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)

3,3',4,4',5-Pentachlorobiphenyl (PenCB), one of the most toxic co-planar polychlorinated biphenyl congeners, specifically induces class Pi glutathione S-transferase (GSTP1) as well as cytochrome P-450 1A1 in primary cultured rat liver parenchymal cells [Aoki, Matsumoto and Suzuki (1993) FEBS Lett. 333, 114-118]. However, the 5'-flanking sequence of the GSTP1 gene does not contain a xenobiotic responsive element, to which arylhydrocarbon receptor binds. Using a chloramphenicol acetyltransferase assay we demonstrate here that the enhancer termed GSTP1 enhancer I (GPEI) is necessary for the stimulation by PenCB of GSTP1 gene expression in primary cultured rat liver parenchymal cells. GPEI is already known to contain a dyad of PMA responsive element-like elements oriented palindromically. It is suggested that a novel signal transduction pathway activated by PenCB contributes to the stimulation of GSTP1 expression.
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PMID:Identification of an enhancer element of class Pi glutathione S-transferase gene required for expression by a co-planar polychlorinated biphenyl. 1005 28

The recent development of several promising new thiourea-containing drugs has renewed interest in the thiourea functionality as a potential toxicophore. Most adverse reactions of thiourea-containing compounds are attributed to the thionocarbonyl moiety. Oxidation of these thionocarbonyl compounds by flavin-containing monooxygenases (FMO) and cytochrome P450 isoenzymes (P450) to reactive sulfenic, sulfinic, or sulfonic acids leads to alkylation of essential macromolecules. To more rationally design thiourea-containing drugs, structure-toxicity relationships (STRs) must be derived. Since for the development of STRs a large number of thiourea-containing compounds must be investigated, it is important to develop rapid in vitro assays for alkylating potential. In this study, the utility of activation of microsomal glutathione S-transferase (mGST) and inactivation of P450 1A1 as markers of the alkylating potential of metabolites of thiourea-containing compounds was investigated. It was found that metabolites of thiourea-containing compounds inactivate P450 1A1 in a time-dependent manner, as evidenced by a decrease in 7-ethoxyresorufin O-dealkylation (EROD) activity. An extent of inactivation of P450 1A1 by 100 microM N-phenylthiourea (PTU) of 64% was found after 10 min. This inactivation was dependent on the presence of NADPH and the presence of the thionosulfur, since the carbonyl analogue of PTU was not found to inactivate P450 1A1, and was partially prevented by heat treatment of the microsomes which is known to selectively inactivate FMO enzymes. Inactivation of P450 1A1 could be reversed by treatment with dithiothreitol, indicating the formation of disulfide bonds. However, thiourea-containing compounds also inhibited the EROD activity of P450 1A1 in a competitive manner. This property complicates the usefulness of the EROD activity of P450 1A1 as a marker for the alkylating potential of thiourea-containing compounds. It was found that metabolites of thiourea-containing compounds could transiently activate the mGST. A maximal level of activation by 100 microM PTU of 162+/-16% was found after 10 min. Activation of mGST by 100 microM PTU was dependent on the presence of NADPH and the presence of the thionosulfur, since the carbonyl analogue of PTU was not found to activate mGST. Activation was completely prevented by heat treatment of the microsomes, indicating involvement of FMO in the bioactivation process. Finally, a series of structurally diverse thiourea-containing compounds were tested for their ability to activate mGST. It appeared that their potency in alkylating mGST was inversely related to their Vmax/Km value for the FMO enzyme. From this study, it is concluded that, whereas activation of mGST in rat liver microsomes may be a useful system with which to investigate the relationship between structure and alkylating potential of thiourea-containing compounds in vitro, inactivation of P450 1A1 is not.
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PMID:Activation of microsomal glutathione S-transferase and inhibition of cytochrome P450 1A1 activity as a model system for detecting protein alkylation by thiourea-containing compounds in rat liver microsomes. 1032 49

Tumour formation may involve interactions between genetic factors and environmental carcinogens. Adenoma formation in APCMin/+ mice is associated homozygous adenomatous polyposis coli (APC) gene mutation, but the effects on carcinogen susceptibility are unknown. This study tests the hypothesis that APCMin/+ adenoma formation is accompanied by changes in metabolic proficiency and carcinogen susceptibility. Cytochrome P450 (CYP)1A1/1A2, glutathione S-transferase (GST)alpha, mu and pi classes and DNA adduct formation were assayed in adenomas and uninvolved mucosa from APCMin/+ mice, before and after benzo[a]pyrene (B[a]P) treatment. In untreated adenomas and mucosa, CYP1A1/1A2 and B[a]P-DNA adducts were undetected but GSTalpha, mu and pi class enzymes were constitutively expressed. In adenomas, B[a]P only induced CYP1A1/1A2 to low level while GSTalpha and pi class enzymes were unaffected. A GST mu band which was absent from mucosa, was induced in adenomas. In mucosa, B[a]P induced CYP1A1/1A2 and GSTalpha and pi, to high levels. B[a]P-DNA adduct levels were 56 +/- 15/10(8) nucleotides (median +/- SE) in adenomas versus 89 +/- 19/10(8) nucleotides in mucosa (P < 0.0001). APCMin adenomas show reduced bioactivation capacity and sustain less DNA damage from B[a]P exposure, than APCMin uninvolved mucosa. These properties could influence mutagenesis and subsequent neoplastic transformation of adenomas.
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PMID:Metabolic proficiency and benzo[a]pyrene DNA adduct formation in APCMin mouse adenomas and uninvolved mucosa. 1035 94

