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)

Phenethyl isothiocyanate (PEITC), a constituent of cruciferous vegetables, has been shown to inhibit chemical carcinogenesis, possibly due to its ability to block the activation or to enhance the detoxification of chemical carcinogens. The present study was conducted to elucidate the biochemical mechanisms involved by characterizing the effects of PEITC on phase I and phase II xenobiotic-metabolizing enzymes. A single dose of PEITC to F344 rats (1 mmol/kg) decreased the liver N-nitrosodimethylamine demethylase (NDMAd) activity (mainly due to P450 2E1) by 80% at 2 h and the activity of NDMAd remained decreased by 40% at 48 h after treatment. The liver pentoxyresorufin O-dealkylase (PROD) activity and P450 2B1 protein level were elevated 10- and 7-fold at 24 h after treatment respectively. The liver microsomal ethoxyresorufin O-dealkylase (EROD) (mainly due to P450 1A) and erythromycin N-demethylase (mainly due to P450 3A) activities were decreased at 2-12 h after treatment and recovered afterwards. The lung microsomal PROD and EROD activities were not significantly affected; whereas, the nasal microsomal PROD and EROD activities were decreased by 40-50%. After a treatment with PEITC, the rates of oxidative metabolism of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) were decreased in liver microsomes by 40-60% at 2 h and recovered gradually; the rates in lung microsomes were markedly decreased by 60-70% at 2 h and remained at the decreased level at 24 h; and the rates in nasal mucosa microsomes were decreased gradually with the lowest activities observed at 18 h (50%) followed by a gradual recovery. Furthermore, the treatment with PEITC resulted in a maximal 5-fold increase of NAD(P)H:quinone oxidoreductase and 1.5-fold increase of glutathione S-transferase activities in the liver, but the activities of these two enzymes were not significantly affected in the lung and nasal mucosa. The sulfotransferase activity in the liver was decreased by 32-48% at 24-48 h after treatment; the nasal activity was increased by 1.8- to 2.5-fold, but the lung activity was not significantly changed. The hepatic UDP glucuronosyltransferase activity was slightly decreased at 2 h but slightly increased at 48 h after treatment, but no changes were observed for the lung and nasal activities. The study demonstrates that PEITC selectively affects xenobiotic-metabolizing enzymes in the liver, lung and nasal mucosa and it is especially effective in inhibiting the P450-dependent oxidation of NNK in the lung and of NDMA in the liver.
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PMID:Effects of phenethyl isothiocyanate, a carcinogenesis inhibitor, on xenobiotic-metabolizing enzymes and nitrosamine metabolism in rats. 147 25

The nonparenchymal cells (NPC) of the liver are primarily located along the sinusoids and therefore are the first cells to encounter blood-borne xenobiotics. To study the possible role of the NPC in the metabolism of xenobiotics, populations of NPC and parenchymal cells (PC) were prepared from rats and various xenobiotic metabolizing enzyme activities investigated. The specific activity of every enzyme studied (ethoxyresorufin deethylase, benzphetamine demethylase, glutathione transferase, UDP glucuronosyltransferase, and microsomal epoxide hydrolase) was 12 to 1000% higher in the PC than in the NPC populations and the patterns of activities between the two populations were remarkably different. The NPC demonstrated a more dramatic induction of enzyme activities in Aroclor 1254-pretreated animals than did the PC. Moreover, despite the generally lower enzyme activities, even after induction, the NPC were damaged by biologically inert xenobiotics which can be metabolized to reactive intermediates. With some compounds, the concentrations required for producing similar damage was much higher in NPC compared with PC, while with other compounds, the NPC were affected by concentrations similar to those required for cytotoxicity in PC. Therefore, the NPC may contribute to the hepatic disposition of xenobiotics and may be adversely affected by reactive intermediates formed. Because of the distinctly different pattern of xenobiotic metabolizing enzymes in the two cell populations, the exact role of the NPC in the control of reactive metabolites and the toxicity produced by them will depend on the structural elements of the xenobiotic in question.
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PMID:Xenobiotic metabolizing enzymes of rat liver nonparenchymal cells. 308 73

