogens adsorbed onto particles which can deposit in the nasal pharyngeal region of the respiratory tract. The purpose of this study was to characterize the metabolic capacity of rat nasal tissue. Both oxidative and nonoxidative enzyme activities were investigated which included aryl hydrocarbon hydroxylase (AHH), epoxide hydrolase (EH), uridine 5'-diphosphate-glucuronyltransferase (UDPGT), and glutathione transferase. Specific enzyme activities of AHH, EH, UDPGT, and glutathione transferase were 0.023, 6.4, 20.4, and 24.8 nmol product per mg protein per min, respectively. Benzo(a)pyrene was metabolized by AHH to dihydrodiols, quinones, and phenols in quantities which were about 10 times greater than those reported for rat lung microsomes. Small, but detectable, quantities of benzo(a)pyrene tetrols were also measured in reaction flasks in which rat nasal tissue was incubated with benzo(a)-pyrene. Attempts to increase the microsomal enzyme activities of AHH, EH, and UDPGT by pretreating rats with various inducing agents by both i.p. injection (phenobarbital, 3-methylcholanthrene, Aroclor 1254, and 2,3,7,8-tetrachlorodibenzo-p-dioxine) and inhalation exposure (BaP) resulted in rat nasal monooxygenases only being induced (2-fold) after pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxine. Phenobarbital increased enzyme activities of EH and UDPGT by about 50%. These data suggest that rat nasal tissue may contain multiple forms of cytochrome P-450 and of EH and UDPGT. The results from this study support the notion that nasal tissue may be important in determining the metabolic fate of inhaled xenobiotics.
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PMID:Some biotransformation enzymes responsible for polycyclic aromatic hydrocarbon metabolism in rat nasal turbinates: effects on enzyme activities of in vitro modifiers and intraperitoneal and inhalation exposure of rats to inducing agents. 630 78


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