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)

Southern armyworm, Spodoptera eridania, larvae were provided ad libitum 0.002-0.25% w/w dichlone, 2,3-dichloro-1,4-naphthoquinone (CNQ). Larval mortality occurred in a time-and-dose dependent manner, with an LC17 of 0.01% and an LC50 of 0.26% CNQ at day-5. Extracts of larvae fed control, 0.01, and 0.25% CNQ diets for 5 days were assayed for antioxidant enzymes. While 0.01% CNQ had a mild effect, 0.25% CNQ profoundly increased levels of all antioxidant enzymes that were examined. The increases as compared to control were: 5.3-, 1.9-, 3.2-, 2.6-, 2.8-, and 3.5-fold higher for superoxide dismutase, catalase, glutathione transferase and its peroxidase activity, glutathione reductase and DT-diaphorase, respectively. At 0.01% CNQ, the thiobarbituric acid reactive substances (TBARS) were similar to the control group. However, despite the induction from 0.25% CNQ of all enzymes examined, the lipid peroxidation was not attenuated; the TBARS were 29.7% over the control value. High mortalities and CNQ-induced pathologies reflected in retarded growth, wasting syndrome, and diuresis clearly indicated that the insect sustained severe oxidant-induced injuries before appropriate defenses were fully mobilized. Thus, this quinone causes an oxidative stress in a model insect species analogous to that observed in mammalian species.
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PMID:Dichlone-induced oxidative stress in a model insect species, Spodoptera eridania. 757 83

Previously we showed that tirapazamine (SR 4233, Win 59075) is cytotoxic towards hepatocytes under conditions of hypoxia but not in 10% or 95% oxygen and that bioreduction by DT-diaphorase or cytochrome P450 is not a major pathway. In the present study, we report that tirapazamine is highly cytotoxic to isolated rat hepatocytes maintained under 1% oxygen and the molecular cytotoxic mechanism has been elucidated. Cytotoxicity was prevented by the cytochrome P450 2E1 inhibitors phenyl imidazole, isoniazid, isopropanol or ethanol, suggesting that cytochrome P450 2E1 catalysed tirapazamine reductive bioactivation. By contrast, dicoumarol, a DT-diaphorase inhibitor, markedly increased tirapazamine-induced cytotoxicity. Cytotoxicity was also inhibited in normal but not DT-diaphorase-inactivated hepatocytes by increasing cellular NADH levels with lactate or ethanol or the mitochondrial respiratory inhibitors. Evidence that oxygen activation contributed to cytotoxicity was that glutathione oxidation occurred well before cytotoxicity ensued and that tirapazamine was more cytotoxic towards catalase- or glutathione reductase-inactivated hepatocytes. Furthermore, polyphenolic antioxidants such as quercetin, caffeic acid or purpurogallin, the radical trap Tempol or the iron chelator desferrioxamine prevented tirapazamine-mediated cytotoxicity. However, the antioxidants diphenylphenylenediamine, butylated hydroxyanisole or butylated hydroxytoluene did not prevent cytotoxicity and malonaldehyde formation was not increased, suggesting that lipid peroxidation was not important. The above results suggest that DT-diaphorase detoxifies tirapazamine whereas reduced cytochrome P450 reduces tirapazamine to a nitrogen oxide anion radical which forms cytotoxic reactive oxygen species as a result of redox cycling.
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PMID:Molecular mechanisms of tirapazamine (SR 4233, Win 59075)-induced hepatocyte toxicity under low oxygen concentrations. 771 Sep 44

Cationic antiseptics--catamine AB, polysept (polymeric derivative of chlorhexidine) as well as cationic protein protamine exhibited a pronounced cytotoxic effect on human skin and lung fibroblasts in cell culture. Their effect was accompanied by augmentation of lipid peroxidation products and by inhibition of DT-diaphorase, LDH, ATPase and glutathione reductase. Introduction of alpha-tocopherol into the cultural medium normalized the rate of lipid peroxidation but did not remove the inhibitory effect on activity of oxidoreductase studied. Blood serum proteins immunoglobulins and albumin diminished significantly the cytotoxic effect of cationic preparations contributing to restoration of all the parameters studied to control values; this phenomenon appears to occur due to nonspecific membrane protective and antioxidation effects of the blood serum proteins.
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PMID:[Some biochemical indicators of the cytotoxic response of human fibroblasts cultured with natural and synthetic polycations]. 779 94

