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)

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

NAD(P)H:quinone reductase, or DT-diaphorase, has been studied primarily in the liver where it appears to function as an antioxidant-like enzyme in the 2-electron reduction of some quinones to less toxic hydroquinones. This property together with new molecular biology evidence that oxidants such as H2O2 can induce gene transcription of DT-diaphorase provide especially intriguing reasons to examine the possibility that lung DT-diaphorase could have an important antioxidant enzyme role versus pulmonary O2 toxicity during exposure to hyperoxia. We found that similar to the 'classical' lung antioxidant enzymes (superoxide dismutase, catalase and glutathione peroxidase) DT-diaphorase activity increased significantly in the late gestational fetal lung; also its activity was altered in the same way as the antioxidant enzymes by prenatal hormonal treatment. Another similarity is that DT-diaphorase activity was induced in the neonatal animal lung during hyperoxia, but not in the adult animal lung. However, using various drug treatments which markedly increased lung DT-diaphorase activity (e.g., 3-methylcholanthrene, butylated hydroxyanisole, methimazole) we found no improved hyperoxic survival in the treated adult rats. Also, dicumarol treatment, which markedly depressed DT-diaphorase activity, did not diminish the hyperoxic survival rate in an O2-tolerant adult rat model. Thus, we conclude that unlike the classical antioxidant enzymes, increased pulmonary DT-diaphorase activity is probably neither necessary nor sufficient to protect against pulmonary O2 toxicity during hyperoxia.
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PMID:Does lung NAD(P)H:quinone reductase (DT-diaphorase) play an antioxidant enzyme role in protection from hyperoxia? 846 17

This article summarizes available data on the chemopreventive efficacies of tea polyphenols, curcumin and ellagic acid in various model systems. Emphasis is placed upon the anticarcinogenic activity of these polyphenols and their proposed mechanism(s) of action. Tea is grown in about 30 countries and, next to water, is the most widely consumed beverage in the world. Tea is manufactured as either green, black, or oolong; black tea represents approximately 80% of tea products. Epidemiological studies, though inconclusive, suggest a protective effect of tea consumption on human cancer. Experimental studies of the antimutagenic and anticarcinogenic effects of tea have been conducted principally with green tea polyphenols (GTPs). GTPs exhibit antimutagenic activity in vitro, and they inhibit carcinogen-induced skin, lung, forestomach, esophagus, duodenum and colon tumors in rodents. In addition, GTPs inhibit TPA-induced skin tumor promotion in mice. Although several GTPs possess anticarcinogenic activity, the most active is (-)-epigallocatechin-3-gallate (EGCG), the major constituent in the GTP fraction. Several mechanisms appear to be responsible for the tumor-inhibitory properties of GTPs, including enhancement of antioxidant (glutathione peroxidase, catalase and quinone reductase) and phase II (glutathione-S-transferase) enzyme activities; inhibition of chemically induced lipid peroxidation; inhibition of irradiation- and TPA-induced epidermal ornithine decarboxylase (ODC) and cyclooxygenase activities; inhibition of protein kinase C and cellular proliferation; antiinflammatory activity; and enhancement of gap junction intercellular communication. Curcumin is the yellow coloring agent in the spice tumeric. It exhibits antimutagenic activity in the Ames Salmonella test and has anticarcinogenic activity, inhibiting chemically induced preneoplastic lesions in the breast and colon and neoplastic lesions in the skin, forestomach, duodenum and colon of rodents. In addition, curcumin inhibits TPA-induced skin tumor promotion in mice. The mechanisms for the anticarcinogenic effects of curcumin are similar to those of the GTPs. Curcumin enhances glutathione content and glutathione-S-transferase activity in liver; and it inhibits lipid peroxidation and arachidonic acid metabolism in mouse skin, protein kinase C activity in TPA-treated NIH 3T3 cells, chemically induced ODC and tyrosine protein kinase activities in rat colon, and 8-hydroxyguanosine formation in mouse fibroblasts. Ellagic acid is a polyphenol found abundantly in various fruits, nuts and vegetables. Ellagic acid is active in antimutagenesis assays, and has been shown to inhibit chemically induced cancer in the lung, liver, skin and esophagus of rodents, and TPA-induced tumor promotion in mouse skin.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Polyphenols as cancer chemopreventive agents. 853 95