After administration of beta-naphthoflavone and Clophen A50 to juvenile rainbow trout, activities of hepatic cytochrome P-450-dependent deethylation of 7-ethoxyresorufin was increased 172- and 49-fold, respectively. Glutathione transferase activity towards 1-chloro 2,4 dinitrobenzene and UDP glucuronosyltransferase activities towards p-nitrophenol, 1-naphthol and testosterone were increased 1.4 to 3.0-fold by beta-naphthoflavone or Clophen A50. However, significant increases of the rate of glucuronidation of 1-naphthol by Clophen A50 and of testosterone by both Clophen A50 and beta-naphthoflavone were only determined when the activities were measured in digitonin activated microsomes. Epoxide hydrolase activity was not affected by beta-naphthoflavone or Clophen A50. The time course of induction of the various xenobiotic metabolizing enzymes exhibited different patterns. 7-Ethoxyresorufin-O-deethylase activity reached peak values 3 and 7 days after the administration of beta-naphthoflavone and Clophen A50, respectively. The rate of induction of glutathione transferase activity and UDP glucuronosyltransferase activities towards p-nitrophenol and 1-naphthol were relatively slow and did not reach distinct peak levels. These activities were still on maximum levels 4-6 weeks after the treatment. Glucuronidation of testosterone reached peak values 1 week after treatment with both beta-naphthoflavone and Clophen A50. The dissimilar patterns of induction of the cytochrome P-450-dependent activities and the various conjugation activities may indicate that these xenobiotic metabolizing enzymes are differently regulated in the rainbow trout liver.
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PMID:Differential induction of cytochrome P-450-dependent monooxygenase, epoxide hydrolase, glutathione transferase and UDP glucuronosyl transferase activities in the liver of the rainbow trout by beta-naphthoflavone or Clophen A50. 392 91

Established cell lines derived from newborn livers of c14CoS/c14CoS and cch/cch mice were examined for differences in menadione toxicity. The 14CoS/14CoS cells exhibit 10-fold higher NAD(P)H:menadione oxidoreductase (NMO1) activity and 3-fold greater concentrations of reduced glutathione (GSH) than the ch/ch cells. In 14CoS/14CoS cells there are also 50% to 3-fold increases in glutathione transferase (GSTA1), UDP glucuronosyltransferase, and the copper, zinc-dependent superoxide dismutase activities. Catalase activity, on the other hand, is six times lower in the 14CoS/14CoS than the ch/ch line. The 14CoS/14CoS cells are two to four times more resistant to menadione killing than ch/ch cells. At concentrations of dicumarol that completely block NMO1 and GSTA1 activities, the 14CoS/14CoS cells show more than twice as much resistance to menadione toxicity than the ch/ch cells. Although superoxide formation is three times higher in untreated 14CoS/14CoS than ch/ch cells, menadione-induced superoxide formation is greater in the dying ch/ch than in the 14CoS/14CoS cells. Cellular resistance to menadione toxicity is correlated with intracellular GSH levels, rather than with the percentage of oxidized glutathione; cytotoxicity is not observed as long as GSH concentrations are sufficiently high (about 5-8 nmol/mg protein). For menadione, the results are consistent with a dominant role of GSH depletion in mediating toxicity and support a protective role for NMO1 activity. This report demonstrates the usefulness of these cell lines as a model system to study mechanisms of oxidative chemically induced toxicity, as well as to understand how intracellular levels of GSH are regulated.
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PMID:Menadione toxicity in two mouse liver established cell lines having striking genetic differences in quinone reductase activity and glutathione concentrations. 769 Sep 96