Various dietary substances modulate the xenobiotic metabolism and may thereby protect against toxicity and carcinogenicity of food toxins. The effects of pure indolyl glucosinolates, which are present in cruciferous vegetables, on induction of specific cytochrome P-450 (CYP) and glutathione S-transferase (GST) isoforms have not been studied previously. In the present study, glucobrassicin (GB) and neoglucobrassicin (NeoGB) were purified from broccoli by use of a single-column method. Furthermore, a mixture containing 48% GB, 36% NeoGB, and 16% 4-methoxyglucobrassicin was obtained. The modulatory effects of the pure GB, NeoGB, and the mixture on activities and levels of hepatic CYP 1A, 2B1/2, and 2E1 and alpha- and mu-GST isoforms were investigated in male Wistar rats. The indolyl mixture was the most powerful and NeoGB the weakest inducer of microsomal hepatic CYP 1A1 protein and 7-ethoxyresorufin O-deethylase activity. Furthermore, intact indolyl glucosinolates were more powerful inducers than the in vitro myrosinase-degraded indolyl glucosinolates. The hepatic 7-methoxyresorufin O-deethylase activities, but not CYP 1A2 protein, were induced by pure GB, whereas the mixture and NeoGB showed only minor effects. Neither CYP 2B1/2 nor 2E1 was induced by the indolyl glucosinolates. None of the hepatic GST subunits analyzed, rGST A1/2, A3, or M3, was induced significantly by the purified indolyl glucosinolates.
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PMID:Modulation of cytochrome P-450 and glutathione S-transferase isoform expression in vivo by intact and degraded indolyl glucosinolates. 1036 14

The effect of 16 d intake of 300 mg carotenoids/kg diet (beta-carotene (beta C), bixin (BX), lycopene (LY), lutein (LU), canthaxanthin (CX) or astaxanthin (AX) on xenobiotic metabolizing enzymes in the liver, lung, kidney and small intestine of male Wistar rats was assessed. A control group received the basal diet (AIN-76) without carotenoids and a positive control group for enzyme induction received 3-methylcholanthrene (3-MC) at 666 mg/kg diet. Cytochrome P450 activity was assessed using the substrates ethoxyresorufin for P450 1A1, methoxyresorufin for P450 1A2, pentoxyresorufin for P450 2B1/2 and benzyloxyresorufin for P450 types 1A1/2, 2B1/2 and 3A. Glutathione-S-transferase (EC 2.5.1.18) and reduced glutathione status were assessed. Carotenoid uptake by the tissues was also determined. 3-MC and the carotenoids BX, CX and AX led to significant increases compared with control in liver, lung and kidney ethoxyresorufin-O-deethylation. Methoxyresorufin-O-demethylation activity was significantly increased in liver and lung by BX, CX and AX but only CX and AX significantly increased activity in kidney. Pentoxyresorufin-O-depentylation and benzyloxyresorufin-O-dearylation increased in liver of 3-MC-, BX-, CX- and AX-treated rats, but to a much lesser degree than for the other two substrates. Benzyloxyresorufin-O-dearylation in lung was significantly decreased by all carotenoids. Activities of any of the measured enzymes in the small intestine were undetectable in all treatment groups except the 3-MC group. Glutathione status was unaffected by any of the treatments. This is the first study identifying the carotenoids BX, CX and AX as inducers of rat lung and kidney xenobiotic metabolizing enzymes.
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PMID:Effect of dietary supplementation with carotenoids on xenobiotic metabolizing enzymes in the liver, lung, kidney and small intestine of the rat. 1043 50

