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)

Piperine, a major component of black pepper and long peppers, has been reported previously to have an effect on the activation and deactivation of some exogenous substances. In the present study, piperine was found to promote DNA damage and cytotoxicity induced by benzo[a]pyrene (B[a]P) in cultured V-79 lung fibroblast cells. The V-79 cells were treated with a non-toxic dose of piperine (1-20 microM) plus 10 microM B[a]P, or pretreated with piperine for 30 min or 2 hr prior to the administration of 10 microM B[a]P. B[a]P cytotoxicity was potentiated significantly by piperine under each experimental condition. The relative plating efficiency (RPE) was 71% when V-79 cells were exposed to 10 microM B[a]P alone. When the culture was exposed to B[a]P plus piperine or pretreated with piperine for 30 min prior to the administration of B[a]P, the RPE values were 63 and 44% (P < 0.001), respectively. Pretreatment with piperine for 2 hr had no significant effect (P > 0.05). Furthermore, the lowest activities (P < 0.05) of glutathione S-transferase (GST) and uridine diphosphate glucuronyl transferase (UDP-GTase) of piperine-treated V-79 cells occurred 30 min to 1 hr after the piperine pretreatment. Pretreatment of V-79 cells with piperine also caused an increase in the covalent binding of B[a]P-diol-epoxide to DNA, 2.3 times greater than that of the V-79 cells without piperine treatment. These results suggest that the promotion by piperine of B[a]P-induced cytotoxicity in V-79 lung fibroblast cells is due to mechanisms that decrease the activities of GST and UDP-GTase and increase the formation of a B[a]P-DNA adduct.
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PMID:Modulatory effect of piperine on benzo[a]pyrene cytotoxicity and DNA adduct formation in V-79 lung fibroblast cells. 820 33

A recent study from our laboratory demonstrated that cyclosporine (CsA), a prototype immunosuppressant, enhanced the growth of carcinogen-induced enzyme altered foci in rat liver, suggesting that CsA may stimulate development of hepatocellular carcinomas. In the present study, we examined (i) whether CsA accelerates development of hepatocellular carcinomas in experimental animals, (ii) whether CsA stimulates the proliferation of resting hepatocyte in vivo and (iii) whether CsA modulates the production of growth factors implicated in liver cell growth, hepatocyte growth factor (HGF), transforming growth factor alpha (TGF alpha) and transforming growth factor beta 1 (TGF beta 1). Foci of hepatocytes, positive for glutathione S-transferase placental form were induced in male F344 rats by a single dose of diethylnitrosamine followed by 7 weeks promotion by a choline-deficient diet. The animals were then divided in two groups, and subsequent development of hepatocellular carcinomas was compared in rats fed a basal diet or a basal diet containing 0.015% CsA. Development of hepatocellular carcinoma was accelerated in the rats maintained on a CsA diet. Feeding a CsA diet as the sole treatment, for 2, 4 and 10 weeks induced significant increases in liver weight, and resulted also in an enhanced incorporation by hepatocytes of 5-bromo-2-deoxy-uridine. Serum levels of glutamate-oxaloacetate transferase, glutamate-pyruvate transferase and lactic dehydrogenase were not altered by feeding a CsA diet. Northern Blot analyses of the expression of HGF, TGF alpha and TGF beta 1 mRNAs in the liver showed similar patterns of expression between rats fed a basal diet and a CsA diet. The levels of HGF mRNA were not altered in the lungs and kidneys of rats fed a CsA diet. These results indicate that CsA stimulates rat liver cell proliferation in vivo without inducing liver cell necrosis, and that this effect may contribute to accelerated development of hepatocellular carcinomas in rats fed a CsA diet. As previously observed with BR 931, a hypolipidemic peroxisome proliferator, stimulation of liver cell growth by CsA did not entail changes in the production of HGF, TGF alpha or TGF beta 1.
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PMID:Cyclosporine stimulates hepatocyte proliferation and accelerates development of hepatocellular carcinomas in rats. 835 42