Established cell lines derived from newborn livers of c14CoS/c14CoS and cch/cch mice have been shown to be genetically resistant (14CoS/14CoS cells) or susceptible (ch/ch cells) to menadione toxicity. These differences are due in part to relatively higher levels of reduced glutathione (GSH) and NAD(P)H:menadione oxidoreductase (NMO1) activity in the 14CoS/14CoS cells. The indolic membrane-stabilizing antioxidant 5,10-dihydroindeno[1,2-b]indole (DHII) was shown previously to protect against various hepatotoxicants in vivo and in primary rat hepatocytes. This report describes how the 14CoS/14CoS and ch/ch cell lines provide a valuable experimental system to distinguish the mechanism of chemoprotection by DHII from menadione toxicity. The addition of 25 microM DHII produced a time-dependent decrease in menadione-mediated cell death in 14CoS/14CoS cells, with little effect on ch/ch cell viability. The maximum protective effect occurred at 24 hr, although the concentration of DHII remained constant for 48 hr. The protective effect of DHII correlated with enhanced glutathione levels (234% increase at 24hr), as well as induction of four enzymes involved in the detoxification and excretion of menadione: NAD(P)H:menadione oxidoreductase (NMO1, quinone reductase), glutathione reductase, glutathione transferase (GST1A1), and UDP glucuronosyltransferase (UGT1*06), with 24-hr maximum induction of 707, 201, 171 and 198%, respectively. Other biotransformation enzymes not directly involved in menadione metabolism (glutathione peroxidase, cytochromes P4501A1 and P4501A2, copper-, zinc-dependent superoxide dismutase, and NADPH cytochrome c oxidoreductase) were not induced by DHII. Menadione-stimulated superoxide production was inhibited 50% by DHII only in 14CoS/14CoS cells, and the inhibition required 24-hr preincubation. Pretreatment with DHII also protected both cell types against the menadione-mediated depletion of GSH, and the increase in percent (oxidized glutathione GSSG), an indicator of oxidative stress. These results suggest that DHII does not protect against menadione toxicity by virtue of its antioxidant or membrane-stabilizing properties. Rather, it acts by inducing a protective enzyme profile that migates redox cycling and facilitates excretion of menadione.
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PMID:Mechanisms of protection from menadione toxicity by 5,10-dihydroindeno[1,2,-b]indole in a sensitive and resistant mouse hepatocyte line. 824 Apr 1

Previous work demonstrated that exposure of laboratory animals including fish to certain organochlorine (OC) insecticides altered the tissue distribution of a subsequent tracer dose of the same [14C]OC. In the present study, 10- to 20-g rainbow trout were exposed to 15 ppm dieldrin in the diet. Fish were subsequently challenged at 2-week intervals with an intraperitoneal injection of 0.1 mg/kg [14C]dieldrin and viscera (liver, bile, mesenteric fat, kidney, and intestine) analyzed for radioactivity, 24 hr later. After 10 and 12 weeks of dieldrin pretreatment, [14C]dieldrin was significantly elevated relative to controls in liver (200%), bile (500%), and fat (500 and 1200% for 10 and 12 weeks, respectively) of pretreated fish. Other tissues were unchanged. Chloroform/methanol extractions revealed a time-dependent increase in label disposition to carcass lipid in controls but not in pretreated fish. Altered disposition could not be explained by changes in total body lipid or induction of total cytochrome P-450 or ethoxyresorufin-O-deethylase, pentoxyresorufin-O-deethylase, glutathione S-transferase, or UDP glucuronosyltransferase activities. In vivo assessment of [14C]dieldrin metabolism revealed no increase in hepatic and only a slight (22%) increase in biliary polar:nonpolar concentration ratio after 9 weeks 20 ppm dieldrin pretreatment. Results suggest that constitutive changes in liver integral to dieldrin sequestration, transport, or excretion may be an adaptive response of trout to chronic OC exposure.
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PMID:Chronic dieldrin exposure increases hepatic disposition and biliary excretion of [14C]dieldrin in rainbow trout. 850 3

