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 effects of a water-soluble extract (WSE) of rosemary and its purified antioxidant rosmarinic acid (RA) on xenobiotic metabolizing enzymes (XME) were studied in rat liver after dietary administration. The modulation of phase I enzymes such as cytochrome P450 (CYP) 1A, 2B, 2E1, 3A, and phase II enzymes such as glutathione S-transferase (GST), quinone reductase (QR) and UDP-glucuronosyltransferase (UGT) was evaluated by measuring enzyme activities with specific substrates. Protein levels of CYPs and rGST A1/A2, A3/A5, M1, M2 and P1 were measured using antibodies in Western blots. Caffeic acid was also studied because it results from RA biotransformation in rat after oral administration. Male SPF Wistar rats received the different compounds at 0.5% (w/w) incorporated into their diet for 2 weeks. WSE, containing RA, flavones and monoterpenes enhanced CYP 1A1, 2B1/2, 2E1 and GST (especially rGST A3/A5, M1 and M2), QR and UGT. On the contrary, no modification of XME was observed in response to RA or CA (except for a slight increase of UGT activity after CA treatment). The induction of XME by WSE could be attributed to flavones, monoterpenes or an additive effect of all components.
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PMID:Effects of a water-soluble extract of rosemary and its purified component rosmarinic acid on xenobiotic-metabolizing enzymes in rat liver. 1126 3

The aim of the present study was to investigate the enhancing effect of dietary sugar on the development of aberrant crypt foci (ACF) in male F344 rats initiated with azoxymethane (AOM). The potential role of sugar as either a co-initiator or a promoter was investigated by giving diets high in sucrose and dextrin (61%) during either the pre-initiation, the initiation, and/or the post-initiation stage of the ACF development. The colonic cell proliferation, activity of colonic phase II enzymes, and a biomarker of lipid peroxidation were additionally examined in order to obtain information on the specific mechanisms involved in the suggested effect of sucrose and dextrin on ACF development. The number of large sized and the total number of ACF were significantly increased by feeding sucrose and dextrin in the post-initiation period. No positive association between colonic cell proliferation and ACF was seen. The level of oxidative stress in the cytosol from the proximal colon and colonic glutathione transferase and quinone reductase was not affected by the sugar treatments. The overall results from this study show that sucrose and dextrin enhance the number of preneoplastic lesions in AOM-initiated rats, and act primarily as promoters in the development of ACF.
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PMID:The influence of simple sugars and starch given during pre- or post-initiation on aberrant crypt foci in rat colon. 1136 33

Cruciferous vegetables contain secondary metabolites termed glucosinolates that break down to products that upregulate hepatic detoxification enzymes. We have previously shown that a mixture of four major glucosinolate breakdown products from Brussels sprouts interact to produce synergistic induction of phase II detoxification enzymes. Here we tested the hypothesis that this synergism is at the level of transcription and is due to the interaction between the oral bifunctional inducer, indole-3-carbinol (I3C), and monofunctional inducer, crambene (1-cyano 2-hydroxy 3-butene). Adult male rats were treated by gavage with either corn oil (vehicle); crambene (50 mg/kg), I3C (56 mg/kg), or a mix of crambene and I3C at the doses shown. Given orally, I3C alone and crambene with I3C caused significant induction of CYP1A activity and CYP1A1 mRNA levels, whereas crambene alone had no significant effect on CYP1A activity or mRNA levels. Crambene and I3C individually caused induction of glutathione S-transferase (GST) and quinone reductase (QR) activity. The mixture of crambene and I3C caused induction of GST and QR that was significantly greater than the sum of the induction by individual treatments. Upregulation of total GST activity was not as great as that of QR, possibly because some subunits did not show this effect. GST Ya2 mRNA showed a synergistic upregulation by crambene and I3C, while Yc1 and Yc2 showed only an additive response. We speculate that this different regulation is partly due to differences in gene sequences within the antioxidant response element and xenobiotic response element in the regulatory region of GST Ya2 compared to those within the regulatory region of the Yc1/Yc2 subunits.
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PMID:The synergistic upregulation of phase II detoxification enzymes by glucosinolate breakdown products in cruciferous vegetables. 1144 30

