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 human colon carcinoma cell lines Caco-2 and HT-29 were exposed to three structurally related naphthoquinones. Menadione (MEN), 1,4-naphthoquinone (NQ), and 2,3-dimethoxy-1,4-naphthoquinone (DIM) redoxcycle at similar rates, NQ is a stronger arylator than MEN, and DIM does not arylate thiols. The Caco-2 cell line was particularly vulnerable to NQ and MEN and displayed moderate toxic effects of DIM. The HT-29 cell line was only vulnerable to NQ and MEN after inhibition of DT-diaphorase (DTD) with dicoumarol, whereas dicoumarol did not affect the toxicity of quinones to Caco-2 cells. DTD activity in the HT-29 and Caco-2 cell lines, as estimated by the dicoumarol-sensitive reduction of 2,6-dichlorophenolindophenol, was 393.7 +/- 46.9 and 6.4 +/- 2.2 nmol NADPH x min(-1) x mg protein(-1), respectively. MEN depleted glutathione to a small extent in the HT-29 cell line, but a rapid depletion similar to Caco-2 cells was achieved when dicoumarol was added. The data demonstrated that the DTD-deficient Caco-2 cell line was more vulnerable to arylating or redoxcycling quinones than DTD-expressing cell lines. Exposure of the Caco-2 cell line to quinones produced a rapid rise in protein disulphides and oxidised glutathione. In contrast to NQ and DIM, no intracellular GSSG was observed with MEN. The relatively higher levels of ATP in MEN-exposed cells may account for the efficient extrusion of intracellular GSSG. The reductive potential of the cell as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction was only increased by MEN and not with NQ and DIM. We conclude that arylation is a major contributing factor in the toxicity of quinones. For this reason, NQ was the most toxic quinone, followed by MEN, and the pure redoxcycler DIM elicited modest toxicity in Caco-2 cells.
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PMID:Quinone toxicity in DT-diaphorase-efficient and -deficient colon carcinoma cell lines. 992 Feb 82

It has previously been shown that rats pre-treated with butylated hydroxyanisole (BHA), a well-known inducer of the enzyme DT-diaphorase, are protected against the harmful effects of 2-methyl-1,4-naphthoquinone. This is consistent with a role for diaphorase in the detoxification of this quinone, but it is not known if increased tissue levels of this enzyme give protection against other naphthoquinone derivatives. In the present study, rats were dosed with BHA and then challenged with a toxic dose of 2-hydroxy-1,4-naphthoquinone, a substance that causes haemolytic anaemia and renal damage in vivo. Pre-treatment with BHA had no effect upon the nephrotoxicity of 2-hydroxy-1,4-naphthoquinone, but the severity of the haemolysis induced by this compound was increased in the animals given BHA. DT-Diaphorase is known to promote the redox cycling of 2-hydroxy-1,4-naphthoquinone in vitro, with concomitant formation of 'active oxygen' species. The results of the present experiment suggest that activation of 2-hydroxy-1,4-naphthoquinone by DT-diaphorase may also occur in vivo and show that increased tissue levels of DT-diaphorase are not always associated with naphthoquinone detoxification.
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PMID:Effect of butylated hydroxyanisole on the toxicity of 2-hydroxy-1,4-naphthoquinone to rats. 1019 May 78

2-Amino-3-carboxy-1,4-naphthoquinone (ACNQ) is a novel growth stimulator for bifidobacteria. The role of ACNQ as a mediator of the electron transfer from NAD(P)H to dioxygen (O(2)) and hydrogen peroxide (H(2)O(2)), proposed in our previous paper, was examined using the cell-free extract and whole cells of Bifidobacterium longum. Continuous monitoring of ACNQ, O(2) and H(2)O(2) by several amperometric techniques has revealed that ACNQ works as a good electron acceptor of NAD(P)H diaphorase and that the reduced form of ACNQ is easily autoxidized and also acts as a better electron donor of NAD(P)H peroxidase than NAD(P)H. The generation of H(2)O(2) by B. longum under aerobic conditions is effectively suppressed in the presence of ACNQ. These ACNQ-mediated reactions would play roles as NAD(P)(+)-regeneration processes. The accumulation of ACNQ in the cytosol has been also suggested. These characteristics of ACNQ seem to be responsible for the growth stimulation of bifidobacteria. Vitamin K(3), which has an extremely low growth-stimulating activity and was used as a reference compound, exhibits much lower activity as an electron transfer mediator. The difference in the activity is discussed in terms of the redox potential and partition property of the quinones.
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PMID:Role of 2-amino-3-carboxy-1,4-naphthoquinone, a strong growth stimulator for bifidobacteria, as an electron transfer mediator for NAD(P)(+) regeneration in Bifidobacterium longum. 1043 42

