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:1.6.5.2 (NQO1)
6,196 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Chemoprevention involves the use of natural or synthetic substances to reduce the risk of developing cancer. Two dietary components capable of mediating chemopreventive activity in animal models by modulation of drug-metabolizing enzymes are sulforaphane, an aliphatic isothiocyanate, and brassinin, an indole-based dithiocarbamate, both found in cruciferous vegetables. We currently report the synthesis and activity of a novel cancer chemopreventive agent, (+/-)-4-methylsulfinyl-1-(S-methyldithiocarbamyl)-butane (trivial name, sulforamate), an aliphatic analogue of brassinin with structural similarities to sulforaphane. This compound was shown to be a monofunctional inducer of NAD(P)H:quinone oxidoreductase [quinone reductase (QR)], a Phase II enzyme, in murine Hepa 1c1c7 cell culture and two mutants thereof. Induction potential was comparable to that observed with sulforaphane (concentration required to double the specific activity of QR, approximately 0.2 microM), but cytotoxicity was reduced by about 3-fold (IC50 approximately 30 microm). In addition, sulforaphane, as well as the analogue, increased glutathione levels about 2-fold in cultured Hepa 1c1c7 cells. Induction of QR was regulated at the transcriptional level. Using Northern blotting techniques, time- and dose-dependent induction of QR mRNA levels were demonstrated in Hepa 1c1c7 cell culture. To further investigate the mechanism of induction, HepG2 human hepatoma cells were transiently transfected with QR-chloramphenicol acetyltransferase plasmid constructs containing various portions of the 5'-region of the QR gene. Sulforaphane and the analogue significantly induced (P < 0.0001) CAT activity at a concentration of 12.5 microM by interaction with the antioxidant responsive element (5-14-fold induction) without interacting with the xenobiotic responsive element. Moreover, both compounds significantly induced mouse mammary QR and glutathione S-transferase activity (feeding of 3 mg/mouse intragastric for 4 days), whereas the elevation of hepatic enzyme activities was less pronounced. Both sulforaphane and the analogue were identified as potent inhibitors of preneoplastic lesion formation in carcinogen-treated mouse mammary glands in organ culture (84 and 78% inhibition at 1 microm, respectively). On the basis of these results, the sulforaphane analogue can be regarded as a readily available promising new cancer chemopreventive agent.
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PMID:Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes. 900 May 67

The spontaneous autoxidation of the neurotoxin 6-hydroxydopamine proceeds by a free radical chain reaction involving the superoxide anion radical and produces the corresponding chromogen 6-hydroxydopamine quinone and hydrogen peroxide. The rate of this reaction is increased in the presence of ceruloplasmin and peroxidase, and reduced by superoxide dismutase, catalase, and DT-diaphorase. We report some explanations of why these proteins may increase or reduce the rate of autoxidation of 6-hydroxydopamine.
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PMID:Modulation of 6-hydroxydopamine oxidation by various proteins. 917 10

