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:1.11.1.7 (peroxidase)
65,474 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aluminum intoxication is currently thought to play a major role in the development of Alzheimer's disease and in certain pathologic manifestations seen during long-term hemodialysis and aging. The hypothesis that aluminum toxicity is mediated via an increased free radical production was tested by studying the effects of two aluminum and five other metallic compounds on the production of luminol-enhanced chemiluminescence (LECL) by human neutrophils. AlCl3, Al2(SO4)3 and FeCl3 were found to stimulate LECL production by human neutrophils whereas FeCl2, CuCl, CuCl2, AuCl3 were inactive. Metal chelators such as Desferal, EDTA and DETAPA suppressed aluminum-induced stimulation and depressed cell-dependent LECL below basal levels. Sodium azide and Cytochalasin B greatly depressed both basal and aluminum-induced stimulation of LECL production, suggesting that, in this system, most of this stimulation was due to myeloperoxidase. These results suggest that high tissue aluminum concentrations may induce cell-tissue lesions by stimulating local production or release of mediators of tissue damage.
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PMID:Aluminum salts stimulate luminol-enhanced chemiluminescence production by human neutrophils. 190 35

Besides 6-ketoprostaglandin F1 alpha, bovine aortic endothelial cells also produced considerable amounts of 6,15-diketoprostaglandin F1 alpha from arachidonic acid, either exogenously added or released from cellular phospholipids. Incubations of particulate fractions of endothelial cells with the cyclic endoperoxides prostaglandin G2 and prostaglandin H2 showed that 6,15-diketoprostaglandin F1 alpha is formed by the action of prostaglandin I2 synthetase on prostaglandin G2. The labile metabolite 15-hydroperoxyprostaglandin I2 is then converted nonenzymatically to the 15-keto derivative. In the presence of reduced glutathione, quantitative analysis of both metabolites by gas chromatography-mass spectrometry showed a significant decrease of 6,15-diketoprostaglandin F1 alpha formation, whereas prostaglandin I2 synthesis was markedly increased. This shift seems to be due to a stimulation of peroxidase by GSH, a well known cofactor of this enzyme. Thus, it seems that a decreased endothelial prostaglandin I2 formation may occur when cellular glutathione levels are reduced as a consequence of oxidant injury and lipid peroxidation. Additionally, ferrous ions seems to be involved in the regulation of endothelial prostaglandin I2 synthesis, since Desferal, a specific ferrous ion chelator that might have antimetastatic properties, produced a pronounced shift from 6,15-diketoprostaglandin F1 alpha to the 6-keto derivative, i.e., prostaglandin I2.
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PMID:Formation of 6,15-diketoprostaglandin F1 alpha from prostaglandin G2 by bovine aortic endothelial cells. 303 65

The iron chelator deferoxamine (Desferal; DSFL) reacts with peroxidases and H2O2 to form the DSFL radical (DSFL.), which can be detected by EPR spectroscopy. We have found that DSFL. formation resulting from exposure to H2O2 and any of a number of different peroxidases is greatly enhanced in the presence of the nitrone spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (4-POBN). This enhancement was seen at 4-POBN concentrations as low as 200 microM. We observed a modest enhancement of DSFL. formation with 2-methyl-2-nitrosopropane. However, no enhancement was seen with 5,5-dimethyl-1-pyrroline 1-oxide (DMPO) or phenyl-tert-butylnitrone. A modest enhancement was also seen with the nitrone compound pyridine N-oxide. 2-Methyl-2-nitrosopropane and pyridine N-oxide were additionally capable of increasing enzymatic peroxidase activity as measured by o-dianisidine and/or tetramethylbenzidine oxidation. Furthermore, at high concentrations of 4-POBN (50 mM) in the absence of DSFL, we detected a peroxidase/H2O2-dependent 12-line EPR spectrum that likely represents a 4-POBN/.4-POBN nitrogen-centered spin adduct. In the presence of both 4-POBN (10 mM) and DMPO (100 mM), an 18-line EPR spectrum was observed consistent with formation of a DMPO/.4-POBN nitrogen-centered spin adduct. Thus, the nitrone spin trap 4-POBN can enhance the peroxidase-mediated formation of DSFL., possibly via the formation of a transient 4-POBN radical species. These data suggest the importance of assessing the potential for nitrone spin traps to both inhibit and enhance biological oxidation prior to their use as potential pharmacological agents.
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PMID:The spin trap alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone stimulates peroxidase-mediated oxidation of deferoxamine. Implications for pharmacological use of spin-trapping agents. 749 57