In a previous study, we showed that naturally occurring organosulfur compounds (OSCs) from garlic and onion modulated the activation of carcinogen via the alteration of cytochromes P450. The present study was undertaken to determine the incidence of the in vivo induction of phase II enzymes by individual OSCs on the genotoxicity of several carcinogens. Diallyl sulfide (DAS), diallyl disulfide (DADS), dipropyl sulfide (DPS) and dipropyl disulfide (DPDS), were administered by gavage (1mmol/kg) to male SPF Wistar rats for 4 consecutive days. The effects of treatments on phase II enzymes and on the genotoxicity of carcinogens were evaluated with hepatic cytosols and microsomes from OSCs-treated rats. DADS strongly increased all the phase II enzymes activities examined, i.e. total glutathione S-transferase (GST) activity, mu GST activity, quinone reductase (QR) activity and epoxide hydrolase (EH) activity. In addition, DADS strongly increased the protein level of rGSTP1. QR activity, total and mu GST activities were also increased by DAS and DPDS whereas DPS increased only mu GST activity and QR activity. To assess the repercussions of these inductions on the genotoxicity of carcinogens, the effects of cytosols or microsomes from OSCs-treated rats on the mutagenicity of (+)-anti-7beta,8alpha-dihydroxy-9alpha,10alpha-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE), styrene oxide (SO) and 4-nitroquinoline 1-oxide (4-NQO) were measured in the Ames test. DADS showed a very effective antimutagenic activity against BPDE, SO and 4-NQO. DAS reduced the mutagenicity of BPDE and SO. In contrast, DPS and DPDS showed little efficient antimutagenic activity since they only reduced the mutagenicity of BPDE and 4-NQO, respectively. Interestingly, DADS appeared to be as effective as ethoxyquin, a model inducer of phase II enzymes, in both inducing phase II enzymes and inhibiting the mutagenicity of carcinogens. This study demonstrated that the antimutagenic activities of OSCs against several ultimate carcinogens were closely related to their ability to induce phase II enzymes.
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PMID:Antimutagenic activity of organosulfur compounds from Allium is associated with phase II enzyme induction. 1144 51

Protective effects of curcumin (U1), one of the major yellow pigments in turmeric and its derivative, tetrahydrocurcumin (THU1), against ferric nitrilotriacetate (Fe-NTA)-induced oxidative renal damage were studied in male ddY mice. Single Fe-NTA treatment (5 mg Fe/kg body intraperitoneally) transiently causes oxidative stress, as shown by the accumulation of lipid peroxidation products and 8-hydroxy-2'-deoxyguanosine in the kidney. Mice were fed with a diet containing 0.5 g/100 g U1 or THU1 for 4 wk. THU1 significantly inhibited 2-thiobarbituric acid reactive substances and 4-hydroxy-2-nonenal-modified proteins and 8-hydroxy-2'-deoxyguanosine formation in the kidney; U1 inhibited only 4-hydroxy-2-nonenal-modified protein formation. To elucidate the mechanisms of protection by U1 and THU1, the pharmacokinetics and radical-scavenging capacities of U1 and THU1 were investigated by HPLC and electron spin resonance spin trapping with 5,5-dimethyl-1-pyrroline-N-oxide, respectively. Induction of antioxidant enzymes was also investigated. The amounts of THU1 and its conjugates (as sulfates and glucuronides) in the liver and serum were larger in the THU1 group than in the U1 group. The amounts of U1 and its conjugates were small even in the U1 group. These results suggest that THU1 is more easily absorbed from the gastrointestinal tract than U1. Furthermore, THU1 induced antioxidant enzymes, such as glutathione peroxidase, glutathione S-transferase and NADPH: quinone reductase, as well as or better than U1 and scavenged Fe-NTA-induced free radicals in vitro better than U1. These results suggest that U1 is converted to THU1 in vivo and that THU1 is a more promising chemopreventive agent.
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PMID:Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. 1148 99

