Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.6.5.2 (NQO1)
 6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of different doses of methylglyoxal (50-400 mg/kg body wt.) were examined using enzymes involved in the antioxidant function, glutathione (GSH) content and lipid peroxidation in the liver and spleen of Swiss albino mice (7-8 week old) after 6, 12 and 24 h. Significant changes were observed predominantly in the liver. The specific activities of superoxide dismutase (SOD), glutathione-S-transferase (GST), catalase, glyoxalase I (gly I) and glyoxalase II (gly II) were found to decrease in the liver. The mode and magnitude of change in the specific activities was seen to depend on the dose of methylglyoxal and the time after its administration. Methylglyoxal also decreased the GSH content and enhanced the lipid peroxidation in the liver. These findings are suggestive of the adverse effect of methylglyoxal on the antioxidant defence system. It is likely that methylglyoxal undergoes a redox cycle and generates the free radicals which in turn lower the antioxidant status in animals. The increased levels of lipid peroxidation provide support for the involvement of free radical processes in the detrimental effects of methylglyoxal. The response of DT-diaphorase (DTD) seems to be adaptive.
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PMID:Influence of methylglyoxal on antioxidant enzymes and oxidative damage. 948 50

Groups of young male adult guinea pigs were fed a diet devoid in supplemental ascorbic acid (AA) or the same diet supplemented with 0.1 or 2.5% AA for four weeks. The animals were then euthanized and Phase I and Phase II drug metabolizing components in the liver were determined. Phase I components are those related to the metabolism of xenobiotics and include microsomal cytochrome P-450 and mixed function oxygenase activities. Phase II components are those related to conjugation and detoxification reactions of xenobiotics and their metabolites and include glutathione-S-transferases (GST), glutathione (GSH), UDP-glucuronyl transferase (UDP-GT) and DT-diaphorase (quinone reductase, QR). Tissue levels of AA increased progressively with increase in AA intake. The Phase I components increased in response to increased intake of AA from 0 to 0.1%, but were unaffected by further increase in AA intake to 2.5%. However, the Phase II components increased with increased intake of AA except for GST. In vitro metabolism of aflatoxin B1 (AFB1) using liver microsomes showed tendency towards increased production of aflatoxin M1 (AFM1) with increase in AA intake. The production of aflatoxin P1 (AFP1) was not affected by AA intake. AFB1-DNA production was increased when AA intake was increased to 0.1%. It was however lowered with further increase in AA intake to 2.5%.
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PMID:Modulation of drug metabolizing enzymes in guinea pig liver by high intakes of ascorbic acid. 950 47

Four glucosinolate derivatives were evaluated individually and as a mixture for their effects on hepatic P4501A (CYP1A), glutathione S-transferase (GST), quinone reductase (QR), glutathione reductase (G-Rd), and GSH levels. Doses of the derivatives were chosen to represent their relative abundance in Brussels sprouts. Adult male F344 rats received either corn oil (vehicle); one of the agents: indole-3-carbinol (I3C, 56 mg/kg), iberin (38 mg/kg), phenylethylisothiocyanate (PEITC, 0.1 mg/kg), or cyanohydroxybutene (crambene, 50 mg/kg); or all of the agents at the doses shown (as a mixture) given by gavage daily for 7 days. The mixture and I3C caused an 11- and 9.4-fold induction of CYP1A, respectively. Crambene and I3C each caused a 1.4-fold increase in GST, while the mixture caused a 2.5-fold increase. Crambene and I3C caused a 2.5- and 1.9-fold increase in QR, respectively. The mixture caused a 6.2-fold increase. Crambene, PEITC, and the mixture caused a 1.8-, 1.6-, and 2.0-fold increase in hepatic GSH levels, respectively. Crambene, I3C, iberin, and the mixture caused 1.3-, 1.4-, 1.2-, and 1.7-fold increases in G-Rd, respectively. In a second study the mixture was given at 60 and 20% of the original dose. CYP 1A, QR, G-Rd, and GST elevations were dose-dependent; GSH levels were not elevated. It is concluded that I3C and crambene are responsible for the majority of enzyme increases seen. A synergistic effect of I3C and crambene was evident on induction of GST and QR, but not on GSH, G-Rd, or P4501A.
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PMID:A comparison of the individual and collective effects of four glucosinolate breakdown products from brussels sprouts on induction of detoxification enzymes. 985 97

