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)

The effect of genetic obesity and phenobarbital treatment on hepatic conjugation pathways was evaluated in the obese Zucker rat. Acetaminophen pharmacokinetic parameters were examined in vivo after a 30-mg/kg acetaminophen intravenous bolus dose in the presence and absence of phenobarbital treatment. Glucuronidation and glutathione conjugation pathways were studied in vitro in obese and lean Zucker rats after phenobarbital treatment. Obese Zucker rats demonstrated a higher glucuronidation capacity as evidenced by a higher formation clearance of acetaminophen glucuronide and greater UDP-glucuronosyltransferase (UDPGT) activity toward acetaminophen and p-nitrophenol compared with lean controls. Sulfate and glutathione conjugation pathways were not affected by genetic obesity. Obese Zucker rats possessed a higher total hepatic glutathione content due to greater liver weight. Phenobarbital treatment enhanced glucuronidation of acetaminophen and structurally related compounds (i.e., p-nitrophenol) similarly in both phenotypes, but the treatment failed to induce morphine UDPGT in the obese Zucker rat. No effect of phenobarbital was observed on sulfate conjugation, gamma-glutamyl cysteine synthetase activity or hepatic glutathione content in obese or lean Zucker rats. Similar increases in glutathione transferase activities were observed in animals of both phenotypes after phenobarbital treatment. This study demonstrates that glucuronidation is enhanced in genetically obese rats, whereas phenobarbital causes normal induction of several enzymes of the glucuronidation and glutathione conjugation pathways in the obese Zucker rat. However, morphine UDPGT was not induced by phenobarbital, suggesting that obese Zucker rats may possess a defect in the induction of this enzyme similar to that already described for the CYP2B gene in this strain.
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PMID:Effect of genetic obesity and phenobarbital treatment on the hepatic conjugation pathways. 851 12

In the previous study (Mutation Res., this issue), we showed that increased levels of dietary casein as the sole protein source for male F344 rats decreased the ability of the uninduced liver S9s to activate 2-aminoanthracene (2AN) to a mutagen in strain TA98 using the spiral Salmonella mutagenicity assay. No effects of dietary casein levels were noted for the ability of uninduced liver S9s to activate the promutagens aflatoxin B1 (AFB) and benzo[a]pyrene (BAP). In the present study, we have extended this study to include liver S9s induced with either Aroclor 1254, phenobarbital or 3-methylcholanthrene (3MC). S9s were derived from individual male F344 rats fed for 6 weeks on semisynthetic diets containing 8%, 12% or 22% methionine-supplemented casein as the sole source of protein (diets were made isocaloric by adjusting the corn starch content). Rats were housed in large, raised-bed cages by groups of three/diet/inducing agent. S9 activation mixtures were prepared at 5 mg of S9 protein/ml of S9 mix. Slopes from the linear portions of the mutagenicity dose-response curves were analyzed by ANOVA comparisons. Assays used to elucidate the phase I activities of microsomal preparations were cytochrome P-450 content, cytochrome-c reductase activity, flavin-containing monooxygenase activity, 7-ethoxyresorufin O-deethylation (EROD) activity, N-demethylation of benzphetamine, and para-nitrophenol O-deethylation. Phase II activities were assayed by estimating glutathione (GSH) content and measuring the metabolism of 1-chloro-2,4-dinitrobenzene (CDNB) by glutathione S-transferase in cytosolic preparations. None of the phase I or phase II endpoints were significantly affected by dietary casein levels. In general, increasing levels of dietary casein resulted in increased body and liver wet weight and amount of S9 protein. Aroclor-induced S9s from rats fed the 22% or 12% casein diet were most effective at activating AFB, depending on the lot of Aroclor used for induction; these divergent results were replicated with two groups of rats for each lot of Aroclor. The observed differences between Aroclor lots are assumed to arise from variation in the mix of PCB isomers. The Aroclor-induced S9s did not exhibit any casein-related effects for the activation of BAP or 2AN. For 3MC-induced S9s, the 12% casein diets produced S9s with the highest ability to activate AFB and BAP when standardized for protein content. Phenobarbital-induced S9s did not demonstrate any dietary casein-related effects on the activation of the three model promutagens. These results illustrate the complex interaction between dietary levels of casein, enzyme inducing agent and promutagen.
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PMID:Effect of dietary casein levels on activation of promutagens in the spiral Salmonella mutagenicity assay. II. Studies with induced rat liver S9. 864 65