The monocyclic monoterpenoid compounds limonene and sobrerol have anticarcinogenic activity when fed during the initiation stage of dimethylbenz[a]anthracene (DMBA)-induced rat mammary carcinogenesis. Here we investigated the potential roles of hepatic glutathione-S-transferase (GST; EC 2.5.1.18) and uridine diphosphoglucuronosyl transferase (UDPGT; EC 2.4.1.17) in monoterpene-mediated chemoprevention. Diets containing the isoeffective anticarcinogenic terpenes, 5% limonene or 1% sobrerol, elevated hepatic GST activity > 2-fold when measured using the general substrate 1-chloro-2,4-dinitrobenzene and 3,4-dichloronitrobenzene for the GST dimer 3-3. However, there were no significant changes in hepatic GST activity when 1,2-epoxy-3-(p-nitrophenoxy)propane was used. We found that both terpene diets increased GST affinity-purified protein 1.5-fold and the HPLC subunit profile. Liver GST subunit 3 had the greatest increase followed by 1 and 4 with no change in subunit 2. Both terpene diets significantly increased the activity of the methylcholanthrene-inducible and the phenobarbital-inducible UDPGT isozymes. We propose that much of the anticarcinogenic activity of these monocyclic monoterpenes during the initiation phase of DMBA carcinogenesis is mediated through the induction of the hepatic detoxification enzymes GST and UDPGT.
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PMID:Effects of anticarcinogenic monoterpenes on phase II hepatic metabolizing enzymes. 850 9

Omeprazole induces CYP1A in the human liver and gut, which has led to concern about possible side effects. The purpose of this study was to compare the effects of omeprazole on phase 1 and phase 2 enzymes in the rat and human. Male rats were treated with intraperitoneal (40 or 80 mg/kg) or oral omeprazole (40 mg/kg) for 5 or 14 days, respectively. The activities and amounts of CYP1A, uridine diphosphate-glucuronosyltransferase, and glutathione transferase were determined in liver and gut. Enzyme activities were also determined in duodenal biopsy specimens from six healthy human volunteers before and after treatment with omeprazole (20 mg/day) for 10 days. Treatment with intraperitoneal omeprazole (40 mg/kg; 80 mg/kg) coinduced uridine diphosphate-glucuronosyltransferase (36%; 66%), glutathione transferase (22%; 50%), and CYP1A (26%; 50%) in rat liver. In rat small intestine, comparable levels of induction were observed for uridine diphosphate-glucuronosyltransferase and glutathione transferase; CYP1A was unaffected. Oral omeprazole had similar effects. Immunoblotting showed corresponding changes in the amounts of these enzymes. Omeprazole increased the activities of CYP1A (19% to 167%; p = 0.014) and uridine diphosphate-glucuronosyltransferase (11% to 68%; p = 0.04) in the duodenal biopsy specimens of all six human volunteers; glutathione transferase was unaffected. Thus, omeprazole coinduced multiple xenobiotic metabolizing enzymes in the rat and human. The pattern of induction differed in the rat and human, consistent with known differences in genetic regulatory elements in the two species.
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PMID:Comparative effects of omeprazole on xenobiotic metabolizing enzymes in the rat and human. 852 27

