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)

In vitro drug metabolism in the Hartley guinea pig was compared with that in two inbred guinea pig strains used as carriers for the line 10 hepatoma. We observed minor differences in enzyme specific activity among the three strains. Three weeks after intradermal inoculation of Strain 2 guinea pigs with line 10 hepatoma cells, cytochrome P450 levels and aminopyrine demethylase activity were significantly decreased. Seven to 10 days after inoculation with the ascites form of the tumor, the activities of aniline and biphenyl hydroxylases, p-aminobenzoic acid N-acetyltransferase, and dichloronitrobenzene glutathione S-aryltransferase, in addition to those of cytochrome P450 and aminopyrine N-demethylase, were probably also described.
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PMID:Effect of strain differences and tumor presence on microsomal drug metabolism in the guinea pig: brief communication. 20 Jul 61

A study of glyceryl trinitrate metabolism by a filamentous fungus, Phanerochaete chrysosporium, carried out with the 14C-labeled substrate, provides evidence for a multienzymatic system leading to di- and mononitrate derivatives. At least two independent enzymatic activities were detected in the cytosolic fraction: an aerobic glutathione S-transferase activity and an anaerobic NADPH-dependent soluble cytochrome P450-like activity. Other hemoproteins with enzymatic activities dependent upon the presence of NADPH or ferrous ions were also detected in the microsomal fraction. Electron paramagnetic resonance spectra characteristic of an interaction between a hemoprotein and nitric oxide appeared in these two subcellular fractions during the anaerobic metabolism of glyceryl trinitrate.
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PMID:Multiple enzymatic pathways involved in the metabolism of glyceryl trinitrate in Phanerochaete chrysosporium. 132 93

1,2-Dithiole-3-thiones are five-membered cyclic sulfur-containing compounds with antioxidant, chemotherapeutic, radioprotective and chemoprotective properties. Several substituted 1,2-dithiole-3-thiones are used medicinally and one of these, oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione], has been recently shown to be an inhibitor of aflatoxin B1 (AFB1) hepatocarcinogenesis in the rat. Structure-activity studies have been undertaken to probe the mechanisms by which dithiolethiones inhibit carcinogenesis. Such studies revealed that unsubstituted 1,2-dithiole-3-thione was more effective than oltipraz at inhibiting aflatoxin-DNA adduct formation in vivo and at inducing electrophile detoxication enzymes in cell culture. In the present studies the effects of dietary administration of 1,2-dithiole-3-thione on the induction of xenobiotic metabolizing enzymes and inhibition of aflatoxin-induced hepatic tumorigenesis were examined. Male F344 rats were fed graded doses of 1,2-dithiole-3-thione (0.001-0.03%) for 4 weeks. During the second and third weeks of 1,2-dithiole-3-thione feeding, rats were dosed by gavage with 250 micrograms of AFB1/kg five times a week. Rats were then restored to control AIN-76A diet 1 week after cessation of AFB1 dosing. At 4 months, focal areas of hepatocellular alteration were identified and quantified by staining sections of liver for gamma-glutamyltranspeptidase (GGT) activity and glutathione S-transferase P (GST-P) expression. Treatment with 1,2-dithiole-3-thione at the lowest dose (0.001%) reduced by greater than 80% the volume of liver occupied by GGT or GST-P foci; higher dietary concentrations provided greater than 98% reductions in the volume per cent of these markers for presumptive preneoplastic lesions. All dietary concentrations of 1,2-dithiole-3-thione resulted in significant elevations in hepatic GST activities. In accord with the protective effects against tumorigenesis, 4- to 6-fold increases in the specific activities of aflatoxin-glutathione conjugation were observed in cytosols prepared from livers of animals fed 1,2-dithiole-3-thione. By contrast, 1,2-dithiole-3-thione did not have any detectable inductive effects on hepatic microsomal cytochrome P450 levels or activities. Dietary administration of 1,2-dithiole-3-thione also elevated activities of GSTs and other phase II enzymes in several extrahepatic organs. This broad pattern of induction of detoxication enzymes by 1,2-dithiole-3-thione supports the potential widespread use of this compound as a protective agent against chemical carcinogenesis and other forms of electrophile toxicity.
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PMID:Potent inhibition of aflatoxin-induced hepatic tumorigenesis by the monofunctional enzyme inducer 1,2-dithiole-3-thione. 134 73