Phenobarbital elicits pleiotropic effects in the liver, including induction of enzymes involved in xenobiotic metabolism. The spectrum of this response was analyzed by differential display of a large population (approximately 7500) of mRNAs in chicken embryo liver treated in vivo with phenobarbital. We identified 29 cDNA fragments that reproducibly and significantly changed in intensity after a 48-hr in ovo treatment. Eighteen of these (62%) were increased, whereas 11 (38%) were decreased. Twenty strongly regulated cDNA fragments were subcloned and further analyzed. Nucleotide sequence analysis revealed three types of genes: (a) those previously described to be regulated by phenobarbital, including CYP2H1, glutathione S-transferase, and uridine diphosphate-glucuronosyltransferase; (b) genes reported herein for the first time to be regulated by phenobarbital, including fibrinogen beta-chain and gamma-chain, retinal glutamine synthetase, apolipoprotein B, two gene products with homologies to elongation factor 1delta and complement factor H, respectively, and (c) several novel genes with hitherto unknown functions. If these data are extrapolated to the entire population of mRNAs of a liver cell, phenobarbital seems to significantly modulate the expression of more than 50 different genes. Our results also demonstrate that a large fraction of genes is negatively regulated by drug treatment.
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PMID:Extent and character of phenobarbital-mediated changes in gene expression in the liver. 905 89

The effect of vitamin E on gamma-glutamyl transpeptidase-positive foci, with or without phenobarbital, was investigated. Groups of six female Sprague-Dawley rats were initiated with diethylnitrosamine (15 mg/kg) at 24 hours of age. After weaning, they were fed diets with 10% (wt/wt) fish oil; the diets contained 0, 5,000 or 15,000 ppm vitamin E supplementation with or without phenobarbital (500 ppm) for six months. Phenobarbital significantly increased liver weight and liver weight as a percentage of body weight (p < 0.05), suggesting a liver hypertrophic effect of phenobarbital. Phenobarbital significantly decreased hepatic phospholipid arachidonate, eicosapentaenoate, and docosahexaenoate (p < 0.05); this may indicate that phenobarbital stimulates phospholipase A2 activity and results in the increased release of polyunsaturated fatty acids from phospholipids and the decrease of hepatic phospholipid polyunsaturated-to-saturated fat ratio. In rats fed phenobarbital, hepatic vitamin E content was lower than in rats fed no phenobarbital; this suggests that phenobarbital causes oxidative stress or induces enzymes that metabolize the vitamin. Phenobarbital exposure significantly increased hepatic prostaglandin F2 alpha and glutathione S-transferase activity (p < 0.05). Vitamin E did not influence hepatic gamma-glutamyl transpeptidase-positive foci area and number with or without phenobarbital, and phenobarbital showed a strong promoting action on enzyme-altered hepatic foci.
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PMID:No inhibition of gamma-glutamyl transpeptidase-positive foci by vitamin E with or without phenobarbital. 912 50

This report describes the establishment and characterization of the mhPKT cell line derived from the liver of a transgenic mouse harboring the simian virus (SV40) large T and small t antigens placed under the control of the 5' regulatory sequence of the rat L-type pyruvate kinase (L-PK) gene. mhPKT cells had a prolonged life span, expressed the SV40-encoded nuclear large T antigen when grown in glucose-enriched medium, and induced tumors when injected subcutaneously into athymic (nu-nu) mice. Growth on petri dishes or filters yielded multiple layers of cuboid cells, with numerous spaces between adjacent cells that were closed by junctional complexes. These bile canaliculi-like structures exhibited numerous microvilli in which villin, an actin-binding brush-border protein, colocalized with actin. These bile canaliculi-like structures appeared to be functional as they accumulated fluorescein. mhPKT cells conserved the expression of the liver-specific transcription factors HNF1, HNF3, HNF4, and DBP together with substantial levels of L-PK and albumin but not alpha-fetoprotein mRNA transcripts. mhPKT cells mainly metabolized testosterone into androstenedione and 6beta-hydroxytestosterone, as in vivo. 3-Methylcholanthrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) markedly increased ethoxyresorufin-O-deethylase activity and the related cytochrome P450 (CYP) 1A1/2 protein, whereas alpha-naphtoflavone antagonized the TCDD-elicited induction. Phenobarbital slightly increased the CYP2B-mediated activities of pentoxyresorufin-O-depentylase, 2beta- and 16beta-testosterone hydroxylase. mhPKT cells also had substantial sulfotransferase, UDP-glucuronyltransferase, and glutathione S-transferase activities. This model may serve as a tool for long-term in vitro studies of xenobiotic metabolism, potent CYP inducers, and hepatocyte damage due to drugs and other factors.
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PMID:Activity and inducibility of drug-metabolizing enzymes in immortalized hepatocyte-like cells (mhPKT) derived from a L-PK/Tag1 transgenic mouse. 926 Sep 6