The reaction between glutathione and 2,5-diaziridinyl-1,4-benzoquinones bearing halogen substituents at C3 and C6 was examined in terms of the formation of glutathionyl-quinone conjugates and semiquinones by HPLC with UV detection, mass spectroscopy and EPR. The reactivity of the halogen atoms toward sulfur substitution is the primary reaction leading to the formation of mono- and di-glutathionyl-substituted quinones. The relative formation of these conjugates depended on the GSH/quinone molar ratios. At GSH/quinone molar ratios below unity, the products observed were the reduced form of the parent quinone, a dithioether derivative and GSSG. Disulfide formation accounted for 60-68% of total GSH consumed. EPR analysis of these reaction mixtures showed a 5-line spectrum (1:2:3:2:1 relative intensities) with 2 equivalent N (aN = 1.98 G) and assigned to the semiquinone form of dichloro- diaziridinylbenzoquinone. Semiquinone quantification by double integration of the EPR signals and interpolation with an adequate standard revealed that the amount of semiquinone formed per GSH consumed was 0.98. At GSH/quinone molar ratios above unity (4, 10 and 100 molar excess of GSH) a pattern of products emerged consisting of 3,6-diglutathionyl quinones with two, one and no aziridinyl moieties, identified by mass spectral analysis. EPR studies revealed that these compounds were minor components of a composite EPR spectrum (a 3-line signal with 1:1:1 relative intensities, 1 equivalent N (aN = 1.73 G) and 1 H (aH = 1.45 G) or a 3-line signal with 1:2:1 relative intensities and 2 equivalent H (aH = 1.4 G). These minor components were assigned to the diglutathionyl conjugates bearing one- or no aziridinyl moiety, respectively. The major component in the EPR signal showed a 3-line spectrum (1:1:1 relative intensity) with 1 equivalent N (aN = 1.7 G) and a g shift of -0.96 G. This spectrum was assigned to a triglutathionyl conjugate of a monoaziridinylbenzoquinone. This major component was also observed when GSH/quinone mixtures were incubated with the two-electron transfer flavoprotein NAD(P)H:quinone oxidoreductase. The semiquinone signals were abolished by superoxide dismutase. In the presence of catalase, the contribution of these components to the overall EPR spectrum was equal. These data are discussed in terms of the one-electron transfer steps encompassed by thiol oxidation and semiquinone formation and the two-electron transfers inherent in sulfur substitution and aziridinyl group loss.
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PMID:Reactions of halogen-substituted aziridinylbenzoquinones with glutathione. Formation of diglutathionyl conjugates and semiquinones. 952 86

Dopamine (DA) is oxidized to the neurotoxic prooxidant species H2O2, OH., and DA quinones. We tested whether dimethyl fumarate (DMF), an electrophile shown to induce a pleiotropic antioxidant response in nonneuronal cells, could reduce the toxicity of DA metabolites in neural cells. Treatment of the N18-RE-105 neuroblastoma-retina hybridoma cell line with 30-150 microM dopamine led to cell death within 24 h, which increased steeply with dose, decreased with higher plating density, and was blocked by the H2O2-metabolizing enzyme catalase. Pretreatment with DMF (30 microM, 24 h) significantly attenuated DA and H2O2 toxicity (40-60%) but not that caused by the calcium ionophore ionomycin. DMF treatment also elevated total intracellular GSH and increased activities of the antioxidant enzymes quinone reductase (QR), glutathione S-transferase (GST), glutathione reductase, and the pentose phosphate enzyme glucose-6-phosphate dehydrogenase. To assess the protective efficacy of QR and GST, a stable cell line was constructed in which these enzymes were overexpressed. Cell death in the overexpressing line was not significantly different from that in a cell line expressing normal QR and GST activities, indicating that these two enzymes alone are insufficient for protection against DA toxicity. Although the relative importance of a single antioxidant enzyme such as QR or GST may be small, antioxidant inducers such as DMF may prove valuable as agents that elicit a broad-spectrum neuroprotective response.
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PMID:Activation of endogenous antioxidant defenses in neuronal cells prevents free radical-mediated damage. 964 52