It has previously been shown that rats pre-treated with butylated hydroxyanisole (BHA), a well-known inducer of the enzyme DT-diaphorase, are protected against the toxic effects of 2-methyl-1,4-naphthoquinone but are made more susceptible to the harmful action of 2-hydroxy-1,4-naphthoquinone. In the present experiments, the effects of BHA have been compared with those of other inducers of DT-diaphorase. Rats were dosed with BHA, butylated hydroxytoluene (BHT), ethoxyquin (EQ), dimethyl fumarate (DMF) or disulfiram (DIS) and then challenged with a toxic dose of the naphthoquinones. All the inducers protected against the haemolytic anaemia induced by 2-methyl-1,4-naphthoquinone in rats, with BHA, BHT and EQ being somewhat more effective than DMF and DIS. A similar order of activity was recorded in the relative ability of these substances to increase hepatic activities of DT-diaphorase, consistent with a role for this enzyme in facilitating conjugation and excretion of this naphthoquinone. In contrast, all the compounds increased the haemolytic activity of 2-hydroxy-1,4-naphthoquinone. DMF and DIS were significantly more effective in this regard than BHA, BHT and EQ. DMF and DIS also caused a much greater increase in levels of DT-diaphorase in the intestine, suggesting that 2-hydroxy-1,4-naphthoquinone is activated by this enzyme in the gut. BHA, BHT and EQ had no effect on the nephrotoxicity of 2-hydroxy-1,4-naphthoquinone, but the severity of the renal lesions was decreased in rats pre-treated with DMF and DIS. The results of the present experiments show that modulation of tissue levels of DT-diaphorase may not only alter the severity of naphthoquinone toxicity in vivo, but may also change the relative toxicity of these substances to different target organs.
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PMID:Effect of inducers of DT-diaphorase on the toxicity of 2-methyl- and 2-hydroxy-1,4-naphthoquinone to rats. 1065 40

In myocardial preparations isolated from guinea pigs, 2-methyl-1, 4-naphthoquinone (menadione) causes an increase in contractility that is strictly related to the generation of reactive oxygen species (ROS) as a consequence of quinone metabolism. In heart, menadione undergoes one-electron reduction to semiquinone, a reaction mainly catalysed by mitochondrial NADH: ubiquinone oxidoreductase. It is also converted to hydroquinone by the soluble two-electron reductase, DT-diaphorase, and is conjugated with GSH by glutathione S-transferase. In order to assess the role of DT-diaphorase in cardiac responses to menadione, we examined the effects of both a specific inhibitor (dicoumarol) and an inducer (beta-naphthoflavone) of the enzyme on the inotropic action of the quinone. In electrically driven left atria of guinea pig, 4 microM dicoumarol significantly enhanced the positive inotropic effect of menadione, especially at the lower concentrations of the quinone. In myocardial preparations isolated from guinea pigs treated with beta-naphthoflavone (80 mg/kg i.p.for 2 days), DT-diaphorase activity was enhanced (+36% with respect to control animals, P < 0. 01), whereas the activities of the other enzymes involved in menadione metabolism were not modified. In these preparations, menadione caused a significantly lower increase in the force of contraction than in atria from untreated animals; moreover, pretreatment with beta-naphthoflavone caused a significant decrease in the menadione-induced oxidative stress, as evaluated from the GSH redox index. Taken together, these results demonstrate that cardiac DT-diaphorase does not contribute to ROS generation, but represents a detoxification system.
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PMID:Protective action of cardiac DT-diaphorase against menadione toxicity in guinea pig isolated atria. 1087 36

The ability of the naturally-occurring naphthoquinone derivatives, juglone and plumbagin, to increase tissue activities of the Phase II detoxification enzymes quinone reductase (QR) and glutathione transferase (GT) has been investigated in rats. Groups of female Sprague-Dawley rats were dosed by oral intubation on 5 consecutive days with either juglone or plumbagin at 12.5, 25, 50, 75, 100 or 125 mumoles/kg/day. The animals were then killed and the activities of QR and GT determined in tissue homogenates. The naphthoquinone derivatives had no significant effect on enzyme activities in the liver, spleen, heart, lung or urinary bladder. Increases in the activities of one or both enzymes were recorded, however, in the caecum, kidney, forestomach, duodenum, colon, glandular stomach and jejunum. The possibility that induction of Phase II enzymes could contribute to the previously-reported ability of juglone and plumbagin to protect animals against chemically-induced intestinal neoplasia is discussed.
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PMID:Induction of quinone reductase and glutathione transferase in rat tissues by juglone and plumbagin. 1090 56

A series of naphthoquinone and benzimidazolequinone phosphorodiamidates has been synthesized and studied as potential cytotoxic prodrugs activated by DT-diaphorase. Reduction of the quinone moiety in the target compounds was expected to provide a pathway for expulsion of the phosphoramide mustard alkylating agent. All of the compounds synthesized were excellent substrates for purified human DT-diaphorase (k(cat)/K(m) = 3 x 10(7) - 3 x 10(8) M(-1) s(-1)). The naphthoquinones were toxic to both HT-29 and BE human colon cancer cell lines in a clonogenic assay; however, cytotoxicity did not correlate with DT-diaphorase activity in these cell lines. The benzimidazolequinone analogues were 1-2 orders of magnitude less cytotoxic than the naphthoquinone analogues. Chemical reduction of the naphthoquinone led to rapid expulsion of the phosphorodiamidate anion; in contrast, the benzimidazole reduction product was stable. Michael addition of glutathione and other sulfur nucleophiles provides an alternate mechanism for activation of the naphthoquinone phosphorodiamidates, and this mechanism may contribute to the cytotoxicity of these compounds.
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PMID:Development of novel quinone phosphorodiamidate prodrugs targeted to DT-diaphorase. 1095 24