Structural and functional analyses were used to investigate the regulation of the inositol 1,4,5-trisphosphate (InsP3) receptor (InsP3R) by Ca2+. To define the structural determinants for Ca2+ binding, cDNAs encoding GST fusion proteins that covered the complete linear cytosolic sequence of the InsP3R-1 were expressed in bacteria. The fusion proteins were screened for Ca2+ and ruthenium red binding through the use of 45Ca2+ and ruthenium red overlay procedures. Six new cytosolic Ca2+-binding regions were detected on the InsP3R in addition to the one described earlier (Sienaert, I., De Smedt, H., Parys, J. B., Missiaen, L., Vanlingen, S., Sipma, H., and Casteels, R. (1996) J. Biol. Chem. 271, 27005-27012). Strong 45Ca2+ and ruthenium red binding domains were localized in the N-terminal region of the InsP3R as follows: two Ca2+-binding domains were located within the InsP3-binding domain, and three Ca2+ binding stretches were localized in a 500-amino acid region just downstream of the InsP3-binding domain. A sixth Ca2+-binding stretch was detected in the proximity of the calmodulin-binding domain. Evidence for the involvement of multiple Ca2+-binding sites in the regulation of the InsP3R was obtained from functional studies on permeabilized A7r5 cells, in which we characterized the effects of Ca2+ and Sr2+ on the EC50 and cooperativity of the InsP3-induced Ca2+ release. The activation by cytosolic Ca2+ was due to a shift in EC50 toward lower InsP3 concentrations, and this effect was mimicked by Sr2+. The inhibition by cytosolic Ca2+ was caused by a decrease in cooperativity and by a shift in EC50 toward higher InsP3 concentrations. The effect on the cooperativity occurred at lower Ca2+ concentrations than the inhibitory effect on the EC50. In addition, Sr2+ mimicked the effect of Ca2+ on the cooperativity but not the inhibitory effect on the EC50. The different [Ca2+] and [Sr2+] dependencies suggest that three different cytosolic interaction sites were involved. Luminal Ca2+ stimulated the release without affecting the Hill coefficient or the EC50, excluding the involvement of one of the cytosolic Ca2+-binding sites. We conclude that multiple Ca2+-binding sites are localized on the InsP3R-1 and that at least four different Ca2+-interaction sites may be involved in the complex feedback regulation of the release by Ca2+.
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PMID:Molecular and functional evidence for multiple Ca2+-binding domains in the type 1 inositol 1,4,5-trisphosphate receptor. 932 22

We investigated the effects of type of dietary fat and phenobarbital on gamma-glutamyl transpeptidase-positive foci development. Four groups of six female Sprague-Dawley rats were initiated with diethylnitrosamine (15 mg/kg) at 24 hours of age. After weaning, they were fed nutritionally complete semipurified diets containing 15% corn oil or 5% corn oil + 10% fish oil and supplemented with 5,000 ppm vitamin E with or without phenobarbital (500 ppm) for three months. Dietary fish oil significantly increased hepatic phospholipid eicosapentaenoate and docosahexaenoate concentrations and decreased arachidonate concentration compared with 15% corn oil (p < 0.05). Corn oil (15%) significantly increased hepatic prostaglandin F2 alpha concentration compared with 10% fish oil (p < 0.05). Phenobarbital significantly stimulated glutathione S-transferase activity in both dietary fat groups (p < 0.05). In the absence of phenobarbital, type of dietary fat showed no effect on hepatic gamma-glutamyl transpeptidase-positive foci development. However, in the presence of phenobarbital, 15% corn oil significantly enhanced gamma-glutamyl transpeptidase-positive foci development compared with 10% fish oil (p < 0.05). Phenobarbital showed a strong tumor-promoting action in both dietary groups. In conclusion, there was an interaction between type of dietary fat and phenobarbital on gamma-glutamyl transpeptidase-positive foci development during hepatocarcinogenesis in rats.
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PMID:Corn oil enhances gamma-glutamyl transpeptidase-positive foci development in the presence of phenobarbital during hepatocarcinogenesis in rats. 934 33