The effects of a number of phenobarbital-type inducers on selected drug-metabolizing enzymes in male F344/NCr rats were determined by measuring specific catalytic activities and/or by measuring the levels of RNA which hybridize with specific probes for the corresponding genes. The effects on hepatic CYP2B1 were assessed by measuring the levels of CYP2B1-specific RNA and benzyloxyresorufin O-dealkylase and testosterone 16 beta-hydroxylase activities. Levels of CYP3A were monitored by measuring the rate of hydroxylation of testosterone at the 6 beta-position. Microsomal epoxide hydrolase activity was determined by measurement of cellular RNA specific for this form and by assaying the hydrolysis of benzo[a]pyrene-4,5-oxide. UDP-glucuronyltransferase activity was assayed by measuring the glucuronidation of 3-hydroxybenz[a]anthracene. Levels of glutathione S-transferase Ya/Yc were measured by quantifying total cellular RNA coding for the proteins. When male F344/NCr rats were administered various doses of phenobarbital or dichlorodiphenyltrichloroethane (DDT), strong correlations between the induction of CYP2B1 and the induction of epoxide hydrolase or UDP-glucuronyltransferase activities were observed. Treatment of rats with barbiturates, hydantoins, halogenated pesticides such as DDT or alpha-hexachlorocyclohexane, 2,4,5,2',4',5'-hexachlorobiphenyl, CYP2B1 inhibitors such as clotrimazole or clonazepam, or such structurally-diverse compounds as 2-hexanone or diallyl sulfide resulted in induction of CYP2B1-mediated enzyme activity and induction of certain other forms of cytochrome P450, microsomal epoxide hydrolase, at least one form of UDP-glucuronyltransferase, and multiple forms of glutathione S-transferase. This suggests that, as a class, compounds which induce CYP2B1 also induce a coordinate hepatic pleiotropic response which includes induction of these other phase I and phase II drug-metabolizing enzymes.
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PMID:A pleiotropic response to phenobarbital-type enzyme inducers in the F344/NCr rat. Effects of chemicals of varied structure. 137 5

Effects of chemically induced hepatic injury on biotransformation enzymes in fish were studied. Sunfish hybrids (Lepomis macrochirus x L. cyanellus) were dosed per os with allyl formate (ALF) and carbon tetrachloride (CCl4), and the induction of liver EROD (7-ethoxyresorufin O-deethylase) activity was subsequently challenged by injections of beta-naphthoflavone (BNF) and benzo[a]pyrene (B[a]P). Hepatotoxicity of chemical treatments was assessed using blood enzymes (ASAT, ALAT, and LDH) along with other biochemical variables. Both hepatotoxicants partially abolished the induction of EROD (maximally by 76-89%), and the decrease in induction was dose related. The cytosolic activity of glutathione S-transferase (GST) in the liver decreased in parallel with the decrease in EROD induction. Fish receiving high doses of ALF exhibited significantly less microsomal and blood plasma proteins and, occasionally, were jaundiced. These symptoms, however, were less sensitive indicators of hepatotoxicity than alterations in liver EROD and GST. Both ALF and CCl4 increased the activities of hepatic enzymes in the blood plasma, indicating cytotoxicity. In addition B[a]P, unlike BNF, also increased plasma activities of LDH and ALAT at a dose inducing liver EROD, implying simultaneous hepatotoxicity at high sublethal levels of this xenobiotic. These data suggest that hepatotoxic chemicals absorbed by fish may act antagonistically by decreasing the degree of induction of the cytochrome P450 system relative to the inherent capacity of inducing xenobiotic chemicals present in the environment. Therefore, when assessing the toxicological status of water using fish health biomarkers, it is advisable to measure a concert of metabolic and biochemical variables instead of any single biomarker.
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PMID:Effects of hepatotoxicants on the induction of microsomal monooxygenase activity in sunfish liver by beta-naphthoflavone and benzo[a]pyrene. 137 51