The role of intracellular thiols in menadione-mediated toxicity was studied in neonatal rat cardiomyocytes. The sensitivity of cardiomyocytes to menadione was greater than that of skeletal muscle cells and 3T3 fibroblasts. Before cell degeneration, menadione induced marked depletion of intracellular thiols and an increase of oxidized glutathione. The sensitivity of these cells to menadione correlated with the level of depletion of intracellular thiols. After incubation of cardiomyocytes with menadione, glutathione reductase activity was inhibited and lipid peroxidation was increased. Both dicumarol (an inhibitor of DT-diaphorase) and diethyldithiocarbamate (an inhibitor of superoxide dismutase) enhanced the capacity of menadione to induce cellular damage and to cause depletion of intracellular glutathione. Decreasing intracellular glutathione by pretreatment of cells with N-ethylmaleimide or buthionine sulphoximine also increased menadione-induced cell degeneration. Preincubation with cysteine or dithiothreitol suppressed the capacity of menadione to damage the cells. Menadione-induced lipid peroxidation was also suppressed by the same treatment. These results show that the oxidative stress induced by menadione in cardiomyocytes results in the depletion of glutathione and protein thiols. Both DT-diaphorase and superoxide dismutase can protect cells from the toxicity of menadione. Cellular thiols are determinants of the responsiveness to menadione.
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PMID:Cellular thiols as a determinant of responsiveness to menadione in cardiomyocytes. 796 57

In the present study, we investigated the effects of high dietary fat on the growth of MX-1 heterotransplanted in athymic mice and its response to mitomycin C (MC) treatment. We found that high fat intake (25% corn oil, w/w) significantly increased tumor growth, but at the same time it also increased the tumor response to MC treatment compared to the control low fat diet (5% corn oil, w/w). In the tumors from mice fed either low (5% w/w) or high (25% w/w) fat, MC treatment induced oxidative challenge, indicated by significantly increased tumor total superoxide dismutase, catalase, glutathione peroxidase, and glutathione S-transferase peroxidase activities, as well as increased tumor lipid peroxidation. On the other hand, glutathione reductase activity was inhibited by MC treatment. Some of the enzymes which are known to activate MC, such as cytochrome b5 reductase and DT-diaphorase, were also induced in the tumor by high dietary fat intake. The enzyme activities in hepatic tissues were also altered by dietary fat and MC treatment but to a lesser extent. We conclude that high dietary fat intake could enhance the chemotherapeutic effect of MC by increasing MC-activating enzyme activities. The observed increase in lipid peroxidation after MC treatment in MX-1 human mammary carcinoma implanted in the nude mice could result from the observed inhibited glutathione reductase activity. It is tempting to speculate that this might be another antineoplastic mechanism for MC in addition to its known role as a bioreductive alkylating agent. Alternatively, glutathione reductase may be a target for bioreductive alkylation.
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PMID:Enhancement of the antineoplastic effect of mitomycin C by dietary fat. 798 42

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

It was found that the activities of prooxidant enzymes (NAD(P)H oxidases and NAD(P)H:cytochrome c reductases) in bovine leukemia virus-transformed calf and lamb embryo kidney fibroblasts (lines Mi-18 and FLK) were by 1.25-18 times higher when compared to corresponding nontransformed calf cells. The activity of DT-diaphorase was also increased by about one order of magnitude in transformed cells. The activities of antioxidant enzymes were almost unchanged (superoxide dismutase), decreased by 13% or 53% (catalase) or increased by 25% or 90% (glutathione reductase) in Mi-18 or FLK cells, respectively. These changes of enzyme activity increased the toxicity of simple redox-cycling quinones (duroquinone, naphthazarin) towards transformed cells, but did not affect the toxicity of daunorubicin. The latter was most probably related to the inhibition of plasma membrane NADH dehydrogenase.
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PMID:The changes of prooxidant and antioxidant enzyme activities in bovine leukemia virus-transformed cells. Their influence on quinone cytotoxicity. 839 4

