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:1.6.99.3 (diaphorase)
5,903 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The small intestine can metabolize a variety of substances and can play a role in the presystemic clearance of ingested compounds. Relatively little is known about the ability of small intestine to catalyze the presystemic reductive metabolism of xenobiotics. 1,3-Dinitrobenzene (1,3-DNB), which is known to undergo reductive biotransformation in an intact, oxygenated isolated perfused intestinal preparation, was used as a model substrate for reductive enzymes of the small intestine of the rat. Subcellular fractions from duodenal, jejunal, and ileal regions of rat small intestinal mucosa were used to characterize the enzyme source(s) of those reductive reactions of 1,3-DNB that are relevant in the oxygenated intestinal tissue. 1,3-DNB was reduced to 3-nitroaniline (3-NA) by cytosol from duodenum and jejunum. The rate of reduction was 2 times faster when incubations contained duodenal rather than jejunal cytosol. Jejunal cytosol-catalyzed reduction of 1,3-DNB was supported by hypoxanthine, NADPH, or NADH. Duodenal microsomes catalyzed the reduction of 1,3-DNB to 3-NA in the presence of supplemental NADPH or NADH; however, the reaction was very slow. Jejunal microsomes, ileal microsomes, and ileal cytosol failed to catalyze the reduction of 1,3-DNB. Studies with chemical inhibitors suggested possible roles for DT diaphorase, glutathione reductase, or xanthine oxidase in the jejunal cytosol-catalyzed reaction. Purified, commercially available xanthine oxidase (from buttermilk) catalyzed the reduction of 1,3-DNB to 3-NA when supplemented with NADH or hypoxanthine.
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PMID:Metabolism of [14C]1,3-dinitrobenzene by rat small intestinal mucosa in vitro. 856 89

Nitroreductase enzymes generally catalyze the reduction of nitroaromatic compounds to the corresponding amines. In contrast, ferredoxin NADP oxidoreductase (FNR), glutathione reductase, xanthine oxidase, and cytochrome c reductase catalyze the NADPH dependent elimination of the nitramine nitro group from 2,4,6-trinitrophenylmethylnitramine to form N-methylpicramide (NMP). Nitrite elimination was inhibited under aerobic conditions. Our results suggest that under aerobic conditions, tetryl is enzymatically reduced to the nitroanion radical which is then involved in the reduction of molecular oxygen. Under anaerobic conditions, the radical is reduced to NMP and nitrite is eliminated.
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PMID:Elimination of nitrite from the explosive 2,4,6-trinitrophenylmethylnitramine (tetryl) catalyzed by ferredoxin NADP oxidoreductase from spinach. 860 4

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

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

1. Addition of Cr VI (dichromate) to isolated rat hepatocytes results in rapid glutathione oxidation, reactive oxygen species (ROS) formation, lipid peroxidation, decreased mitochondrial membrane potential and lysosomal membrane rupture before hepatocyte lysis occurred. 2. Cytotoxicity was prevented by "ROS" scavengers, antioxidants, and glutamine (ATP generator). Hepatocyte dichlorofluorescin oxidation (to determine ROS/Cr V formation) was inhibited by mannitol (a hydroxyl radical scavenger) or butylated hydroxyanisole and butylated hydroxytoluene (antioxidants). 3. The Cr VI reductive mechanism required for toxicity are not known. Cytotoxicity was also prevented by cytochrome P450 inhibitors, particularly CYP 2E1 inhibitors, but not inhibitors of DT diaphorase or glutathione reductase. This suggests that P450 reductase and/or reduced cytochrome P450 contributes to Cr VI reduction to Cr IV. 4. Glutathione depleted hepatocytes were resistant to Cr (VI) toxicity and much less dichlorofluorescin oxidation occurred. Reduction of dichromate by glutathione or cysteine in vitro was also accompanied by oxygen uptake and was inhibited by Mn II (a Cr IV reductant ). Cr VI induced cytotoxicity and ROS formation was also inhibited by Mn II which suggests that Cr IV and Cr IV.GSH mediate "ROS" formation in isolated hepatocytes. 5. In conclusion Cr VI cytotoxicity is associated with mitochondrial/lysosomal toxicity by the biological reactive intermediates Cr IV and "ROS".
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PMID:Biological reactive intermediates that mediate chromium (VI) toxicity. 1176 36