A new gene, RRN11, has been defined by certain rrn mutants of Saccharomyces cerevisiae which are defective specifically in the transcription of 35 S rRNA gene by RNA polymerase I (pol I). We have cloned the gene and found that it encodes a protein of 507 amino acids. We have used a strain with the chromosomal RRN11 deleted and carrying HA1 epitope-tagged RRN11 on a plasmid to isolate a protein complex containing the protein encoded by RRN11. This protein complex complemented rrn6 mutant extracts, which were previously shown to be deficient in the essential pol I transcription factor called Rrn6/7 complex or core factor (CF). The CF complex was previously shown to consist of three proteins, the 102- and 60-kDa subunits encoded by RRN6 and RRN7, respectively, and the 66-kDa subunit. The results of the above complementation experiments combined with mobility of Rrn11p in SDS-polyacrylamide gel electrophoresis analysis relative to Rrn6p and Rrn7p led to the conclusion that RRN11 encodes the 66-kDa subunit of CF. Glutathione S-transferase-Rrn11p fusion protein was found to bind strongly to 35S-labeled Rrn6p and Rrn7p but only weakly to 35S-labeled TATA-binding protein. Similarly, glutathione S-transferase-Rrn7p fusion protein bound strongly to 35S-labeled Rrn6p and Rrn11p but only weakly to 35S-labeled TATA-binding protein. These results are consistent with the fact that one can purify CF consisting of Rrn6p, Rrn7p, and Rrn11p from yeast cell extracts, but the purified complex does not contain TATA-binding protein. RRN11 was shown to be an essential gene, and [3H]uridine pulse experiments demonstrated directly that RRN11 is essential for rDNA transcription by pol I in vivo. Thus all three subunits of CF are essential for rDNA transcription. Because of the resemblance of CF to mammalian essential pol I transcription factor SL1, the amino acid sequences of Rrn11p and the other two subunits of CF were compared with those of the three TATA-binding protein-associated factors (TAFs) in the human SL1, TAFI48, TAFI63, and TAFI110. No significant similarity was detected between two sets of the proteins. Similarity as well as differences between CF and SL1 are discussed.
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PMID:RRN11 encodes the third subunit of the complex containing Rrn6p and Rrn7p that is essential for the initiation of rDNA transcription by yeast RNA polymerase I. 870 72

Induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene (BHT) was studied in the male ddY mouse and Chinese hamster. In mice given 0.05 and 0.15% BHT in the diet for 14 days cytochrome P-450 contents and the activities of uridine diphosphate-glucuronyl transferase (UDP-GT) and pentoxyresorufin O-dealkylase were markedly increased, while in those fed 0.15% BHT testosterone 6 alpha-, 16 alpha- and 16 beta-hydroxylases were greatly increased, which indicated induction of cytochrome P-450 isozymes of the CYP2B family. Western blot analysis also showed an increased level of the isozyme immunorelated to rat CYP2B2 by BHT feeding. The activities of aryl hydrocarbon hydroxylase, ethoxycoumarin O-deethylase (ECOD), erythromycin N-demethylase and glutathione S-transferase (GST) remained unchanged. In Chinese hamsters given 0.05 and 0.15% BHT in the diet for 14 days activities of ECOD and GST were induced, but cytochrome P-450 contents and the activities of other enzymes were unaffected. Testosterone 15 alpha-hydroxylase was induced in hamsters fed 0.15% BHT. These findings suggested that BHT administration in the hamster induced CYP2A2-type isozyme, which was confirmed by Western blot analysis. BHT treatment enhanced activation of benzo[a] pyrene (B[a]P) as determined by the mutagenicity test, especially in Chinese hamsters. The results suggest that BHT treatment induces specific isozymes of drug-metabolizing enzymes and might modify the expression of toxicities of other chemicals.
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PMID:Differential induction of isozymes of drug-metabolizing enzymes by butylated hydroxytoluene in mice and Chinese hamsters. 876 52

The influence of dietary fibre on the biological effects of glucosinolates was investigated in gnotobiotic rats harbouring a human whole faecal flora. Animals were fed for 6 wk with diets containing 12% rapeseed meal (RSM) supplemented or not supplemented with 10% inulin (INL) or oat fibre. Both fibre types enhanced the liver hypertrophy due to RSM to equal extents, but had different effects on the other glucosinolate-related toxic effects. INL partially restored a normal thyroid hormone status whereas kidney weight, goitre and growth deficit were increased on exposure to the diet containing oat fibre. Oat fibre and, to a lesser extent, INL modulated the alterations of digestive xenobiotic-metabolizing enzymes (XME) induced by RSM. They counter-balanced the induction of hepatic cytochrome P-450 and lessened the induction of uridine diphosphate-glucuronosyltransferase in the liver but did not modify depletion of its activity in the small intestine. On the other hand, they enhanced the induction of glutathione S-transferase in the liver and the large intestine but not in the small intestine. These findings give new evidence that the biological effects of naturally occurring non-nutrient compounds are closely dependent on the composition of the diet. Two mechanisms are proposed to explain the different influence of INL and oat fibre on RSM toxicity. Their different fermentative characteristics could lead to a modulation of the bacterial metabolism of glucosinolates in the caecum. Alternatively, their own action on the digestive XME could modify the subsequent metabolism of bacterial glucosinolate derivatives.
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PMID:Modulation of the biological effects of glucosinolates by inulin and oat fibre in gnotobiotic rats inoculated with a human whole faecal flora. 888 67