In order to examine whether fenbendazole has tumor-promoting activity, a total of 70 male Fischer 344 rats were initiated with a single intraperitoneal injection of 100 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone; beginning 1 wk later, rats were given a diet containing 3,600; 1,800; 600; 200; 70; or 0 ppm of fenbendazole for 8 wk. Subgroups of 5 rats each from the DEN+ 1,800; DEN+0; 1,800; and 0 ppm groups were euthanatized after 1 wk of fenbendazole treatment, and the remaining animals were euthanatized at 8 wk. After 1 wk, relative liver weights (ratios to body weights) were significantly increased in the DEN+ 1,800 and 1,800 ppm groups, and based on light microscopy, periportal hepatocellular hypertrophy was evident in these groups. After 8 wk, relative liver weights were significantly increased in the groups given > or =600 ppm with or without DEN initiation. Periportal hepatocellular hypertrophy, characterized by a marked increase in smooth endoplasmic reticulum, was observed in the groups given > or =600 ppm with or without DEN initiation. Induction of cytochrome P-450 (CYP) 1A2, 2B1, or 4A1 was noted in the fenbendazole-treated groups with or without DEN initiation; that associated with CYP 1A2 was most marked. Positive immunostaining for anti-CYP 1A1/2 or CYP 2B1/2 was observed diffusely in the livers of animals in the DEN+1,800 and DEN+3,600 ppm groups. The numbers and areas of connexin 32 (Cx32)-positive spots per square centimeter in centrilobular hepatocytes were significantly decreased in an almost dose-dependent manner with fenbendazole treatment after DEN initiation. In situ hybridization for Cx32 mRNA revealed a remarkable decrease in its expression in the centrilobular hepatocytes in the DEN+70 ppm group. The numbers of glutathione S-transferase placental-form positive single cells (plus mini foci) were significantly increased in the DEN+ 1,800 and DEN+3,600 ppm groups. Since those agents that induce CYP 2B1/2 isozymes and reduce Cx32 in centrilobular hepatocytes have been suggested to be liver tumor promoters, the present results indicate that fenbendazole may be a liver tumor promoter.
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PMID:Liver tumor promoting effects of fenbendazole in rats. 1052 35

Quercetin is one of the most abundant of the naturally occurring flavonoids. It has been estimated that about 25-50 mg of quercetin are consumed from the daily diet. The chemopreventive effect of quercetin on dietary carcinogen has been intensely studied in animal models; however, knowledge regarding the molecular mechanism is still limited. In this study, the human hepatoma Hep G2 cell line was used to investigate how quercetin prevents benzo[a]pyrene (B[a]P)-induced DNA adducts. The Hep G2 cells were treated with 10 microM B[a]P for 18 hours in the presence or absence of quercetin. The DNA adduct levels, evaluated by 32P postlabeling, decreased in a dose-dependent manner after treatment with quercetin. Cytochrome P-450 1A1 (CYP1A1) and glutathione S-transferase involvement have been well demonstrated in the modulation of B[a]P-induced DNA damage. From the assays of both enzyme activities, quercetin inhibits CYP1A1-linked ethoxyresorufin O-dealkylase activity more effectively than glutathione S-transferase activity. To elucidate the molecular mechanisms, reverse transcriptase-polymerase chain reaction and Western blot were used to evaluate whether the decrease in CYP1A1 enzyme activity by quercetin is mediated because of alterations of CYP1A1 transcription or mRNA stability. The results indicated that quercetin significantly inhibits B[a]P-induced CYP1A1 mRNA and protein expression. From these findings, we conclude that quercetin suppresses B[a]P-induced DNA damage in human Hep G2 cells by altering CYP1A1 gene expression. Thus we suggest that dietary quercetin may have a long-term preventive effect on chemical carcinogenesis, especially in people who eat a diet rich in fruits and vegetables.
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PMID:Quercetin inhibits benzo[a]pyrene-induced DNA adducts in human Hep G2 cells by altering cytochrome P-450 1A1 gene expression. 1069 72

Reactive oxygen species (ROS) induced damage to DNA plays a major role in carcinogenesis. In order to estimate the level of oxidative damage and its role in breast cancer, 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined in DNA isolated from human breast tissue. Furthermore, we investigated whether polymorphisms in genes for enzymes involved in generation and elimination of ROS had any association with the level of 8-OHdG in breast tissue. In this study, the level of 8-OHdG in DNA was measured by the high performance liquid chromatography-electrochemical detector (HPLC-ECD) method. Genotypes of cytochrome P450 (CYP)1A1, glutathione S-transferase (GST)M 1, GSTP1 and catechol O-methyltransferase (COMT) were determined by PCR-based restriction fragment length polymorphism analysis. A total of 61 Japanese patients were included in the study. The mean level of 8-OHdG in DNA of breast cancer tissues was 2.07 +/- 0.95 per 10(5) dG residues, while the mean level of 8-OHdG in DNA of non-cancerous breast tissues was 1.34 +/- 0.46 per 10(5) dG residues. The 8-OHdG levels in DNA of breast cancer tissues were significantly higher than those of their corresponding non-cancerous breast tissues (P < 0.0001). There was negative correlation between the clinical stage and the mean level of 8-OHdG in DNA of breast cancer tissues. Furthermore, patients with genotype of high GSTP1 activity had lower level of 8-OHdG in DNA of breast cancer tissues than others. On the contrary, the mean level of 8-OHdG in DNA of breast cancer tissues was higher among patients with genotype of high COMT activity. Our findings support the assumption that cancer cells are more exposed to oxidative stress than adjacent non-cancerous tissue. Genetic polymorphisms in enzymes involved in ROS metabolism may have a role in individual susceptibility to oxidant-related breast disease. At the same time, reduction of oxidative stress is thought to be a very important measure for primary prevention of breast cancer.
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PMID:Increased formation of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine, in human breast cancer tissue and its relationship to GSTP1 and COMT genotypes. 1076 27