The chemoprotective effects of cruciferous vegetables against cancer has been linked to the induction of detoxification enzymes, including the phase II enzymes, glutathione S-transferases (GST) and quinone reductase (QR). Four glucosinolate breakdown products found in Brussels sprouts and previously shown individually to affect detoxification enzymes--(1-cyano-2-hydroxy-3-butene (Crambene), indole-3-carbinol (I3C), phenylethyl isothiocyanate (PEITC) and 1-isothiocyanato-3-(methylsulfinyl)-propane (IBN) were administered to male F344 rats by oesophageal intubation for 7 days both as a mixture and individually to assess the effect of these compounds on GST and QR activity in the pancreas, an organ previously shown to be affected by cruciferous diets. The doses of each compound in the mixture (50 mg Crambene/kg, 56 mg I3C/kg, 0.1 mg PEITC/kg and 38 mg IBN/kg) were chosen to represent the relative proportions of the parent glucosinolate for each compound in Brussels sprouts and shown to be below the toxic threshold for all the compounds. In rats receiving the mixture, pancreatic QR and GST activities were elevated 31- and 1.7-fold, respectively, while glutathione (GSH) was elevated threefold. On an individual basis, Crambene alone caused a 21-fold elevation of QR and 1.5-fold elevation of GST activities, while pancreatic GSH was elevated by both Crambene and PEITC 2.6- and twofold, respectively. No other significant effects of individual components were found. When the mixture was administered at 60% of the original dose, pancreatic QR and GST activities were elevated 12- and 1.4-fold, respectively, and pancreatic GSH was elevated 1.5-fold. At 20% of the original dose, pancreatic GSH was unaffected and QR and GST activities were elevated 2.7- and 1.3-fold, respectively. The results of these studies suggest that a diet rich in cruciferous vegetables may produce phase 11 enzyme induction in the pancreas, and that Crambene may be the most active component.
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PMID:Induction of rat pancreatic glutathione S-transferase and quinone reductase activities by a mixture of glucosinolate breakdown derivatives found in Brussels sprouts. 966 11

Maintenance of cellular homeostasis is a critical survival trait when cells are exposed to electrophilic chemicals. Because conjugation and elimination of these toxins is dependent upon sequential and coordinated metabolic pathways, acquired resistance through a gradual adaptive response would rarely be expected to be the consequence of changes in one gene product. Human HT29 colon cancer cells chronically exposed to EA have acquired resistance to the drug. Commensurate with resistance, EA is more effectively conjugated to GSH and effluxed from the resistant cells. Using directed and random (differential display) approaches, a number of detoxification and/or protective gene products have been shown to be expressed at elevated levels. These include gamma-GCS (approximately 3-fold), GST-pi (approximately 3-fold), MRP (approximately 3-fold), NQO1 (approximately 3-fold), DDH (20-fold), and SSP 3521, a transcriptional regulator (approximately 3-fold). Multiple mechanisms contribute to these increases, including enhanced transcriptional rate and prolonged mRNA and protein half lives. Further indications for the involvement of transcriptional regulators is found in HL60 adriamycin-resistant cells which overexpress MRP, GST-pi and gamma-GCS and also have 15-20-fold more DNA-dependent protein kinase. It is possible that this enzyme serves as an early stress response gene which may activate downstream transcription factors. Intriguingly, the catalytic subunit of DNA-dependent protein kinase has a high avidity for [35S]azidophenacyl-GSH. High levels of GSH conjugates indicate cell stress and it would seem reasonable to speculate that DNA-dependent protein kinase may serve as a receiver and transmitter of signals which contribute to drug resistance and maintain cell viability.
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PMID:Coordinate changes in expression of protective genes in drug-resistant cells. 967 55

Novel thiazolidine prodrugs were prepared by the condensation of L-cysteine with aldose disaccharides. Using a disaccharide in prodrug construction allows for a terminal cyclic sugar moiety to be present on the prodrug, which may allow the delivery of the agent to specific receptors, such as the asialoglycoprotein receptor (ASGPR) of hepatocytes, that require specific structural motifs for recognition. Three L-cysteine prodrugs were synthesized with a pendant cyclic galactose moiety; two related glucose-bearing prodrugs were synthesized for comparison. The prodrugs were designed to release L-cysteine, which is then available to support glutathione (GSH) biosynthesis and provide cytoprotection against a variety of toxic insults. Protection studies in Swiss-Webster mice used acetaminophen (575 mg/kg), a well-documented hepatotoxin which depletes GSH at overdose. Three prodrugs performed exceptionally well against acetaminophen-induced hepatotoxicity, as measured by increased survival and improved histological profiles of liver tissue after 48 h. In further experimentation, two of the disaccharide-based prodrugs, prepared from alpha- and beta-lactose, were compared with the monosaccharide-based compound prepared from ribose. Co-administration of the selected prodrugs with a 400 mg/kg dose of acetaminophen to Swiss-Webster mice prevented the short-term depletion in hepatic GSH and also reduced hepatotoxicity as determined by histological damage and serum levels of alanine aminotransferase. A single dose of the prodrugs alone had no effect on hepatic drug metabolizing enzymes [glutathione S-transferase (GST), NAD(P)H:quinone oxidoreductase (QOR), UDP-glucuronosyltransferase (UGT), and cytochrome P450], but, concordant with the reduction of hepatotoxicity, the latentiated forms prevented the significant elevation in QOR activity and mRNA and GST mRNA elicited by acetaminophen itself. GST activity, UGT activity and mRNA, and cytochrome P450 concentration were all unaffected by acetaminophen or the prodrugs. These studies identified novel L-cysteine prodrugs with potentially useful hepatoprotective activity. However, no structure-activity relationships were obvious. In addition, the occurrence of targeted delivery to hepatocytes remains ambiguous.
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PMID:Differential chemoprotection against acetaminophen-induced hepatotoxicity by latentiated L-cysteines. 981 87

