Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.5.1.18 (glutathione S-transferase)
 22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extrapolation of in vitro data to predict occurrences in vivo is an uncertain process at best. In this study, clearance concepts initially developed to describe elimination of drugs and other substances by kidney and liver have been extended to calculate pulmonary extraction of circulating benzo(a)pyrene 4,5-oxide. Apparent kinetic parameters (Km and Vmax) for pulmonary microsomal epoxide hydrolase and cytosolic glutathione S-transferase were estimated by using in vitro enzyme assays, and whole tissue Vmax values of the two epoxide-metabolizing pathways were determined. From these data, a whole organ extraction ratio for benzo(a)pyrene 4,5-oxide was derived. The calculated extraction ratio (nearly one) was greater than, but in reasonable agreement with, the measured extraction ratio determined by using isolated perfused rabbit lungs exposed to circulating benzo(a)pyrene 4,5-oxide. The actual extraction ratio was 0.64 +/- 0.04 (x +/- S.D.,N = 3), which indicated that the rabbit lung was capable of removing a large percentage of circulating benzo(a)pyrene 4,5-oxide in a single pass through the organ. Therefore, the lung may play an important role in removing and biotransforming circulating arene oxides, as the entire cardiac output passes through the pulmonary capillary bed.
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PMID:Prediction of pulmonary benzo(a)pyrene 4,5-oxide clearance: a pharmacokinetic analysis of epoxide-metabolizing enzymes in rabbit lung. 719 Jun 5

trans-Stilbene oxide has been found to be a new type of inducer of drug-metabolizing systems. In order to identify the true inducer and to determine the structural requirements for induction, rats were treated with metabolites and structural analogues of stilbene. Subsequently, hepatic levels of cytochrome P-450, microsomal epoxide hydrolase, and cytoplasmic glutathione S-transferase were assayed. All three enzymes were induced by cis- and trans-stilbene and cis- and trans-stilbene oxide. In addition, epoxide hydrolase and glutathione S-transferase activities were induced by benzoin and benzil. In contrast, the diols and benzoic acid had little, if any, effect. The main conclusions drawn from these findings are that: (1) trans-stilbene oxide itself seems to be the inducer of drug-metabolizing enzymes; and (2) benzil is more selective as an inducer of epoxide hydrolase than is trans-stilbene oxide. Attempts to induce epoxide hydrolase with other structural analogues of stilbene led to the following conclusions: (1) two phenyl rings are required for induction; (2) the induction is not as great if the rings are substituted or one of the ring carbon atoms is replaced by a nitrogen; (3) a carbon bridge between the phenyl groups generally results in a greater induction, especially if the bridge contains an epoxy group or one or two keto groups.
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PMID:Induction of drug-metabolizing systems and related enzymes with metabolites and structural analogues of stilbene. 721 12

Changes in hepatic drug-metabolizing enzymes after intraperitoneal treatment of rats with 2-acetylaminofluorene have been investigated. This treatment was found to increase microsomal epoxide hydrolase to 762%, cytochrome P-450 to 143%, NADPH-cytochrome c reductase to 160%, cytochrome b5 to 171%, cytoplasmic DT-diaphorase to 229% and soluble glutathione S-transferase activities to 200-250% of control values. These increases were time- and dose-dependent, being maximal after injection of 50 mg 2-acetylaminofluorene/kg body wt. once daily for 5 days. Enzyme markers for the plasma membrane, mitochondria, lysosomes and the soluble cytoplasm were not affected by treatment with 2-acetylaminofluorene. The present study indicates that this induction is different from that obtained with phenobarbital and 3-methylcholanthrene and more closely resembles that seen with trans-stilbene oxide.
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PMID:Characterization of the induction of drug-metabolizing enzymes by 2-acetylaminofluorene. 722 16

Milk from lactating goats fed tansy ragwort (Senecio jacobaea) was evaluated for its ability to influence hepatic drug metabolism. The milk after being freeze-dried was fed to male rats for 1 week ad lib. A significant reduction in the activities of hepatic aminopyrine N-demethylase and aryl hydrocarbon hydroxylase was obtained. There was no significant change in the activities of microsomal epoxide hydrolase and cytosolic glutathione S-transferase. The data suggest that consumption of milk from goats fed Senecio jacobaea produces a selective alteration of the activities of hepatic drug-metabolizing enzymes.
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PMID:Effect of consumption of milk from goats fed Senecio jacobaea on hepatic drug metabolizing enzyme activities in rats. 730 64