Iron chelators have been shown to protect against oxygen free radical injury occurring in association with ischemia/reperfusion (I/R). Tumor necrosis factor alpha (TNF) represents a major mediator of the pulmonary and hepatic injury occurring after hepatic I/R since pretreatment with anti-TNF antibody results in significant protection against both the lung and liver injury following this insult. We were therefore interested in the possible association of the protective actions of deferoxamine (Desferal) following hepatic I/R and subsequent TNF release. A rat model of hepatic I/R was used to evaluate this; four experimental groups were studied. Animals in I/R underwent 90 min of hepatic ischemia with subsequent reperfusion. DES-I/R animals were pretreated with 200 mg of deferoxamine and VEH-I/R rats were given an equivalent amount of vehicle prior to hepatic I/R. SHAM animals underwent sham laparotomy alone. Plasma specimens were obtained and analyzed for TNF using a cytolytic bioassay based on the WEHI 164 subclone 13 cell line. Mean peak TNF levels following deferoxamine pretreatment was 110.38 +/- 24.68 pg/ml, as compared to mean peak TNF levels of 213.64 +/- 38.09 pg/ml in the VEH-I/R group (P < 0.01). Lung injury following hepatic I/R was evaluated by assessment of pulmonary microvascular permeability and by evaluation of pulmonary neutrophil infiltration as measured by pulmonary myeloperoxidase (MPO) content. Pretreatment with deferoxamine resulted in a significant decrease in lung leak as compared to animals pretreated with vehicle prior to I/R (DES-I/R = 0.192 +/- 0.013, VEH-I/R = 0.690 +/- 0.050; P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Desferal attenuates TNF release following hepatic ischemia/reperfusion. 793 22

Rat liver microsomes were examined for their ability to oxidize the mycotoxin ochratoxin A (OTA) to 4(R)-4-hydroxyochratoxin A [(R)-4-OH-OTA] and 4(S)-4-hydroxyochratoxin A [(S)-4-OH-OTA] and to induce OTA-dependent lipid peroxidation. Microsomes isolated from rats pretreated with pregnenolone-16 alpha-carbonitrile greatly induced both (R)-4-OH-OTA and (S)-4-OH-OTA formation whereas isoniazid pretreatment primarily induced (S)-4-OH-OTA. (R)-4-OH-OTA and (S)-4-OH-OTA formation showed significant differences with respect to pH optima, effect of antioxidants, and iron chelators. (R)-4-OH-OTA showed a pH optimum of 6.5 and was not inhibited by the antioxidants butylated hydroxyanisole or N,N-diphenyl-1,4-phenylenediamine or the iron chelators. Desferal or bathophenanthrolinedisulfonic acid. In contrast, both (S)-4-OH-OTA and lipid peroxidation showed a pH optimum of 7.0 and both activities were sensitive to inhibition by the above antioxidants and iron chelators. Lipid peroxidation was not involved in (S)-4-OH-OTA formation since addition of linoleic acid hydroperoxide to microsomes did not give rise to (S)-4-OH-OTA. Cytochrome P450 appeared to be essential since other hemoproteins like horseradish peroxidase and hemoglobin were ineffective in metabolizing OTA in the presence of hydroperoxides. The results suggest that (R)-4-OH-OTA is formed by normal mixed-function oxidation but that (S)-4-OH-OTA formation may involve free iron. It is likely that an active Fe2(+)-oxygen complex, formed via NADPH-cytochrome P450 reductase and cytochrome P450-dependent reduction of free Fe3+ followed by oxygen binding, serves as the species inducing lipid peroxidation and at least part of (S)-4-OH-OTA formation.
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PMID:Possible role of an iron-oxygen complex in 4(S)-4-hydroxyochratoxin a formation by rat liver microsomes. 826 56

Oxidative modification of human low-density lipoprotein (LDL) is thought to play a major role in the development of atherosclerosis. Free hemin, hemoglobin, myoglobin, and horseradish peroxidase (HRP) were reported in different studies as promoters of LDL lipid oxidation. Based on our previous finding that hemin induced oxidative crosslinking of the LDL protein, apolipoprotein B (apo B) (Y. I. Miller and N. Shaklai (1994) Biochem. Mol. Biol. Int. 34, 1121-1129), we compared the ability of free hemin and the above hemoproteins to induce peroxidation modification of apo B using SDS-PAGE. The levels of the final products of lipid peroxidation were determined as thiobarbituric acid-reactive substances. Hemoglobin and myoglobin were found to be as active as free hemin and all these were much more active than the classic peroxidase HRP. Moreover, the products of oxidized apo B differed: hemoglobin, myoglobin, and hemin induced mostly covalent aggregates, while HRP caused fragmentation of apo B. Hemoglobin reactivity was expressed at low H2O2 concentrations even in the absence of molecular oxygen. Desferal, along with other antioxidants, inhibited the hemoglobin-induced LDL oxidation independently of its iron-chelating property. The high peroxidative reactivity of hemoglobin is explained by its ability (unlike HRP) to transfer the oxidative equivalents from the heme active site, through the globin, to LDL. The apo B radicals thus formed are terminated, yielding intermolecular crosslinked protein. It is suggested that small amounts of the highly reactive hemoglobin in plasma, suffice to trigger LDL protein oxidation (along with its lipid oxidation), thereby inflict the atherosclerosis precondition.
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PMID:Hemoglobin induced apolipoprotein B crosslinking in low-density lipoprotein peroxidation. 861 Oct 31