The expression of intrinsic resistance to cisplatin in two lung cancer cell lines, one derived from a small cell carcinoma (SW1271) and the other from an adenocarcinoma (A549), relative to a drug-sensitive small cell line SW900, was characterized by: (i) expression of cross-resistance to mitomycin C and cadmium chloride, but increased sensitivity to adriamycin and etoposide; (ii) significantly decreased cisplatin uptake; (iii) elevated levels of glutathione which could be reduced by buthionine L-sulfoximine resulting in significant sensitization of the cells to cisplatin; (iv) a lack of consistent modification of metallothionein content and expression of levels of glutathione S-transferase, glutathione reductase and glutathione peroxidase or of activities of DT-diaphorase or catalase; (v) significantly reduced total DNA-platination levels immediately following a 1 h cisplatin treatment with 10 micrograms/ml (33.3 microM); (vi) increased removal of Pt-GG and Pt-AG adducts by the A549 cells, consistent with increased repair capacity, but a lack of removal of these major adducts by the SW1271 cells indicative of tolerance of this drug-induced DNA damage. These data therefore provide evidence of differential formation, repair and tolerance of DNA damage following exposure of three human lung carcinoma cell lines to cisplatin.
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PMID:Evidence of differential cisplatin-DNA adduct formation, removal and tolerance of DNA damage in three human lung carcinoma cell lines. 840 Mar 52

The extent of ferrihemoglobin formation in human erythrocytes by 4-nitrosophenetol and its metabolisation rate strongly depended on the availability of cellular GSH. Ferrihemoglobin formation rate was increased by inhibition of the red cell glutathione reductase, and 4-nitrosophenetol disappeared more slowly. When red cells were completely depleted from SH groups, ferrihemoglobin formation was retarded, despite 4-nitrosophenetol was hardly metabolized. In turn, the glutathione status of human red cells was strongly affected by 4-nitrosophenetol. GSSG, which was produced in large amounts, was reduced, as long as the reducing system was intact. The decreased total glutathione content, however, did not recover completely, indicating formation of stable glutathione S-conjugates. The active export of the stable model glutathione thioether S-(2,4-dinitrophenyl)glutathione was strongly inhibited by 4-nitrosophenetol. A Lineweaver-Burk plot of the transport data suggested a competitive inhibition mechanism, presumably caused by glutathione adducts. The results indicate that the strong pi-donor substituent in 4-nitrosophenetol enables metabolic reactions with glutathione, producing biological effects hitherto not observed with nitrosobenzene. Bicyclic arylamines and glutathione S-conjugates may cause ferrihemoglobin formation that is not brought about by the diaphorase reaction. The latter may be responsible for transport inhibition of GSSG and other glutathione S-conjugates.
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PMID:Effects of the phenacetin metabolite 4-nitrosophenetol on the glutathione status and the transport of glutathione S-conjugates in human red cells. 843 97

One mechanism by which chemicals cause cellular injury is the formation of reactive oxygen species. In vitro studies have shown that metallothionein (MT), a small metal-binding, sulfhydryl-rich, readily inducible protein, can scavenge reactive oxygen species, especially hydroxyl radicals. Nevertheless, whether or not MT protects against oxidative stress in the intact animal is not known. Experimental induction of MT could help to clarify this question, however, it is unclear whether agents that induce MT also influence known antioxidant systems. Therefore, the present study was designed to determine whether the well-known MT inducers are specific for induction of MT or whether they might also influence other hepatic systems that protect against oxidative stress. Male rats were administered cadmium chloride (Cd; 30 mumol/kg, s.c.), zinc chloride (Zn; 1000 mumol/kg, s.c.), alpha-hederin (alpha-H, 30 mumol/kg, s.c.) or lipopolysaccharide (LPS; 1 mg/kg, s.c.) 24 h prior to measurement of antioxidant systems. Zn and alpha-H increased hepatic GSH concentration 20% and 55%, respectively. Cd significantly increased, whereas LPS reduced, the activities of selenium-dependent glutathione peroxidase and glutathione reductase. Glutathione S-transferases were not altered by any of the inducers. Cd also increased DT-diaphorase activity. Cd, Zn and alpha-H all decreased catalase activity 20-35%, while the activity of superoxide dismutase was unaffected by the inducers. The amount of total cytochrome P450 enzymes and cytochrome b5 were decreased by LPS, Cd and alpha-H, while Zn appeared to have no effect. The activities of P450 enzymes towards testosterone oxidation were also decreased by LPS, Cd and alpha-H. In conclusion, all four MT inducers examined affect systems known to protect cells against oxidative stress. Therefore, using these chemicals to determine the in vivo role of MT in protecting against oxidative stress poses difficulties.
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PMID:Effect of several metallothionein inducers on oxidative stress defense mechanisms in rats. 856 Apr 99


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