1. The influence of the endogenous steroid epoxides 16 alpha, 17 alpha-epoxyestra-1,3,5(10)-trien-3-ol (estroxide) and 16 alpha, 17 alpha-expoxiandrost-4-en-3-one (androstene oxide) and their metabolic precursors estra-1,3,5(10), 16-tetraen-3-ol (estratetraenol) and androsta-4, 16-dien-3-one (androstadienone) on the specific activities of hepatic microsomal and soluble epoxide hydrolase, glutathione S-transferase, dihydrodiol dehydrogenase, and 7-ethoxycoumarin deethylase was investigated in the male Sprague-Dawley rat. 2. Both estroxide and estratetraenol induced microsomal epoxide hydrolase activity towards styrene oxide and estroxide itself 2-2.5-fold and glutathione conjugation of 1-chloro-2,4-dinitrobenzene (CDNB) 1.6-fold after intraperitoneal administration of a high dose of compound (300 mg per kg of body weight). 3. In addition, estroxide decreased 7-ethoxycoumarin deethylation down to 20% of the activity observed in the untreated rat, whereas estratetraenol enhanced the activity of soluble epoxide hydrolase towards trans-stilbene oxide by a factor of 1.7. 4. In contrast, neither androstene oxide nor androstadienone showed a significant influence on any of the parameters under investigation. Dihydrodiol dehydrogenase was not significantly changed by any of the treatments.
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PMID:Induction of rat liver microsomal epoxide hydrolase by its endogenous substrate 16 alpha, 17 alpha-epoxyestra-1,3,5-trien-3-ol. 761 50

The chemopreventive properties of allyl sulfides on carcinogenesis may be related to the modulation of drug-metabolizing enzymes involved in carcinogen activation or detoxication. In order to investigate the effects of diallyl sulfide (DAS) and diallyl disulfide (DADS) on intestinal and hepatic drug-metabolizing enzymes, rats were fed a diet containing 0.2% of either allyl sulfide. The DADS enhanced intestinal epoxide hydrolase (EH) and cytochrome P-450 (P-450) 2B1/2 protein levels and the activities of pentoxy- and benzyl-oxyresorufin O-dealkylases, arylhydrocarbon hydroxylase, microsomal epoxide hydrolase, p-nitrophenol UDP-glucuronyl transferase and glutathione S-transferase, and decreased nitrosodimethylamine demethylase activity. In liver, DADS produced similar effects and, in addition, increased P-450 1A1/2 protein level and phenoxazone metabolizing activities (ethoxy- and methoxyresorufin O-dealkylases), p-hydroxybiphenyl UDP-glucuronyl transferase, and decreased P-450 2E1 level. The DAS enhanced only EH activity in the small intestine and induced P-450 2B1/2 and epoxide hydrolase protein levels. In liver, DAS produced similar effects as DADS. The different effects of DAS on intestinal drug-metabolizing enzymes, compared to liver, could be ascribed to less metabolism of this compound in small intestine. It is also suggested that DAS and DADS may not yield the same metabolites and therefore would have different effects on intestinal drug-metabolizing enzymes.
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PMID:Differential effects of dietary diallyl sulfide and diallyl disulfide on rat intestinal and hepatic drug-metabolizing enzymes. 772 75

The induction of a variety of drug-metabolizing enzymes by polychlorinated biphenyl (PCB) congeners that elicit a 2,3,7,8,-tetrachlorodibenzo-p-dioxin (TCDD)-type hepatic pleiotropic response, including 2,3,3',4,4'-pentachlorobiphenyl (BZ 105), 2,3',4,4',5-pentachlorobiphenyl (BZ 118), 2,3,3',4,4',5-hexachlorobiphenyl (BZ 156), and 3,3',4,4',5,5'-hexachlorobiphenyl (BZ 169) was examined. Following dietary exposure to the individual congeners for 5 days, livers were removed and catalytic assays for cytochrome P450 (CYP) isozymes 1A1 and 1A2 were performed. Additionally, total cellular RNA coding for hepatic drug-metabolizing genes (CYP 1A1, CYP 1A2, microsomal epoxide hydrolase, glutathione S-transferase [GST] Ya/Yc, and the TCDD-inducible isozyme of aldehyde dehydrogenase [ALDH] was quantified. 3-Methylcholanthrene (MC), TCDD, or BZ 156 (32 ppm) caused nearly maximal induction of the CYP 1A proteins but lower induction of the other genes. When the dose-response curves for induction of various drug-metabolizing genes (CYP 1A1 and 1A2, microsomal epoxide hydrolase, the GST Ya/Yc subfamily and ALDH) were examined, a spectrum of ED50s (half-maximal inductions) was observed. While CYP 1A2 exhibited an ED50 of 1.7 ppm, the induction of ALDH was shifted far to the right (ED50 > 11 ppm). Thus, different genes in a single tissue may display different dose-response characteristics. The potency (extent of induction of CYP 1A1 activity resulting from a given dietary dose) was BZ 169 >> BZ 156 > BZ 118 > BZ 105. In contrast, the potencies of the four congeners for CYP 1A1 induction were nearly equivalent when related to hepatic PCB burden, apparently due to the preferential accumulation in the liver of BZs 169 and 156 following low-level administration in the diet.
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PMID:Relative potencies of induction of hepatic drug-metabolizing enzyme genes by individual PCB congeners. 778 61