MX100 is an Escherichia coli K12 genotoxicity tester strain, especially developed for mechanistic studies of chemical mutagens and carcinogens. For the study of the role of specific enzymes in the bioactivation and bioinactivation of carcinogens, it is necessary to characterize MX100 as far as its metabolic bio(in)activation capacities are concerned. In this study such a characterization is performed in two types of cell-free lysates, one derived from stationary phase cells, grown in rich medium (SR-lysates) and one from exponentially growing cells (log phase), cultured in minimal medium (LM-lysates). Six Phase I enzyme activities of aromatic NADPH hydroxylase, NADH hydroxylase, flavin-containing monooxygenase (FMO), nitroreductase, DT-diaphorase and NADPH ferredoxin:oxidoreductase were determined. Activities of six Phase II enzymes glutathione S-transferases (GSTs), N-aryl acetyltransferase (NAT), arylamine sulphotransferase, UDP-glucuronyltransferase and epoxide hydratase and of the Phase III enzyme cysteine conjugate beta-lyase were subsequently assessed. In addition, five antioxidant enzymes: superoxide dismutase (SOD), catalase, glutathione (GSH)-reductase, GSH-peroxidase and alkyl hydroperoxide reductase; as well as concentrations of glutathione (GSH) and its disulphide (GSSG), were measured. The activity parameters of all enzymes were compared with those obtained in similar lysates of the Salmonella strain TA100 and in rat liver preparations. The results indicate that MX100 as well as TA100 contain relatively low oxidative but high reductase Phase I activities. Both strains demonstrated low activities for the Phase II conjugation enzymes except for GSTs. In MX100, relatively high activities were detected for all antioxidative enzymes, activities which were lower in TA100. Significant differences in activities were observed between the SR-lysates derived from stationary phase/rich medium and LM-lysates from log phase/minimal medium cells for nitroreductase, GST, SOD, catalase, NADPH ferredoxin:oxidoreductase as well as in GSH content. In general, we described for the first time a metabolic characterization of the E.coli tester strain MX100 and the Salmonella typhimurium strain TA100 and discussed the results in terms of its significance for carcinogen bioactivation and bioinactivation capacities.
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PMID:Characterization of enzyme activities and cofactors involved in bioactivation and bioinactivation of chemical carcinogens in the tester strains Escherichia coli K12 MX100 and Salmonella typhimurium LT2 TA100. 923 69

Tirapazamine (TPZ, 3-amino-1,2,4-benzotriazine 1,4-di-N-oxide, SR 4233, WIN 59075) is a bioreductive antitumor agent with a high selective toxicity for hypoxic cells. The selective hypoxic toxicity of TPZ results from the rapid reoxidation of the one-electron reduction product, the TPZ radical, in the presence of molecular oxygen with the concomitant production of superoxide radical. Under hypoxia the TPZ radical kills cells by causing DNA double-strand breaks and chromosome aberrations. However, the mechanism of aerobic cytotoxicity is still a matter of debate. In this study, we investigated the mechanism of aerobic cytotoxicity by adapting human lung adenocarcinoma A549 cells to aerobic TPZ exposure and characterizing the changes associated with drug resistance. The adapted cells were resistant to aerobic TPZ exposures (with dose-modifying factors of up to 9.2), although hypoxic sensitivity was largely unchanged. Relative to the parental A549 cell line, adaptation to continuous aerobic TPZ exposure resulted in increased levels of manganese superoxide dismutase (up to 9.4-fold), moderate increases in glutathione reductase (up to 2.1-fold), and loss of both quinone oxidoreductase (DT-diaphorase) activity and NADPH cytochrome P450 reductase activity. There was essentially no change in the activity of the cytoplasmic form of superoxide dismutase (CuZnSOD), catalase, or glutathione peroxidase. The increased activity of antioxidant enzymes in the resistant cell lines (in particular MnSOD) strongly suggests that reactive oxygen species are, in large part, responsible for the toxicity of TPZ under aerobic conditions, and is consistent with aerobic and hypoxic drug cytotoxicity resulting from different mechanisms.
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PMID:Adaptation of human tumor cells to tirapazamine under aerobic conditions: implications of increased antioxidant enzyme activity to mechanism of aerobic cytotoxicity. 927 29