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

These studies examined the ability of garlic powder or allyl sulfur compounds to modify selenite protection against 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary epithelial cell DNA adducts. In Study 1, female rats (n = 5) were fed diets containing sodium selenite at 0.1, 0.5, or 1.0 mg Se/kg and garlic powder at 0, 20, or 40 g/kg diet. Total DNA adducts correlated inversely with selenite or garlic powder intake. Garlic powder enhanced the selenite inhibition of mammary DNA adducts. In Study 2, selenite (2.0 mg Se/kg diet), garlic powder (20 g/kg diet), water-soluble S-allyl cysteine (SAC; 5.2 mumol/kg diet), and oil-soluble diallyl disulfide (DADS; 5.2 mumol/kg diet) inhibited (p < 0.05) total DNA adducts by 45%, 40%, 80%, and 75%, respectively. Combining selenite with garlic powder, SAC, or DADS further inhibited DNA adducts. Selenite, but not garlic powder, SAC, or DADS, enhanced liver glutathione S-transferase and uridine diphosphate-glucuronosyltransferase activities. Selenite, garlic powder, SAC, or DADS did not affect liver cytochrome P-450 1A1 activities. The present studies provide evidence that synergistic protection against the initiation of DMBA carcinogenesis occurs when selenite is supplemented in conjunction with garlic or its allyl sulfur components.
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PMID:Garlic powder and allyl sulfur compounds enhance the ability of dietary selenite to inhibit 7,12-dimethylbenz[a]anthracene-induced mammary DNA adducts. 912 44

Bacterial peptidoglycan biosynthesis includes four enzymatic reactions in which successive amino acid residues are ligated to uridine diphospho-N-acetylmuramic acid (UDP-MurNAc). By comparing the amino acid sequences of MurC, -D, -E, and -F proteins from various bacterial genera, four regions of homology were identified. A profile search of Swissprot for related sequences revealed that these regional similarities were present in the folyl-gamma-polyglutamate ligases. These sequence homologies appear to track with catalytic function: both enzyme families proceed through an ordered kinetic mechanism and form product via an acyl phosphate intermediate. Two highly conserved residues in region II were examined through site-directed mutagenesis of the murein D-alanyl-D-alanine-adding enzyme from Escherichia coli (murF; E158 and H188). All mutations were highly detrimental to activity with enzyme specific activity reductions of 200-4500-fold, validating the critical nature of these residues. DNA sequence analysis from three E. coli mutants harboring the murC3 (G344D), murE1 (G344K, A495S), and murF2 (A288T) mutations revealed the presence of point mutation(s) closely associated with the fourth of these aligned regions. The murF2 allele, expressed and purified as a glutathione S-transferase::MurF2 fusion, was 181-fold less catalytically active at 30 degrees C and was further reduced at the nonpermissive temperature (42 degrees C). Thus the murF2 temperature-sensitive phenotype arises from a point mutation within a highly conserved region within this protein family. These data argue that these proteins comprise a superfamily of three substrate amide ligases that share significant structural and catalytic homologies.
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PMID:Conditionally lethal Escherichia coli murein mutants contain point defects that map to regions conserved among murein and folyl poly-gamma-glutamate ligases: identification of a ligase superfamily. 916 95


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