Ellagic acid (EA), a naturally occurring plant polyphenol possesses broad chemoprotective properties. Dietary EA has been shown to reduce the incidence of N-2-fluorenylacetamide-induced hepatocarcinogenesis in rats and N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumors. In this study changes in the expression and activities of specific rat hepatic and esophageal mucosal cytochromes P450 (P450) and phase II enzymes following dietary EA treatment were investigated. Liver and esophageal mucosal microsomes and cytosol were prepared from three groups of Fisher 344 rats which were fed an AIN-76 diet containing no EA or 0.4 or 4.0 g/kg EA for 23 days. In the liver total P450 content decreased by up to 25% and P450 2E1-catalyzed p-nitrophenol hydroxylation decreased by 15%. No changes were observed in P450 1A1, 2B1 or 3A1/2 expression or activities or cytochrome b5 activity. P450 reductase activity decreased by up to 28%. Microsomal epoxide hydrolase (mEH) expression decreased by up to 85% after EA treatment, but mEH activities did not change. The hepatic phase II enzymes glutathione S-transferase (GST), NAD(P)H:quinone reductase [NAD-(P)H:QR] and UDP glucuronosyltransferase (UDPGT) activities increased by up to 26, 17 and 75% respectively. Assays for specific forms of GST indicated marked increases in the activities of isozymes 2-2 (190%), 4-4 (150%) and 5-5 (82%). In the rat esophageal mucosa only P450 1A1 could be detected by Western blot analysis and androstendione was the only P450 metabolite of testosterone detectable. However, there were no differences in the expression of P450 1A1, the formation of androstendione or NAD(P)H:QR activities between control and EA-fed rats in the esophagus. Although there was no significant decrease in overall GST activity, as measured with 1-chloro-2,4-dinitrobenzene (CDNB), there was a significant decrease in the activity of the 2-2 isozyme (66% of control). In vitro incubations showed that EA at a concentration of 100 microM inhibited P450 2E1, 1A1 and 2B1 activities by 87, 55 and 18% respectively, but did not affect 3A1/2 activity. Using standard steady-state kinetic analyses, EA was shown to be a potent non-competitive inhibitor of both liver microsomal ethoxyresorufin O-deethylase and p-nitrophenol hydroxylase activities, with apparent Ki values of approximately 55 and 14 microM respectively. In conclusion, these results demonstrate that EA causes a decrease in total hepatic P450 with a significant effect on hepatic P450 2E1, increases some hepatic phase II enzyme activities [GST, NAD-(P)H:QR and UDPGT] and decreases hepatic mEH expression. It also inhibits the catalytic activity of some P450 isozymes in vitro. Thus the chemoprotective effect of EA against various chemically induced cancers may involve decreases in the rates of metabolism of these carcinogens by phase I enzymes, due to both direct inhibition of catalytic activity and modulation of gene expression, in addition to effects on the expression of phase II enzymes, thereby enhancing the ability of the target tissues to detoxify the reactive intermediates.
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PMID:The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes. 862 97

The dioxin-inducible mouse [Ah] battery contains at least six genes that "cross-talk" with one another and are believed to play important roles in reproduction and development, and in environmental toxicity, cancer, and oxidative stress. In addition to two P450 genes, Cyp1a1 and Cyp1a2, this laboratory has shown that the four Phase II [Ah] genes include: NAD(P)H:menadione oxidoreductase (Nmo1); a cytosolic "class 3" aldehyde dehydrogenase (Ahd4); a UDP glucuronosyltransferase having 4-methylumbelliferone as substrate (Ugt1a6); and a glutathione transferase having 2,4-dinitro-1-chlorobenzene as substrate (Gsta1, Ya). The Ah receptor-mediated coordinate induction is controlled positively in all six [Ah] battery genes. Oxidative stress up-regulates the four Phase II [Ah] genes. This laboratory is generating conventional, plus inducible, knockout mouse lines having homozygous disruptions in the above-mentioned genes; this novel methodology is described herein. If the conventional knockout is healthy and viable, the mouse line would be useful for studies involving environmental agents. If the conventional knockout is lethal during development, this model would be important for developmental biology, but the inducible (also called conditional) knockout can still be used--at selected ages and even in selected tissue or cell types--for studies designed to understand the mechanisms involved in reproduction and development, and in environmental toxicity, cancer, and oxidative stress.
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PMID:How knockout mouse lines will be used to study the role of drug-metabolizing enzymes and their receptors during reproduction and development, and in environmental toxicity, cancer, and oxidative stress. 906 27