The effects of cortical tissue preparations (CTP) from human brain on the production of reactive oxygen species (ROS) has been investigated with several biochemical model reactions. As indicators for ROS, fragmentation of the methionine derivatives, alpha-keto-gamma-methylthiobutyric acid (KMB) or 1-amino-cyclopropane-1-carboxylic acid (ACC), yielding ethene have been used. With these systems we have shown that production of OH-radical-type oxidants by the xanthine oxidase (XOD)-system is strongly stimulated by CTP. This activity is due to intrinsic iron ions since ethene formation from KMB is stimulated by EDTA, inhibited by desferrioxamine (Desferal) and also visible with heat-denatured CTP. CTP by themselves have no XOD activity. 3-Hydroxykynurenine (3HK) is another possible substrate for XOD but produces H2O2 without XOD-catalysis, whereas allopurinol is not inhibiting. CTP contain measurable NAD(P)H oxidoreductase activity, producing OH- radical- type oxidants at the expense of NADPH and (to a lesser extent) NADH as electron donors, shown as redox-cycling of 2-methyl-5-hydroxy-1,4-naphthoquinone, plumbagin. Ethene formation from KMB is also driven by both morpholinosydnonimine (SIN) or ONOOH. The reaction driven by SIN is stimulated by CTP and inhibited by catalase, SOD and hemoglobin. Since ethene release from KMB driven by ONOOH is inhibited by CTP the mechanisms driving KMB fragmentation are different for SIN and ONOOH. Furthermore CTP contain approx. 4 U catalase activity per mg protein and very weak peroxidase (POD) activity shown as ACC fragmentation yielding ethene in the presence of both H2O2 and KBr or NaCl. Since ACC binds to CTP and both compounds, ACC and KMB are natural products, present in food (ACC) or synthesized from methionine in vivo (KMB), these compounds may represent protecting agents in systems where reactive oxygen species are formed. One might even speculate that the production of ethene at these membrane receptor sites may have biological functions, since ethene is known to possess anaesthetic activities.
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PMID:Pro- and antioxidative properties of cortical tissue preparations from human brain exhibiting NMDA-receptor characteristics. 1043 95

Ochratoxin A (OTA), a nephrotoxic and nephrocarcinogenic mycotoxin, leads to the formation of DNA adducts after administration to animals. This could be due to an epigenetic effect. In vitro assays can exclude an indirect effect, where the xenobiotic can generate, in vivo, endogenous reactive compounds which give adducts on DNA. Microsomes prepared from mice or rabbit kidney and liver, used as metabolic activators, were incubated in the presence of commercial salmon testes DNA and OTA, with NADPH or arachidonic acid used as cofactors. Upto 126 DNA adducts for 10(9) nucleotides were detected using the 32P postlabeling method after incubation with the mouse kidney system. Similar results were obtained with rabbit kidney microsomes. Using liver microsomes, the number of DNA adducts detected was much lower. When NADPH was used as a cosubstrate (to explore the cytochrome P450 metabolic pathways), with mice kidney microsomes, the adduct level was only 44% of the one obtained with arachidonic acid. These results lend support to the hypothesis of the preferential activation of OTA by the peroxidase activity of prostaglandin synthases and/or lipoxygenases to direct genotoxic metabolites, and are in agreement with the previously obtained results after in vivo treatment of mice. In order to identify the nucleotides of DNA modified by the OTA metabolites, dAMP, dGMP, dTMP and dCMP were used as substrates under the same conditions as with DNA. The adducts were found only on dGMP. The total adduct level was of 344 adducts per 10(9) nucleotides with the appearance of three major adducts in the presence of arachidonic acid. With NADPH, 271 adducts were obtained per 10(9) nucleotides, with again three major adducts, but only two of them were similar to two adducts obtained in the presence of arachidonic acid. Desferal (desferrioxamine B methanesulphonate), at a 50 microM concentration, did not reduce the adduct level. Adducts were also obtained when polydG, polydC and dG-p-dG were used as alternative substrates, whereas no adducts were obtained with polydA, polydT and polydC. The major adduct obtained after incubation of DNA with OTA, comigrated with the major adduct obtained with dGMP, in two chromatographic solvents. These results show that OTA is metabolized to genotoxic metabolite(s) which interact with the guanine residues of DNA.
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PMID:In vitro DNA and dGMP adducts formation caused by ochratoxin A. 1090 17