Oltipraz [5-(2-pyrazinyl)-4-methyl-1,2-dithiole-3-thione] is a synthetic dithiolethione with chemopreventive activity against carcinogen-induced neoplasia of liver, lung, and colon in several animal model systems. Protection from tumor formation is associated with elevation of Phase II enzymes, including glutathione (GSH) transferase and NAD(P)H:quinone oxidoreductase (DT-diaphorase) in experimental carcinogenesis models in vivo. To investigate the time and dose relationships of the pharmacological action of oltipraz and to develop a model for its investigation, a human colon adenocarcinoma HT29 cell line was primarily used. In this cell line, oltipraz resulted in increased activity of both GSH transferase and DT-diaphorase. At the maximum effective concentration (100 microM), the elevation of GSH transferase was 3-fold and that of DT-diaphorase was 2-fold. The optimal duration of oltipraz exposure to HT29 cells was 24 h, following which the peak in enzyme activity was observed at 24 h after removal of the drug, and activity had almost returned to control levels after 72 h in drug-free media. Steady-state mRNA levels for DT-diaphorase were observed to increase during the period of drug exposure and remained elevated, even as catalytic activities declined to control levels, suggesting additional mechanisms for control of the activity of this enzyme. More prolonged drug exposure was associated with less induction of the detoxication enzymes, prompting an investigation of the possible toxicity of oltipraz to these cells. Although the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay revealed inhibition of proliferation (IC50, 100 microM oltipraz), a clonogenic assay demonstrated no loss of clonogenicity. Oltipraz is known to be extensively metabolized in many species; two major metabolites include a 3-ketone (metabolite 2, M2) and a molecular rearrangement to a pyrrolopyrazine derivative (metabolite 3, M3), numerous conjugates of which are formed in vivo. To investigate the potential cause of the lag in response, we synthesized two major oltipraz metabolites (M2 and M3) and tested their efficacy in enzyme induction. The activity of DT-diaphorase was induced similarly by both oltipraz and M2 (2.6- versus 2.8-fold baseline) at 100 microM, whereas M3 was inactive at all concentrations. M2 also resulted in a 5.8-fold elevation of steady-state DT-diaphorase mRNA levels. Both enzyme activity and steady-state mRNA peaked at 24 h as with the parent compound. Thus, the oxidative desulfuration of oltipraz results in the formation of an active metabolite, but this process is not rate limiting for the induction of detoxicating enzymes. These data support the use of intermittent schedules in oltipraz in clinical trials of chemoprevention because of evidence of attenuation of response. The metabolite M2, but not M3, is as active as the parent compound and may be considered for clinical development in its own right.
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PMID:Cellular kinetics of induction by oltipraz and its keto derivative of detoxication enzymes in human colon adenocarcinoma cells. 981 50

Humans ingest about 1 g of flavonoids daily in their diet, and they are increasingly being associated with cytoprotective antitumour properties. The mechanism(s) responsible for these effects have not yet been elucidated but may involve interaction with xenobiotic metabolising enzymes to alter the metabolic activation of potential carcinogens. We have investigated the effect of the flavonoids, quercetin (Q), myricetin (M) and epicatechin (E) on the growth, morphology and enzyme activities of MCF7 human breast cancer cells. Of the three flavonoids studied only Q caused a decrease in cell protein content and decreased the reduction of MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium). It also inhibited protein, DNA and RNA synthesis to the greatest extent. Q and M increased intracellular reduced glutathione (GSH) content, and Q altered the morphology of the cells after 24 h exposure to 25 microM. E and Q inhibited the O-deethylation of ethoxyresorufin (EROD) catalysed by cytochrome P450 CYPIA. In contrast, M increased the EROD reaction 2-fold. Q increased the activity of DT-diaphorase, NADPH cytochrome c reductase and glutathione reductase, while E increased only NADPH cytochrome c reductase activity. The effects on enzyme activities in vitro suggest that there is not only the potential for flavonoids to alter metabolic activation of carcinogens but also of therapeutically administered drugs in vivo. We are at present investigating the synergy between anti-cancer drugs and flavonoids in terms of anti-tumour efficacy.
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PMID:The effect of the flavonoids, quercetin, myricetin and epicatechin on the growth and enzyme activities of MCF7 human breast cancer cells. 992 Apr 63


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