This study was conducted to examine the effects of dietary carbohydrate [starch or sucrose (500 g/kg diet)] and myo-inositol (2 g/kg diet) on metabolic changes in rats fed 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT) (0.7 g/kg diet). Dietary DDT enhanced serum and hepatic lipids and hepatic thiobarbituric acid reactive substances (TBA-RS), elevated hepatic activities of lipogenic enzymes such as malic enzyme (ME), glucose-6-phosphate dehydrogenase (G6PD) and fatty acid synthetase (FAS), increased hepatic cytochrome P-450 content and the activities of drug-metabolizing enzymes such as aminopyrine N-demethylase, glutathione S-transferase and 4-nitrophenol-UDP glucuronosyltransferase (4NP-UDPGT) and raised hepatic ascorbic acid and serum copper. Dietary sucrose promoted the increases in hepatic concentrations of total lipids, triglyceride and cholesterol, hepatic activity of ME, hepatic TBA-RS, cytochrome P-450 content and serum copper due to DDT feeding when compared to DDT administered in a starch based diet. Dietary myo-inositol significantly depressed the rises in hepatic concentrations of total lipids, triglyceride and cholesterol and the activities of ME and G6PD due to DDT feeding regardless of dietary carbohydrate quality. Dietary starch supplemented with myo-inositol potentiated the enhancements in hepatic activities of Phase II drug-metabolizing enzymes such as glutathione S-transferase and 4NP-UDPGT due to DDT feeding. These results suggest that dietary starch and myo-inositol can protect DDT fed rats against an accumulation of hepatic lipids, which might be mainly ascribed to the depression of hepatic lipogenesis. In addition, the present study implies that the supplementation of myo-inositol to high starch diet might improve the function of drug-metabolizing enzymes exposed to DDT.
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PMID:Effects of dietary carbohydrate and myo-inositol on metabolic changes in rats fed 1,1,1-trichloro-2,2-bis (p-chlorophenyl) ethane (DDT). 1266 99

Several naturally occurring plant phenols were shown to inhibit the mutagenicity and/or tumorigenicity of chemical carcinogens, including polycyclic aromatic hydrocarbons (PAHs). In this study, the effect of the topical application of three structurally diverse phenolic acids and trihydroxystilbene, resveratrol, on epidermal aryl hydrocarbon hydroxylase (AHH), phase II enzymes, as well as the binding of benzo[a]pyrene (B[a]P) and 7,12-dimethylbenz[a]anthracene (DMBA) to epidermal DNA were compared. The single, topical application of 8 and 16 mumol of protocatechuic or chlorogenic acid increased the activity of AHH by 10-30%, whereas resveratrol in a dose of 16 mumol almost completely (99%) inhibited the enzyme activity. Phenolic acids also increased the activities of phase II enzymes. Resveratrol did not affect the glutathione S-transferase activity but induced UDP glucuronosyltransferase (by approximately 100-150%) and to a lesser extent NAD(P)H:quinone oxidoreductase. In a dose of 16 micromol all phenolic acids afforded 40-50% inhibition of covalent benzo[a]pyrene-diol-epoxide (B[a]PDE) binding to DNA. Resveratrol had no effect on B[a]PDE adduct formation but reduced the levels of all the major DMBA adducts. Phenolic acids, particularly tannic acid, mostly affected the formation of syn- and anti-DMBADE dAdo adducts. These results indicate that both the modulation of carcinogen activating enzymes and the prevention of their ultimate metabolites binding to DNA by naturally occurring phenolics are involved in the antitumorigenic activity of these compounds. For phenolic acids, however, their interactions with reactive PAH metabolites and/or blocking of a specific binding site in a genome seem more important. Derivatives of stilbene, such as resveratrol, affect DNA adduct formation and thus the initiation of tumorigenesis through the interaction with the Ah receptor rather than the scavenging active metabolites.
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PMID:Alteration in phase I and II enzyme activities and polycyclic aromatic hydrocarbons-DNA adduct formation by plant phenolics in mouse epidermis. 1520 80


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