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

In the present study, we investigated the effects of high levels of dietary fish oil on the growth of MX-1 human mammary carcinoma and its response to mitomycin C (MC) treatment in athymic mice. We found that high levels of dietary fish oil (20% menhaden oil + 5% corn oil, w/w) compared to a control diet (5% corn oil, w/w) not only lowered the tumor growth rate, but also increased the tumor response to MC treatment. We also found that high levels of dietary fish oil significantly increased the activities of tumor xanthine oxidase and DT-diaphorase, which are proposed to be involved in the bioreductive activation of MC. Since menhaden oil is highly unsaturated, its intake caused a significant increase in the degree of fatty acid unsaturation in tumor membrane phospholipids. This alteration in tumor membrane phospholipids made the tumor more susceptible to oxidative stress, as indicated by the increased levels of both endogenous lipid peroxidation and protein oxidation after feeding the host animals the menhaden oil diet. In addition, the tumor antioxidant enzyme activities, catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPOx), and glutathione S-transferase peroxidase (GSTPx), were all significantly enhanced by feeding a diet high in fish oil. MC treatment caused further increases in tumor lipid peroxidation and protein oxidation, as well as in the activities of CAT, SOD, GPOx, and GSTPx, suggesting that MC causes oxidative stress in this tumor model which is exacerbated by feeding a diet high in menhaden oil. Thus, feeding a diet rich in menhaden oil decreased the growth of human mammary carcinoma MX-1, increased its responsiveness to MC, and increased its susceptibility to endogenous and MC-induced oxidative stress, and increased the tumor activities of two enzymes proposed to be involved in the bioactivation of MC, that is, DT-diaphorase and xanthine oxidase. These findings support a role of these two enzymes in the bioactivating of MC and indicate that the type of dietary fat may be important in tumor response to therapy.
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PMID:Dietary menhaden oil enhances mitomycin C antitumor activity toward human mammary carcinoma MX-1. 856 32

NADPH-cytochrome1 P450 reductase and DT-diaphorase catalyze and one- and two-electron reduction of adrenochrome to its o-semiquinone and o-hydroquinone, respectively. Under aerobic conditions both adrenochrome o-semiquinone and o-hydroquinone proved to be unstable, undergoing autoxidation with concomitant oxygen consumption and continuous NADPH and NADH oxidation. Molecular oxygen was found to play a predominant role in autoxidation of o-semiquinone during reduction of adrenochrome catalyzed by NADPH-cytochrome P450 reductase. In addition, molecular oxygen, in the presence of manganese, was found to be responsible for the majority of autoxidation of o-semiquinone. However, the role of superoxide radicals in the autoxidation of leucoadrenochrome during the reduction of adrenochrome by DT-diaphorase was found to be predominant. Catalase different significantly with respect to NADPH and NADH oxidation during reduction of adrenochrome catalyzed by NADPH-cytochrome P450 reductase and DT-diaphorase. Catalase increased NADPH oxidation slightly, while NADH oxidation was inhibited during reduction of adrenochrome by NADPH cytochrome P450 reductase and DT-diaphorase, respectively. The presence of manganese in the incubation mixture was found to increase the prooxidant role of catalase on autoxidation during one-electron reduction of aminochrome catalyzed by NADPH cytochrome P450 reductase. A marked difference in the inhibitory effect of superoxide dismutase on oxygen consumption during adrenochrome reduction catalyzed by NADPH-cytochrome P450 reductase and DT-diaphorase was also observed. A possible mechanism for reduction of adrenochrome by NADPH-cytochrome P450 reductase and DT-diaphorase and a role for superoxide dismutase and catalase are proposed.
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PMID:Effects of superoxide dismutase and catalase during reduction of adrenochrome by DT-diaphorase and NADPH-cytochrome P450 reductase. 859 36