The enzyme DT-diaphorase mediates the two-electron reduction of quinones to hydroquinones. It has previously been shown that the toxicity of 2-methyl-1,4-naphthoquinone to rats is decreased by pre-treatment of the animals with compounds that increase tissue levels of this enzyme. In contrast, the severity of the haemolytic anaemia induced in rats by 2-hydroxy-1,4-naphthoquinone was increased in animals with high levels of DT-diaphorase. In the present experiments, the effect of alterations in tissue diaphorase activities on the toxicity of a third naphthoquinone derivative, 2,3-dimethyl-1,4-naphthoquinone, has been investigated. This compound induced severe haemolysis and slight renal tubular necrosis in control rats. Pre-treatment of the animals with BHA, a potent inducer of DT-diaphorase, diminished the severity of the haemolysis induced by this compound and abolished its nephrotoxicity. Pre-treatment with dicoumarol, an inhibitor of this enzyme, caused only a slight increase in the haemolysis induced by 2,3-dimethyl-1,4-naphthoquinone, but provoked a massive increase in its nephrotoxicity. Modulation of DT-diaphorase activity in animals may therefore not only alter the severity of naphthoquinone toxicity, but also cause pronounced changes in the site of toxic action of these substances. The factors that may control whether induction of DT-diaphorase in animals will decrease or increase naphthoquinone toxicity are discussed.
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PMID:Effects of modulation of tissue activities of DT-diaphorase on the toxicity of 2,3-dimethyl-1,4-naphthoquinone to rats. 1124 24

beta-lapachone (beta-lap) is a lipophilic o-naphthoquinone isolated from the bark of the lapacho tree. Initial observations proved its capability for inhibiting growth of Yoshida tumor and Walker 256 carcinosarcoma. beta-Lap redox-cycling in the presence of reductants and oxygen yields "reactive oxygen species" (ROS: O2-, OH and H2O2) which cytotoxicity led to assume its role in beta-lap activity in cells. beta-Lap inhibited DNA synthesis in Trypanosoma cruzi as well as topoisomerases I and II, poly(ADP-ribose) polymerase (PARP) in different cells. These enzymes are essential for maintaining DNA structure. beta-Lap inhibited growth of a large variety of tumor cells including epidermoid laringeal cancer, prostate, colon, ovary and breast cancer and also different types of leukemia cells. Advances in knowledge of apoptosis ("programmed cell death") and necrosis provided useful information for understanding the mechanism of beta-lap cytotoxicity. Thiol-dependent proteases (Calpaine), kinases (e.g. c-JUN NH2-terminal kinase), caspases and nucleases are involved in beta-lap cytotoxicity. These enzymes activity, as well as ROS production by beta-lap redox-cycling, would be essential for beta-lap cytotoxicity. Diaphorase and NAD(P)H-quinone reductase, which catalyse beta-lap redox-cycling and ROS production, seem to play an essential role in beta-lap activity. On these grounds, clinical applications of beta-lap have been suggested.
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PMID:[Cytotoxicity of beta-lapachone, an naphthoquinone with possible therapeutic use]. 1147 85

It has been suggested that the enzymes DT-diaphorase and superoxide dismutase act in concert to prevent redox cycling of naphthoquinones and thus protect against the toxic effects of such substances. Little is known, however, about the scope of this process or the conditions necessary for its operation. In the presence of low levels of DT-diaphorase, 2-methyl-1,4-naphthoquinone was found to undergo redox cycling. This was very effectively inhibited by SOD, and in the presence of both enzymes the hydroquinone was maintained in the reduced form. The inhibitory effect of the enzyme combination was overcome, however, at high concentrations of the quinone, or by small increases in pH. Furthermore, redox cycling was re-established by addition of haemoproteins such as cytochrome c and methaemoglobin. DT-diaphorase and SOD strongly inhibited redox cycling by 2,3-dimethyl- and 2,3-dimethoxy-1,4-naphthoquinone, but not that of 2-hydroxy-, 5-hydroxy- or 2-amino-1,4-naphthoquinone. Inhibition of redox cycling by a combination of DT-diaphorase and SOD is therefore not applicable to all naphthoquinone derivatives, and when it does occur, it may be overwhelmed at high quinone concentrations, and it may not operate under slightly alkaline conditions or in the presence of tissue components capable of initiating hydroquinone autoxidation.
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PMID:Concerted action of DT-diaphorase and superoxide dismutase in preventing redox cycling of naphthoquinones: an evaluation. 1169 95


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