To exert cytotoxicity chromium VI (Cr(VI)) has to be reduced inside cells. This is achieved through both enzymatic and non-enzymatic mechanisms. Enzymatic mechanisms include DT-diaphorase, cytochrome P450, and NADPH cytochrome c reductase, and non-enzymatic mechanisms involve reduced glutathione (GSH) and ascorbic acid. The extent of cytotoxicity of Cr(VI) may thus be influenced by the availability of non-enzymatic reductants, and by the activities of the reductase enzymes. In the present paper we have investigated the effect of pretreatment with the inducing agents, phenobarbitone (PB) and 3-methylcholanthrene (3-MC), on the response of rat hepatocytes to Cr(VI). Pretreatment with PB increased the activity of NADPH cytochrome c reductase, and 3-MC increased DT-diaphorase activity in hepatocytes. Both inducers increased cytochrome P450 content, while neither influenced intracellular GSH content or the activity of glutathione reductase. Pretreatment with either PB or 3-MC resulted in amelioration of Cr(VI) toxicity both in terms of hepatocyte viability, and to a greater extent, in terms of Cr(VI) induced GSH loss. We propose that the inducing agents increase the amount of enzymatic reduction of Cr(VI) relative to non-enzymatic reduction. Thus, less GSH is used in the reduction of Cr(VI), and intracellular GSH does not fall as rapidly as in cells from control animals therefore cell integrity is better maintained. Exposure to environmental inducing agents in vivo may also alter the response of human tissues to Cr(VI).
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PMID:Pretreatment of rats with the inducing agents phenobarbitone and 3-methylcholanthrene ameliorates the toxicity of chromium (VI) in hepatocytes. 1220 17

Enzymatic reduction of physiological Fe(III) complexes of the "labile iron pool" has not been studied so far. By use of spectrophotometric assays based on the oxidation of NAD(P)H and formation of [Fe(II) (1,10-phenanthroline)3]2+ as well as by utilizing electron paramagnetic resonance spectrometry, it was demonstrated that the NAD(P)H-dependent flavoenzyme lipoyl dehydrogenase (diaphorase, EC 1.8.1.4) effectively catalyzes the one-electron reduction of Fe(III) complexes of citrate, ATP, and ADP at the expense of the co-enzymes NAD(P)H. Deactivated or inhibited lipoyl dehydrogenase did not reduce the Fe(III) complexes. Likewise, in the absence of NAD(P)H or in the presence of NAD(P)+, Fe(III) reduction could not be detected. The fact that reduction also occurred in the absence of molecular oxygen as well as in the presence of superoxide dismutase proved that the Fe(III) reduction was directly linked to the enzymatic activity of lipoyl dehydrogenase and not mediated by O2. Kinetic studies revealed different affinities of lipoyl dehydrogenase for the reduction of the low molecular weight Fe(III) complexes in the relative order Fe(III)-citrate > Fe(III)-ATP > Fe(III)-ADP (half-maximal velocities at 346-485 microm). These Fe(III) complexes were enzymatically reduced also by other flavoenzymes, namely glutathione reductase (EC 1.6.4.2), cytochrome c reductase (EC 1.6.99.3), and cytochrome P450 reductase (EC 1.6.2.4) with somewhat lower efficacy. The present data suggest a (patho)physiological role for lipoyl dehydrogenase and other flavoenzymes in intracellular iron metabolism.
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PMID:Reduction of Fe(III) ions complexed to physiological ligands by lipoyl dehydrogenase and other flavoenzymes in vitro: implications for an enzymatic reduction of Fe(III) ions of the labile iron pool. 1296 36