This study was undertaken to determine the mechanism of resistance of a human bladder cancer cell line SCaBER to mitomycin C (MMC). The IC50 value for MMC in SCaBER cells was higher by 2.7 fold by 1-h drug exposure colony formation assay as compared to another bladder cancer cell line J82. NADPH cytochrome P450 reductase and DT-diaphorase activities were significantly lower in SCaBER cells as compared to those of J82 suggesting that relatively resistance of SCaBER cells to MMC may be due to inefficient drug activation. Further support for this conclusion derives from the observation that sensitivities of J82 and SCaBER cells to BMY25282, a MMC analogue with lower quinone reduction potential, were similar. MMC dependent lipid peroxidation (an indicator of oxygen free radical formation) was higher in SCaBER cells than in J82. The activities of anti-oxsidative enzymes GSH peroxidase and catalase did not differ significantly in these cells. These results suggest that resistance of SCaBER cells to MMC may not be due to the reduced free radical formation in these cells. MMC induced DNA interstrand cross-link (ISC) formation was markedly lower in SCaBER cells than in J82. Taken together, these results suggest that SCaBER cell resistance to MMC may be due to the reduced drug activation and ISC formation in these cells.
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PMID:[Mechanism of resistance to mitomycin C in a human bladder cancer cell line]. 869 71

The group I aziridinylquinone anti-cancer agents mitomycin C, diaziquone or trenimon were much more cytotoxic to DT-diaphorase-enriched L5178Y/HBM10 lymphoblasts than parental L5178Y cells and caused little oxygen activation. Furthermore, inactivation of cellular DT-diaphorase prevented cytotoxicity whereas catalase did not affect cytotoxicity. This suggests that DT-diaphorase activated these agents and the hydroquinone formed mediated DNA alkylation, crosslinking and cytotoxicity. The group II quinone agents phenanthrenequinone, 2-amino-1, 4-naphthoquinoneimine or naphthazarin were also more cytotoxic to L5178Y/HBM10 cells than parental cells and caused considerable oxygen activation. Inactivation of DT-diaphorase, however, prevented both oxygen activation and cytotoxicity. Furthermore added catalase decreased cytotoxicity, whereas catalase inactivation enhanced cytotoxicity. This suggests that DT-diaphorase activated these agents and the hydroquinone formed caused extensive oxygen activation sufficient to cause DNA oxidative damage and cytotoxicity. The group III quinone agents menadione, 2,3-dimethoxy-1,4-naphthoquinone and 2,6-dimethoxy-benzoquinone, on the other hand, were more cytotoxic to the parental cells than L5178Y/HBM10 cells and caused less oxygen activation than group II agents. Furthermore, inactivation of DT-diaphorase enhanced cytotoxicity and prevented oxygen activation than group II agents. Oxygen activation was therefore also attributed to hydroquinone autoxidation. However catalase did not affect cytotoxicity towards parental cells. This suggests that DT-diaphorase detoxified group III quinones and that cytotoxicity may involve DNA oxidative damage by the semiquinone radicals.
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PMID:Cytotoxic mechanisms of anti-tumour quinones in parental and resistant lymphoblasts. 876 40