Male Fischer rats were maintained for a period of 17 weeks on an iron-deficient diet along with suitable controls. The effect of long term deprivation of iron on xenobiotic metabolism was studied by the activities of various drug metabolising enzymes in both liver as well as extra-hepatic tissues like lungs, kidneys and intestinal mucosa (I.M.). The results show that among the Phase I (activating) enzymes, the hepatic activities of benzo(a)pyrene hydroxylase (AHH) and microsomal epoxide hydrolase (mEH) are significantly reduced in iron deficiency. The other parameters of the activating system, namely cytochrome P450, aminopyrene demethylase (ADM) and aniline hydroxylase (AH), are not altered. Of the two Phase II (conjugating) enzymes studied, only uridine diphospho glucuronyl transferase (UDPGT) is found to be depressed, but not glutathione S-transferase (GST) in liver in iron deficiency. Activities of Phase I enzymes are markedly lowered in extra-hepatic tissues compared to liver; such depression is not observed in conjugating enzymes. Iron deficiency does not seem to make much impact on the enzyme activities of extra-hepatic tissues. Overall, the hepatic results suggest a defect in detoxification mechanisms in iron deficiency. Such impairment may very well predispose an iron-deficient host to an increased risk of carcinogenesis.
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PMID:Effect of long term iron deficiency on the activities of hepatic and extra-hepatic drug metabolising enzymes in Fischer rats. 785 40

The effect of age and gender on the in vitro biotransformation of 2-methylpropene, an alkene metabolized to 2-methyl-1,2-epoxypropane, was studied. The epoxide concentration and the epoxide metabolizing enzymatic activities were investigated in male and female Brown Norway rats of different ages. Liver tissue of senescent rats was exposed to smaller 2-methyl-1,2-epoxypropane concentrations than that of young animals, although changes during ageing were rather modest. With advancing age a feminization of male glutathione S-transferase and cytosolic epoxide hydrolase activities was found, as well as a significant decline of the female microsomal epoxide hydrolase activity and an increase of the cytochrome P-450 content in the oldest female rats.
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PMID:Age- and gender-related changes in the hepatic metabolism of 2-methylpropene and relationship to epoxide metabolizing enzymes. 793 1

We constructed a complementary DNA (cDNA) library from mRNAs of rat liver induced by an initiating dose of a chemical carcinogen, N-nitrosodiethylamine (DEN). Using a differential hybridization with cDNA probes prepared from mRNAs of control and DEN-treated rat liver, eight cDNAs of which expression was altered by an acute single dose of DEN were cloned. Colony hybridization and nucleotide sequencing demonstrated six independent cDNA clones. These were known genes encoding liver-specific proteins such as microsomal epoxide hydrolase (mEH; epoxide hydrolase, EC 3.3.2.3), albumin, transthyretin, CYP2B7, CYP1A2 (microsomal cytochrome P450, EC 1.14.14.1) and argininosuccinate synthetase (EC 6.3.4.5). Quantitative Northern blot hybridization was carried out to measure the mRNA content of DEN-initiated rat liver at various times after DEN injection. We also analyzed the expression of glutathione transferase P (GST-P; glutathione transferase, EC 2.5.1.18), c-jun and glyceraldehyde-3-phosphate dehydrogenase (GAPDH; glyceraldehyde-phosphate dehydrogenase, EC 1.2.1.12). A single injection of DEN increased the mRNA levels of mEH, beta-actin and c-jun markedly and those of GST-P and GAPDH moderately, but decreased the mRNA levels of CYP2B7, CYP1A2, albumin and argininosuccinate synthetase. Transthyretin mRNA content was not changed, indicating that it was a false-positive clone picked up by chance. These dramatic changes in liver gene expression after acute exposure to DEN are discussed in terms of acute reactions to the massive damage to the DNA and self-defense mechanisms against toxic xenobiotics.
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PMID:Acute changes in liver gene expression in the N-nitrosodiethylamine-treated rat. 805 60


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