The ability of rosemary to modulate cytochrome P450 (CYP) and detoxication enzymes in rat liver was evaluated by comparing the effects of dried leaves and leaf extracts with different chemical compositions: essential oil (EO) containing monoterpenes, a dichloromethane extract (DCME) containing phenolic diterpenes and a water-soluble extract (WSE) containing phenolic compounds such as rosmarinic acid and flavonoids. Chemical analyses were done in order to characterize the composition of extracts. Male Wistar rats received the leaves or extracts of rosemary in their diet at 0.5% (w/w) for 2 weeks. The effects of such treatments were evaluated for CYP (1A, 2B, 2E1), glutathione S-transferase (GST), NAD(P)H: quinone reductase (QR) and UDP-glucuronosyltransferase (UGT) activities and on protein levels (immunoblot analyses). Expression of specific UGT isoforms (mRNA semi-quantification by RT-PCR) was measured. Our study reports that EO selectively induced CYP, particularly CYP2B. WSE enhanced both CYP and detoxication enzymes. DCME acted as a monofunctional inducer, inducing GST, QR and UGT, in particular UGT1A6. Considering the specific pattern of induction obtained with DCME and WSE treatment, it should be relevant to evaluate the chemopreventive potency of these extracts on carcinogenesis in animal models.
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PMID:Induction of cytochrome P450 and/or detoxication enzymes by various extracts of rosemary: description of specific patterns. 1149 67

The potential antitumor effect of thymoquinone (TQ), the main constituent of the volatile oil of Nigella sativa seed, on fibrosarcoma induced by 20-methylcholanthrene (MC) in male Swiss albino mice was investigated in vivo and in vitro. Administration of TQ (0.01% in drinking water) I week before and after MC treatment significantly inhibited the tumor incidence and tumor burden by 43% and 34%, respectively, compared with the results in the group receiving MC alone. Moreover, TQ delayed the onset of MC-induced fibrosarcoma tumors that appeared at 12 weeks and produced less MC-induced mortality. Lipid peroxide accumulation, decreased glutathione (GSH) content, and decreased activities of glutathione S-transferase (GST) and quinone reductase (QR) were observed in the liver of MC-induced tumor-bearing mice. TQ alone showed a significant induction in the enzyme activities of hepatic GST and QR. Mice treated with TQ along with MC showed reduction in hepatic lipid peroxides and increased GSH content and increased enzyme activities of GST and QR as compared to results of the control group. The in vitro studies showed that TQ inhibited the survival of fibrosarcoma cells with IC50 of 15 microM. Conversely, TQ inhibited the incorporation of [3H] thymidine in fibrosarcoma cells with IC50 of microM. Our data indicate the potential of TQ as a powerful chemopreventive agent against MC-induced fibrosarcoma tumors. The possible modes of action of TQ may be through its antioxidant activity and interference with the DNA synthesis coupled with enhancement of detoxification processes.
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PMID:Inhibitory effects of thymoquinone against 20-methylcholanthrene-induced fibrosarcoma tumorigenesis. 1153 Oct 13

Two population-based, case-control studies have documented reduced risk of prostate cancer in men who consume cruciferous vegetables. Cruciferae contain high levels of the isothiocyanate sulforaphane. Sulforaphane is known to bolster the defenses of cells against carcinogens through up-regulation of enzymes of carcinogen defense (phase 2 enzymes). Prostate cancer is characterized by an early and near universal loss of expression of the phase 2 enzyme glutathione S-transferase (GST)-pi. We tested whether sulforaphane may act in prostatic cells by increasing phase 2 enzyme expression. The human prostate cancer cell lines LNCaP, MDA PCa 2a, MDA PCa 2b, PC-3, and TSU-Pr1 were treated with 0.1-15 microM sulforaphane in vitro. LNCaP was also treated with an aqueous extract of broccoli sprouts. Quinone reductase enzymatic activity, a surrogate of global phase 2 enzyme activity, was assayed by the menadione-coupled reduction of tetrazolium dye. Expression of NQO-1, GST-alpha, gamma-glutamylcysteine synthetase-heavy and -light chains, and microsomal GST was assessed by Northern blot analysis. Sulforaphane and broccoli sprout extract potently induce quinone reductase activity in cultured prostate cells, and this induction appears to be mediated by increased transcription of the NQO-1 gene. Sulforaphane also induces expression of gamma-glutamylcysteine synthetase light subunit but not the heavy subunit, and this induction is associated with moderate increases in intracellular glutathione levels. Microsomal and alpha-class glutathione transferases were also induced transcriptionally. Sulforaphane induces phase 2 enzyme expression and activity significantly in human prostatic cells. This induction is accompanied by, but not because of, increased intracellular glutathione synthesis. Our findings may help explain the observed inverse correlation between consumption of cruciferae and prostate cancer risk.
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PMID:Potent induction of phase 2 enzymes in human prostate cells by sulforaphane. 1153 46