Male B6C3F1 mice were exposed to 4000 ppm methylene chloride (MC) for 6 hr/day, 5 days/week for up to 13 weeks. Groups of mice were killed at intervals from Day 2 to Week 13. Whole lungs were examined morphologically, immunocytochemically, and biochemically. Biochemical and morphological examination was also performed on isolated Clara cells. The major initial morphological effect seen in lungs was acute Clara cell damage after one exposure to MC. However, this damage appeared to resolve after five consecutive daily exposures to MC. After a 2-day interval the Clara cell lesion reappeared on subsequent reexposure to MC. However, the severity of the lesion decreased over the duration of the study. The appearance and disappearance of the lesion in the Clara cell correlated well with the activity of cytochrome P450 monooxygenase in the Clara cell as assessed immunocytochemically (cytochromes P450IIB 1 and 2) in the whole lung and biochemically in the freshly isolated Clara cell (determined by ethoxycoumarin O-dealkylation and aldrin epoxidation). When there was a marked decrease in cytochrome P450 monooxygenase activity the lesion was not present. This suggested that with time the lung (Clara cell) has developed tolerance to MC possibly due to the inactivation of a cytochrome P450 isozyme. The glutathione S-transferase metabolism of MC by the lung cytosol remained virtually unaltered throughout the study. Events accompanying the discussed changes include (1) a significant increase in nonprotein sulfhydryl in the lungs of all exposed animals, (2) altered plating characteristics of the isolated Clara cells from exposed lungs after 24 hr in culture, and (3) an increase in the number of bronchiolar cells in the S-phase after the first exposure to MC. The study also demonstrates the advantages of target cell isolation and study over whole lung biochemical investigation alone.
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PMID:Methylene chloride--an inhalation study to investigate pathological and biochemical events occurring in the lungs of mice over an exposure period of 90 days. 137 20

Male mice were exposed via their diet to perfluoro fatty acids of various chain-lengths (2-10 carbon atoms) at different doses (0.02 and 0.1% weight) and for different periods of time (2-10 days). Thereafter, we monitored effects on liver and body weights and a number of hepatic parameters, including mitochondrial protein content, microsomal contents of cytochromes P450 and b5, NADPH-cytochrome P450 reductase activity [measured as NADPH-cytochrome c reductase (EC 1.6.2.3)], microsomal and cytosolic epoxide hydrolase (EC 3.3.2.3) activities, cytosolic DT-diaphorase (EC 1.6.99.2), glutathione transferase (EC 2.5.1.18), glutathione peroxidase (EC 1.11.1.9) and superoxide dismutase (EC 1.15.1.1) activities, and levels of thiobarbituric acid-reactive material (as an indicator of lipid peroxidation) in the mitochondrial subfraction. The most dramatic changes observed were a 5-9-fold increase in mitochondrial protein, a 3-6-fold increase in the microsomal content of cytochrome P450, a 3-10-fold increase in cytosolic DT-diaphorase activity, an approximately 2-fold increase in cytosolic epoxide hydrolase activity and as much as a 60% decrease in the level of thiobarbituric acid-reactive compounds in the mitochondrial fraction. Smaller increases in microsomal epoxide hydrolase activity and decreases in cytosolic glutathione peroxidase activity were also observed. Of the perfluoro fatty acids tested, perfluorooctanoic acid caused the largest changes in the parameters examined here. Dietary exposure of mice to a 0.02% dose of this substance for 10 days results in a maximal or near-maximal effect in most cases.
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PMID:Effects of perfluoro fatty acids on xenobiotic-metabolizing enzymes, enzymes which detoxify reactive forms of oxygen and lipid peroxidation in mouse liver. 141 40

The hepatocarcinogenic responses of rats to aflatoxin B1 (AFB1) are believed to depend on microsomal activation of the toxin, followed by macromolecular binding. Dietary protein insufficiency is reported to reduce the level of microsomal metabolism, and therefore would be expected to reduce the AFB1-induced carcinogenicity. Indeed, diminished hepatocarcinogenicity in low-protein diet fed weanling rats that had received AFB1 has been reported. In the present study, carcinogenicity and other toxic effects of AFB1 (0.5 p.p.m.) fed to weanling male Fischer F344 rats on a low-protein diet (5%) or normal-protein (20%) diet for up to 8 weeks were examined. In our study, in contrast with the previous report, all animals that had survived some initial toxicity were found to have developed hepatic tumors or hyperplastic gamma-glutamyltransferase-positive foci a year later. The low-protein diet also produced sub-acute toxicity after AFB1 exposure in the weanling rats, leading to severe histological changes, and the death of about half the animals after 3-4 weeks of exposure. Animals fed an AFB1-containing normal-protein diet also exhibited AFB1-induced hepatocarcinogenicity, but not the sub-acute toxicity. The levels of hepatic enzymes involved in AFB1 metabolism were examined in animals fed the low- or normal-protein diets in the absence of AFB1. The low-protein diet, fed to 3 week weanlings for the subsequent 5 weeks, decreased hepatic cytochrome P450 levels, as well as the in vitro capacity of microsomal fractions to form AFB1-8,9-dihydrodiol, an index of AFB1-8,9-epoxide formation. Rats on a normal-protein diet did not show these changes. This discrepancy between the observed increase in sub-acute toxicity and decrease in microsomal activities in the low-protein fed animals implies that the toxic effects observed in these rats were not directly related to metabolic activation of the toxin. In contrast to the diminished microsomal in vitro AFB1 activation, however, in vivo AFB1-DNA adduct formation ability in rats receiving the low-protein diet in the absence of AFB1 was found to become elevated more rapidly during the 5 week experimental feeding period, compared with animals receiving the normal-protein diet. This was accompanied by a more rapid fall in the levels of AFB1-glutathione S-transferase isozyme activity in the low-protein fed animals. The results of this study on weanling rats support the importance of AFB1-GSH in protecting against the carcinogenic responses to AFB1, and probably also the sub-acute toxicity of the latter.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of dietary protein level on aflatoxin B1 actions in the liver of weanling rats. 142 44