The human placenta oxidizes several xenobiotics, although the spectrum of substrates and metabolic activities when compared with the liver appears restricted. Maternal cigarette smoking or PCB exposure increase the expression of CYP1A1. This induced activity is able to catalyze the activation of benzo(a)pyrene into DNA-bound adducts, both in vitro and in vivo. Studies with RT-PCR technique have demonstrated that first trimester placentae express at the mRNA level CYP1A1, 1A2, 2C, 2D6, 2E1, 2F1, 3A4, 3A5, 3A7 and 4B1 and at full term CYP1A1, 2E1, 2F1, 3A3/4, 3A5 and 3A7. However, more detailed studies on cDNA probes or with specific antibodies or 'diagnostic' substrates for other than CYP1A1, 2E1 and 3A gene products have yielded negative results. Studies on human placenta and a chorioncarcinoma cell line, JEG 3 cells, boulster the concept that placental CYP1A1 and 1B1 - although their expression is Ah receptor and ARNT mediated - is controlled by distinct mechanisms. Aromatase, CYP19, and cholesterol side-chain cleaving, CYP11B, genes, proteins and activities are catalytically active in human placentae throughout the pregnancy and those parameters do not seem to be affected by maternal cigarette smoking but rather maternal health status. However, the substrate binding pocket of aromatase accepts as its substrate several xenobiotics and is responsible for constitutive xenobiotic biotransformations.Functional placental glutathione S-transferase, N-acetyl transferase and epoxide hydrolase are expressed via one gene each and their function reflects the placenta as an endocrine organ rather than a xenobiotic-metabolizing unit. However, markers for oxidative stress can be detected in decreased glutathione S-transferase activities.Because human placenta has quite well defined metabolic characteristics, and obtaining placental samples will not meet any drastic ethical difficulties, it could be used more intensively as a source of metabolizing enzymes in in vitro studies during the course of a drug development program. The human placenta, or its subcellular organelles, could serve as a real alternative model for an extrahepatic tissue in replacing recombinant expression systems especially if CYP11, 19, 1A1 or potentially 2E1 are target enzymes for potential metabolic interactions.
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PMID:The expression and regulation of drug metabolism in human placenta. 1083 48

Interrelationships among induction of cytochrome P-450 (CYP) 1A1/2, decrease in connexin 32 (Cx32), and liver tumor-promoting activity by beta-naphthoflavone (BNF) in the promotion stage were examined in a 2-stage liver carcinogenesis model. A total of 20 male Fischer 344 rats were initiated with a single intraperitoneal injection of 150 mg/kg of diethylnitrosamine (DEN) or were given the saline vehicle alone. Starting 2 weeks later, they were fed a diet containing 2%, 1%, or 0% BNF for 6 weeks. All animals were subjected to a two-thirds partial hepatectomy at week 3 and were sacrificed at week 8. Absolute and relative liver weights were significantly increased in the DEN+BNF groups as compared to the DEN-alone group. Diffuse hepatocellular hypertrophy with cytoplasmic eosinophilia, sometimes accompanied by development of adenoma-like hepatic foci, was observed in the BNF-treated rats. Remarkable induction of cytochrome CYP 1A1/2 and significant increase in CYP 2E1 were noted in the DEN+BNF groups, and positive immunohistochemical staining for both was observed diffusely. The areas of Cx32-positive spots per hepatocyte in the centrilobular areas of livers of the BNF-treated rats were significantly decreased, but no changes were observed in periportal areas. The numbers and areas of foci positive for glutathione S-transferase placental form were increased in the BNF-treated groups. These results suggest that BNF is a liver tumor promoter that, unlike phenobarbital, does not induce CYP 2B1/2 isozymes, and there seems to be no direct relationship between CYP 1A1/2 induction and Cx32 reduction in BNF hepatocarcinogenesis.
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PMID:Liver tumor-promoting effect of beta-naphthoflavone, a strong CYP 1A1/2 inducer, and the relationship between CYP 1A1/2 induction and Cx32 decrease in its hepatocarcinogenesis in the rat. 1093 40


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