Oxygen radical generating systems, namely, Cu(II)/ H2O2, Cu(II)/ascorbate, Cu(II)/NAD(P)H, Cu(II)/ H2O2/catecholamine and Cu(II)/H2O2/SH-compounds irreversibly inhibited yeast glutathione reductase (GR) but Cu(II)/H2O2 enhanced the enzyme diaphorase activity. The time course of GR inactivation by Cu(II)/H2O2 dependent on Cu(II) and H2O2 concentrations and was relatively slow, as compared with the effect of Cu(II)/ascorbate. The fluorescence of the enzyme Tyr and Trp residues was modified as a result of oxidative damage. Copper chelators, catalase, bovine serum albumin and HO. scavengers prevented GR inactivation by Cu(II)/H2O2 and related systems. Cysteine, N-acetylcysteine, N-(2-dimercaptopropionylglycine and penicillamine enhanced the effect of Cu(II)/H2O2 in a concentration- and time-dependent manner. GSH, Captopril, dihydrolipoic acid and dithiotreitol also enhanced the Cu(II)/H2O2 effect, their actions involving the simultaneous operation of pro-oxidant and antioxidant reactions. GSSG and trypanothione disulfide effectively protected GR against Cu(II)/H2O2 inactivation. Thiol compounds prevented GR inactivation by the radical cation ABTS.+. GR inactivation by the systems assayed correlated with their capability for HO. radical generation. The role of amino acid residues at GR active site as targets for oxygen radicals is discussed.
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PMID:Inactivation of yeast glutathione reductase by Fenton systems: effect of metal chelators, catecholamines and thiol compounds. 945 90

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

The role of microsomal NADPH:cytochrome P450 reductase (P450 reductase) and cytosolic NAD(P)H:quinone oxidoreductase 1 (NQO1 or DT-diaphorase) in the mutagenicity of benzo(a)pyrene-3,6-quinone (BP-3,6-Q) was studied using supF tRNA gene as the mutational target. pUB3 carrying the supF tRNA gene upon transformation into the Escherichia coli ES87 cells exhibited a spontaneous mutation frequency of 0.62 x 10(-6). Chemical modification of the pUB3 DNA with BP-3,6-Q caused a fourfold increase in the mutation frequency, compared with the spontaneous mutations. P450 reductase catalysed metabolic activation of BP-3,6-Q into reactive products (semiquinone and reactive oxygen species), which caused a further increase in the mutation frequency to eightfold over spontaneous mutations. Oxygen radical scavengers (SOD and catalase) blocked the P450 reductase-activated BP-3,6-Q-induced stimulation of mutations. This indicates that redox cycling of the semiquinone leading to the generation of reactive oxygen species (ROS) was directly responsible for the increased mutation frequency of P450 reductase-activated BP-3,6-Q. Analysis of the mutation spectra revealed that P450 reductase-activated BP-3,6-Q showed a significantly higher preference for frameshift mutations, particularly deletions, compared with the spontaneous mutations and the mutations generated by benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE). The single most frequently observed mutation by P450 reductase-activated quinone (semiquinone + ROS) was deletion of a single guanosine. Among the base substitutions, G:C --> T:A, G:C --> A:T and G:C --> C:G were also noticed. Interestingly, NQO1 competed with P450 reductase and specifically prevented the P450 reductase-activated BP-3,6-Q-induced mutations. However, BP-hydroquinone (BP-3,6-HQ) generated during the metabolic reduction of BP-3,6-Q catalysed by NQO1 caused specific mutations involving the deletion of a single cytosine from the DNA sequence 5'-CCCCC-3' in supF tRNA gene at a significantly high frequency. A similar cytosine deletion was also observed with benzoquinone hydroquinone (HQ), indicating that the deletion of cytosine is associated with a hydroquinone class of compounds. These results suggest that: (1) quinones and P450 reductase-activated products of quinones (semiquinones and ROS) are mutagenic compounds; (2) the mutational spectra of quinones, semiquinones and hydroquinones differ from each other with respect to their mutational frequency and specificity; (3) NQO1 competes with P450 reductase and protects the cells from quinone mutagenicity; and (4) the NQO1 -metabolized quinones (hydroquinones), if not eliminated, cause specific mutations that are not observed with quinones and P450 reductase-activated quinones (semiquinones and ROS).
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PMID:NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones. 951 48