A study has been made of calf thymus and liver tissue to ascertain the position of the nucleus with respect to mechanisms capable of hydrogen transfer. Although previous work had shown that reduced pyridine nucleotide coenzymes are produced in the course of nuclear metabolism, it has now been established that the flavoprotein system of cytochrome c reductase, cytochrome c, and most, if not all, of other flavoproteins are absent from nuclei. Metabolites capable of cytochrome c reduction, notably ascorbic acid and glutathione, have been demonstrated in the nuclei. Glutathione reductase has been found present in nuclei only to a minor extent, suggesting that nuclear glutathione might function largely in a capacity other than that of hydrogen carrier in the nucleus. Although no enzymatic relation could be established between ascorbic acid and hydrogen transfer in nuclei) it was possible to demonstrate a close association between ascorbic acid concentration and the mitotic process in lily anthers. The significance of the anaerobic character of nuclear metabolism to chromosome function is discussed.
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PMID:The position of the cell nucleus in pathways of hydrogen transfer: cytochrome C, flavoproteins, glutathione, and ascorbic acid. 1319 14

In brain mitochondria, state 4 respiration supported by the NAD-linked substrates glutamate/malate in the presence of EGTA promotes a high rate of exogenous H2O2 removal. Omitting EGTA decreases the H2O2 removal rate by almost 80%. The decrease depends on the influx of contaminating Ca2+, being prevented by the Ca2+ uniporter inhibitor ruthenium red. Arsenite is also an inhibitor (maximal effect approximately 40%, IC50, 12 microm). The H2O2 removal rate (EGTA present) is decreased by 20% during state 3 respiration and by 60-70% in fully uncoupled conditions. H2O2 removal in mitochondria is largely dependent on glutathione peroxidase and glutathione reductase. Both enzyme activities, as studied in disrupted mitochondria, are inhibited by Ca2+. Glutathione reductase is decreased by 70% with an IC50 of about 0.9 microm, and glutathione peroxidase is decreased by 38% with a similar IC50. The highest Ca2+ effect with glutathione reductase is observed in the presence of low concentrations of H2O2. With succinate as substrate, the removal is 50% less than with glutamate/malate. This appears to depend on succinate-supported production of H2O2 by reverse electron flow at NADH dehydrogenase competing with exogenous H2O2 for removal. Succinate-dependent H2O2 is inhibited by rotenone, decreased DeltaPsi, as described previously, and by ruthenium red and glutamate/malate. These agents also increase the measured rate of exogenous H2O2 removal with succinate. Succinate-dependent H2O2 generation is also inhibited by contaminating Ca2+. Therefore, Ca2+ acts as an inhibitor of both H2O2 removal and the succinate-supported H2O2 production. It is concluded that mitochondria function as intracellular Ca2+-modulated peroxide sinks.
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PMID:Respiration-dependent removal of exogenous H2O2 in brain mitochondria: inhibition by Ca2+. 1463 20

The enzymatic activity of five enzymes viz. Glutathione S-transferases, Esterases, NADH dehydrogenase, NADH oxidase and Glutathione reductase were assessed under the influence of Indole butyric acid (IBA) (400 ppm) in the nymphs (48-52h old) of mustard aphid, Lipaphis erysimi fed on radish plants treated for 13, 25 and 37h. The activity of Glutathione S-transferases, Esterases and NADH dehydrogenase increased compared to that found in the control of the same age group of nymphs and it was concluded that these enzymes might be involved in the metabolism of IBA. The other two enzymes, NADH oxidase and Glutathione reductase showed no significant increase in their activity compared to that in the control of the same age group. It was hypothesized that the latter enzymes do not play any significant role in the metabolism of IBA.
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PMID:Evaluation of the possible role of five enzymes in the metabolism of IBA in mustard aphid, Lipaphis erysimi (Kalt.). 1552 74


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