Aziridinylbenzoquinones are a group of antitumor agents that elicit cytotoxicity by generating either alkylating intermediates or reactive oxygen species. The mechanism of toxicity may not always, however, involve profound damage of cellular constituents, but may involve a cytostatic effect through interference with the cell cycle. In this context, we have examined the induction of the cell cycle inhibitor p21 (WAF1, CIP1, or sdi1), whose overexpression suppresses the growth of various tumor cells, in human tumor cells metabolizing 3,6-diaziridinyl-1,4-benzoquinone (DZQ) and its C2,C5-substituted derivatives: 2,5-bis-(carboethoxyamino) (AZQ) and 2, 5-bis-2(-hydroxyethylamino) (BZQ). Both DZQ and AZQ were effectively activated by HCT116 human colonic carcinoma cells; the activation of the former involved largely a dicoumarol-sensitive activity, whereas that of the latter appeared to be accomplished primarily by one-electron transfer reductases. BZQ was not a substrate for the dicoumarol-sensitive enzyme in HCT116 cells. Cellular activation of the first two quinones was associated with formation of oxygen-centered radicals as detected by EPR in conjunction with the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide. The redox transitions of DZQ involved hydroxyl radical formation and were strongly inhibited by catalase, whereas those of AZQ showed a strong superoxide anion component sensitive to superoxide dismutase. These signals were suppressed by N-acetylcysteine with concomitant production of a thiyl radical adduct. This suggests an effective electron transfer between the thiol and free radicals formed during the activation of these quinones. DZQ and AZQ induced significantly the expression of p21 in HCT116 cells, but a 10-fold higher concentration of AZQ was required to achieve the level of induction elicited by DZQ. BZQ had little effect on p21 expression. p21 induction at both mRNA and protein levels correlated with the inhibition of either cyclin-dependent kinase activity or cell proliferation. p21 induction elicited by the above quinones was inhibited by N-acetylcysteine, whereas the non-sulfur analog, N-acetylalanine, was without effect. Catalase and superoxide dismutase did not effect p21 induction by aziridinylbenzoquinones in HCT116 cells, thus suggesting that extracellular sources of oxygen radicals generated by plasma membrane reductases have no influence in the expression of this gene. Hydrogen peroxide, a product of quinone redox cycling, elicited an increase of p21 mRNA levels in HCT116 and K562 human chronic myelogenous leukemia cells. The latter lacks p53, one of the activators of p21 transcription, thus suggesting that p21 expression can be accomplished in a p53-independent manner in these cells. This study suggests that p21 induction is mediated by an increase in the cellular steady-state concentration of oxygen radicals and that the greater effectiveness in p21 induction by DZQ may be related to its efficient metabolism by NAD(P)H:quinone oxidoreductase activity in HCT116 cells.
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PMID:Induction of p21 mediated by reactive oxygen species formed during the metabolism of aziridinylbenzoquinones by HCT116 cells. 894 36

Since the toxicity of diesel exhaust particles (DEP) after intratracheal injection, was suppressed by pretreatment with superoxide dismutase (SOD) modified with polyethylene glycol (Sagai et al. Free Rad. Biol. Med. 14: 37-47; 1993), the possibility that superoxide could be enzymatically and continuously generated from diesel exhaust particles (DEP), was examined. Nicotinamide-adenine dinucleotide phosphate, reduced (NADPH) oxidation was stimulated during interaction of a methanol extract of DEP with the Triton N-101 treated microsomal preparation of mouse lung whereas the cytosolic fraction was less active, suggesting that DEP contains substrates for NADPH-cytochrome P450 reductase (EC 1.6.2.4, P450 reductase) rather than DT-diaphorase. When purified P450 reductase was used as the enzyme source, the turnover value was enhanced approximately 260-fold. Quinones appeared to be served as substrate for P450 reductase because reaction was inhibited by addition of glutathione (GSH) to form those GSH adduct or pretreatment with NaBH4 to reduce those to the hydroxy compounds although a possibility of nitroarenes as the alternative substrates cannot be excluded. A methanol extract of DEP (37.5 micrograms) caused a significant formation of superoxide (3240 nmol/min/mg protein) in the presence of P450 reductase. Electron spin resonance (ESR) experiments revealed that hydroxyl radical was formed as well. The reactive species generated by DEP in the presence of P450 reductase caused DNA scission which was reduced in the presence of superoxide dismutase (SOD), catalase, or hydroxyl radical scavenging agents. Taken together, these results indicate that DEP components, probably quinoid or nitroaromatic structures, that appear to promote DNA damage through the redox cycling based generation of superoxide.
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PMID:Generation of reactive oxygen species during interaction of diesel exhaust particle components with NADPH-cytochrome P450 reductase and involvement of the bioactivation in the DNA damage. 898 Oct 40


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