Induction mode of the hepatic drug-metabolizing enzymes was studied in Corn snake (Elaphe guttata emoryi). Treatment of snakes with 3-methylcholanthrene or phenobarbital produced no effects on liver weight and total content of cytochromes P450 and b5. Treatment with 3-methylcholanthrene significantly induced the activities of arylhydrocarbon hydroxylase, 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-dealkylase, whereas those of ethoxycoumarin O-deethylase, benzphetamine N-demethylase, erythromycin N-demethylase and testosterone hydroxylases were not affected. 3-Methylcholanthrene-induced activities of 7-ethoxyresorufin O-deethylase and 7-pentoxyresorufin O-dealkylase were inhibited by 20 microM alpha-naphthoflavone by 98% and 73%, respectively. Phenobarbital-treatment caused a significant induction of the activities of erythromycin N-demethylase and testosterone 6 beta-hydroxylase, but did not affect those of the other phase I enzymes and the other testosterone hydroxylases. The activities of UDP-glucuronyltransferase and glutathione S-transferase were not affected by either 3-methylcholanthrene or phenobarbital administration. Immunoblotting showed that 3-methylcholanthrene-treatment induced a protein band related to hamster CYP1A2, and decreased the intensity of the two bands detected with anti-rat CYP2B1. Phenobarbital-treatment did not affect the intensity of CYP2B-related proteins. The results suggest that snake liver has multiple forms of cytochrome P450, notably those inducible by 3-methylcholanthrene.
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PMID:Modulation of snake hepatic cytochrome P450 by 3-methylcholanthrene and phenobarbital. 966 83

A characteristic feature of the class Theta glutathione S-transferase (GST) T1-1 is its ability to activate dichloromethane and dibromoethane by catalysing the formation of mutagenic conjugates. The level of the GSTT1 subunit within tissues is an important determinant of susceptibility to the carcinogenic effects of these dihaloalkanes. In the present study it is demonstrated that hepatic GST activity towards these compounds can be elevated significantly in female and male Fischer-344 rats by feeding these animals on diets supplemented with cancer chemopreventive agents. Immunoblotting experiments showed that increased activity towards the dihaloalkanes is associated with elevated levels of the GSTT1 subunit in rat liver. Sex-specific effects were observed in the induction of GSTT1 protein. Amongst the chemopreventive agents tested, indole-3-carbinol proved to be the most potent inducer of hepatic GSTT1 in male rats (6.2-fold), whereas coumarin was the most potent inducer of this subunit in the livers of female rats (3. 5-fold). Phenobarbital showed significant induction of GSTT1 only in male rat liver and had little effect in female rat liver. Western blotting showed that class Alpha, Mu and Pi GST subunits are not co-ordinately induced with GSTT1, indicating that the expression of GSTT1 is determined, at least in part, by mechanisms distinct from those that regulate levels of other transferases. The increase in amount of hepatic GSTT1 protein was also reflected by an increase in the steady-state level of mRNA in response to treatment with chemopreventive agents and model inducers. Immunohistochemical detection of GSTT1 in rat liver supported the Western blotting data, but showed, in addition to cytoplasmic staining, significant nuclear localization of the enzyme in hepatocytes from some treated animals, including those fed on an oltipraz-containing diet. Significantly, the hepatic level of cytochrome P-450 2E1, an enzyme which offers a detoxification pathway for dihaloalkanes, was unchanged by the various inducing agents studied. It is concluded that the induction of GSTT1 by dietary components and its localization within cells are important factors that should be considered when assessing the risk dihaloalkanes pose to human health.
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PMID:Increased bioactivation of dihaloalkanes in rat liver due to induction of class theta glutathione S-transferase T1-1. 979 3

Administration of tamoxifen (TAM) (20 mg/kg per day p.o.) for 6 weeks to female lambda/lacI transgenic rats caused a 4-fold increase in mutation frequency (MF) at the lacI gene locus in the livers of dosed animals compared with controls. After cessation of dosing, the MF showed a further increase with time at 2, 12 and 24 weeks, respectively. Phenobarbital promotion of similarly treated animals resulted in no increase in mutation frequency compared with TAM alone. Treatment with phenobarbital or TAM+phenobarbital resulted in time-dependent increases in liver weight compared with the corresponding controls. There was an increase in cell proliferation in the phenobarbital and TAM+phenobarbital groups, and at 24 weeks in the TAM dosed animals compared with controls. There was also a progressive increase in the number of GST-P expressing foci in the livers of TAM and TAM + phenobarbital rats compared with controls. The induction of cell proliferation and GSTP foci in the rat liver by phenobarbital is consistent with its ability to promote tamoxifen-initiated liver tumours in the rat. If the lacI gene is regarded as being representative of the rat genome in general (albeit that the gene is bacterial) the above observations suggest that promotion by tamoxifen confers selective advantage on mutated genes at loci that contribute to the tumour phenotype and that promotion of rat liver tumours by tamoxifen is not dependent simply upon the enhancement of cellular proliferation.
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PMID:Tamoxifen mutagenesis and carcinogenesis in livers of lambda/lacI transgenic rats: selective influence of phenobarbital promotion. 1112 69


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