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

The biologic functions attributed to the nucleophosphoprotein p53 have been increasing in recent years. Some studies suggested that wild type p53 is responsible for cell cycle arrest brought about as a response to exposure of mammalian cells to DNA-damaging agents. This cell cycle arrest occurs in order for cells to repair the damaged macromolecules. Extensively damaged cells are also thought to undergo apoptosis via the p53-dependent or -independent signal transduction pathways. In this study, we investigated the ability of diaziridinylbenzoquinones to increase p53 levels in the human breast cancer cell line MCF-7. Diaziquone (AZQ), an anticancer agent, and its derivatives, diaziridinequinone (DZQ) and methyldiaziridinequinone (MeDZQ), induced p53 in a dose- and time-dependent manner as measured by the electrophoretic mobility shift assay. Wild type p53 induction by AZQ was suppressed when DT-diaphorase activity was inhibited by pretreating the cells with dicumarol. Aside from their potent alkylating activity, these agents also undergo redox cycling as evidenced by oxygen consumption and the production of reactive oxygen species (ROS). Inhibition of ROS production by the antioxidant enzyme catalase reduced AZQ- and DZQ-mediated p53 induction by about 45%. Thiotepa, a non-quinone aziridine-containing agent, and 1,4-benzoquinone (p-BQ), a redox cycling quinone, increased p53 levels. The nonalkylator oxygen-radical-generating agent menadione (MD) caused p53 induction only when MCF-7 cells were allowed to recover in drug-free media. On the basis of these data, we propose that the bioreductive activation of AZQ is a prerequisite for p53 induction. Moreover, the induction of p53 by AZQ requires both the quinone and the aziridine moieties of the AZQ molecule. Although AZQ and its analogues increased p53 levels in MCF-7 cells, p53 induction in these cells may not be responsible for the apoptosis seen upon treatment of MCF-7 cells with these agents. The uncoupling of p53 induction and apoptosis is evidenced by the generation of nucleosomal DNA laddering in aziridinequinone-treated T47D cells, a breast cancer cell line bearing a p53 mutation.
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PMID:Induction of p53 by the concerted actions of aziridine and quinone moieties of diaziquone. 954 7

In recent years, the concept of cancer chemoprevention has matured greatly. Significant reversal or suppression of premalignancy in several sites by chemopreventive agents appears achievable. This article summarizes experimental data on chemopreventive effects of tea polyphenols in different tumor bioassay systems. Tea (Camellia sinensis) is cultivated in about 30 countries, and is the most widely consumed beverage in the world. Three main commercial tea varieties--green, black, and oolong--are usually consumed, but most experimental studies demonstrating the antimutagenic and anticarcinogenic effects of tea have been conducted with water extract of green tea, or a polyphenolic fraction isolated from green tea (GTP). The majority of these studies have been conducted in a mouse skin tumor model system where tea is fed either as water extract through drinking water, or as purified GTP. GTP has been shown to exhibit antimutagenic activity in vitro, and inhibit carcinogen- as well as UV-induced skin carcinogenesis in vivo. Tea consumption has also been shown to afford protection against chemical carcinogen-induced stomach, lung, esophagus, duodenum, pancreas, liver, breast, and colon carcinogenesis in specific bioassay models. Several epicatechin derivatives (polyphenols) present in green tea have been shown to possess anticarcinogenic activity; the most active is (-)-epigallocatechin-3-gallate, which is also the major constituent of GTP. The mechanisms of tea's broad cancer chemopreventive effects are not completely understood. Several theories have been put forward, including inhibition of UV- and tumor promoter-induced ornithine decarboxylase, cyclo-oxygenase, and lipoxygenase activities, antioxidant and free radical scavenging activity; enhancement of antioxidant (glutathione peroxidase, catalase, and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of lipid peroxidation, and anti-inflammatory activity. These properties of tea polyphenols make them effective chemopreventive agents against the initiation, promotion, and progression stages of multistage carcinogenesis.
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PMID:Tea antioxidants in cancer chemoprevention. 959 Nov 94


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