The modifying effects of dietary administration of capsaicin, which is the principal pungent capsicum fruit, and rotenone, which is a naturally occurring pesticide derived from Derris and Lonchorcarpus species, on azoxymethane (AOM)-induced colon tumorigenesis were investigated in male F344 rats. Gavage with capsaicin and rotenone significantly elevated phase II enzymes, glutathione S-transferase (GST) and quinone reductase (QR), in the liver and colon. In an aberrant crypt foci (ACF) bioassay, feeding of capsaicin and rotenone at a dose of 500 ppm for 4 weeks significantly inhibited ACF formation induced by AOM (20 mg/kg body weight, once a week for 2 weeks). In a subsequent long-term study designed to confirm the protective effects of both compounds on ACF development, one group was treated with AOM alone and four other groups received the carcinogen treatment plus diets containing 500 ppm test compounds for 4 weeks (initiation phase) and for 34 weeks (post-initiation phase). Two groups were treated with capsaicin or rotenone alone (500 ppm in diet) and one group was maintained on the basal diet. At the termination of the study, dietary exposure of capsaicin during the initiation phase was found to significantly reduce the incidence of colonic adenocarcinoma (60% vs. 24%, 60% reduction, P=0.0407). Rotenone feeding during the post-initiation phase also reduced the frequency of colonic adenocarcinoma (60% vs. 19%, 68% reduction, P=0.0226). Our results suggest that two natural compounds, capsaicin and rotenone, might be useful for the prevention of human colon cancers.
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PMID:Chemoprevention of azoxymethane-induced rat colon carcinogenesis by dietary capsaicin and rotenone. 1160 90

This study analyses the expression and induction of several drug-metabolising enzyme activities involved in either phase I or phase II biotransformations in NCTC 2544 human keratinocytes. The phase I activities 7-ethoxycoumarin O-deethylase (ECOD), 7-ethoxyresorufin O-deethylase (EROD) and 7-pentoxyresorufin O-depenthylase (PROD) were easily detectable in basal conditions. During incubations lasting up to 144 h in the presence of the classical cytochrome P450 inducers beta-naphthoflavone (BNF), 3-methylcholanthrene (MC) and phenobarbital (PB), a considerable and significant increase in all the three activities was observed. PROD activity was induced up to 4.5-fold after 96 h in the presence of PB. The MC-induced ECOD and EROD activities were also dose-dependently inhibited by alpha-naphothflavone, which was given to the cells during the incubation with CYP 1A1 inducers. Also the PB-induced PROD activity was decreased by the simultaneous addition of the CYP 2B inhibitor metyrapone. Both cytochrome P450 inhibitors were used at non-cytotoxic concentrations. The phase II enzymes glutathione S-transferase, aldehyde dehydrogenase and quinone reductase were all highly expressed and inducible by MC. The exposure (24 h) of the cells to four hair dyes used in cosmetic formulations resulted in a marked increase in ECOD activity. All data give sustained evidence for the suitability of NCTC 2544 cell line to skin toxicology studies.
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PMID:Induction by xenobiotics of phase I and phase II enzyme activities in the human keratinocyte cell line NCTC 2544. 1169 72


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