The artifactual generation of the biomarker for oxidative stress, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), during the workup procedure for its analysis is a difficult problem to solve, and the responsible factors are unclear. Here, peroxide removal and other antioxidant procedures during workup were compared using a limited amount of rat liver (50 mg) as starting material, with subsequent hydrolysis of 50 microg of DNA. A cold (0 degrees C) high salt GTC (4 M guanidine thiocyanate) nonphenol DNA extraction method was developed where DNA is quickly isolated. GSH (reduced glutathione) generated artifactual formation of 8-oxodG during the workup procedure, whereas H(2)O(2) removal using catalase, Fe(3+) removal and passivation using desferal, peroxide removal using glutathione peroxidase, ebselen and a peroxidase mimic lowered the 8-oxodG levels, all identifying peroxides as the responsible oxidants. Desferal was more protective when excluding Mg(2+) and Ca(2+) from buffers but was found to disturb the electrochemical detector when repeatedly injected five to six times, even at 100 microM. Addition of the OH(*) scavenger ethanol in all steps at 2% v/v had no protective effect. Zn(2+) was found necessary for efficient DNA hydrolysis using nuclease P(1), which was poor below 37 degrees C. Use of water substitutes was tested but inhibited DNA hydrolysis completely. H(2)(18)O could, however, work for mass spectrometry methods. Long-term (38 days) storage of 0.5% v/v Triton X-100 generated more 8-oxodG than Tween 20 when incubated with free dG. The cold GTC DNA extraction method was used for analysis of freshly isolated human lymphocytes/monocytes from 60 healthy men using catalase and TEMPO as antioxidants, giving a background level of 0.074 +/- 0.027 8-oxodG/10(5) dG (or 16 8-oxodG/10(8) nucleotides or 1943 8-oxodG/nuclei) which is probably the lowest value obtained yet. No increase with age was seen. Oxidation of dG to 8-oxodG during workup was found to fit a mathematically defined curve, and a calculated background level of 0.047 8-oxodG/10(5) dG was obtained. To obtain more reliable results it is recommended that control samples are included during the workup procedure, having an equal amount of cells (or DNA) as the exposed samples.
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PMID:Optimization of the workup procedure for the analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine with electrochemical detection. 1189 91

Peroxidase activity in human saliva is composed of salivary peroxidase (80%), of salivary glandular origin, and myeloperoxidase (20%), of leukocyte origin. The term oral peroxidase (OPO) is used here to denote the total activity of both peroxidase species. Using the 2-nitrobenzoic acid-thiocyanate assay, OPO activity was measured in the saliva of nonsmokers after exposure to gas-phase cigarette smoke (CS) in an in vitro system using three puffs of CS in 1 h. A marked decrease of 76% of activity was observed following three puffs of CS. In order to elucidate the mechanism by which CS caused loss of OPO activity, several oxidants and antioxidants were applied to saliva in vitro in the presence and absence of CS. No protection for CS-induced loss of OPO activity occurred in the presence of glutathione, N-acetylcysteine, ascorbic acid, or Desferal. Exposure of saliva to purified aldehydes present in CS did not significantly affect OPO loss of activity. Similarly, ascorbic acid in the presence of FeCl(3) and nicotine also had no effect on OPO activity. Exposure of OPO to cyanate at levels present in CS caused a 65-70% loss of OPO activity, which was reversible after 24 h of dialysis. Moreover, hydroxocobalamin, a known cyanate chelator, could prevent CS- and potassium cyanide-induced inactivation of OPO by 70-90%. The results show that hydrogen cyanide, known to be present in microgram amounts per cigarette, is likely to be the species in CS responsible for loss of salivary OPO activity. The finding of reduced salivary OPO levels after CS exposure may represent a contributory mechanism for CS-related compromises in antimicrobial defenses in the aerodigestive tract.
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PMID:Effect of cigarette smoke on oral peroxidase activity in human saliva: role of hydrogen cyanide. 1464 92


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