1. The inductive effect of N-benzylimidazole (NBI) on hepatic microsomal and cytosolic drug-metabolizing enzyme activities in aryl hydrocarbon (Ah)-responsive C57BL/6N (B6) and Ah-non-responsive DBA/2N (D2) mouse strains was determined and compared with that caused by beta-naphthoflavone (BNF). 2. Relative Ah-responsiveness of the two strains was confirmed by measurement of BNF-induced ethoxyresorufin deethylase (EROD) activity and ELISA immunoquantification. BNF markedly induced EROD activity only in the Ah-responsive B6 mouse strain (65-fold increase). 3. NBI (150 mg/kg per day for 3 days) increased cytochrome P450 concentration similarly in both strains (40 and 60% in B6 and D2 strains, respectively). Compared with BNF treatment of the B6 strain, increases in EROD activity following NBI treatment were only minor. In addition, EROD activity increases were greater in the Ah-nonresponsive D2 strain (300%) than in the Ah-responsive B6 strain (100%) suggesting the possibility of an induction mechanism different from that of recognized Ah receptor agonists. 4. Induction of UDP-glucuronosyltransferase activity (p-nitrophenol acceptor) by BNF was greater in the Ah-responsive B6 strain than in the Ah-non-responsive D2 strain. NBI failed to induce this activity in either strain. 5. Induction of glutathione S-transferase activity towards 1-chloro-2,4-dinitrobenzene following NBI treatment occurred to the same extent (25% increase) as that seen following BNF treatment, in the Ah-responsive B6 strain. Neither xenobiotic affected this activity in the Ah-non-responsive D2 strain. 6. Although NBI is a major inducer, possessing Ah-like inducing properties in rat, it caused only minor changes in murine drug metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:N-benzylimidazole-mediated changes in hepatic drug-metabolizing enzyme activities in Ah-responsive and Ah-non-responsive mice. 149 85

The effects of three acid condensation products of indole-3-carbinol (I3C), i.e. 3,3'-diindolylmethane (DIM), 5,6,11,12,17,18-hexahydrocyclonona[1,2-b:4,5-b':7,8-b"]tri-indole (CTI) and 2,3-bis[3-indolylmethyl]indole (BII), on cytochrome P450 and phase II enzymes were studied in primary cultures of rat and cynomolgus monkey liver cells. In rat hepatocytes all three indole derivatives dose-relatedly induced the ethoxyresorufin O-dealkylation (EROD) activity (to 24-fold) and 7 alpha-hydroxylation of testosterone (to 4-fold), whereas all three decreased the 16 alpha- and 2 alpha-testosterone hydroxylation (DIM to 60%, CTI and BII to a mere 5% of the control cells). Treatment of monkey hepatocytes with DIM and BII enhanced the EROD activity to 6- and 9-fold, respectively. Furthermore, BII decreased the 6 beta-hydroxylation of testosterone (to 60% of the untreated cultures) in monkey cells. Phase II enzymes were also affected. In rat hepatocytes DIM, CTI and BII enhanced DT-diaphorase (DTD) (= NAD(P)H-quinone reductase) activity, and DIM and BII the glucuronidation of 1-naphthol. In monkey cells BII only enhanced DTD, and no changes were observed in the glucuronidation of 1-naphthol after treatment with either DIM or BII. The indole derivatives did not affect glutathione S-transferase activity and sulfation of 1-naphthol in either rat or monkey hepatocytes. These results identify two novel acid condensation products of I3C, CTI and BII, as potent compounds in affecting biotransformation in rat as well as in monkey hepatocytes.
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PMID:Acid reaction products of indole-3-carbinol and their effects on cytochrome P450 and phase II enzymes in rat and monkey hepatocytes. 156 68


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