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)

Despite its recognition as the most prevalent HIV associated cancer, speculation still abounds regarding the pathogenesis of AIDS-related Kaposi's sarcoma (AIDS-KS). However, it has been established that both cytokines, e.g. IL-6, and HIV-associated products, e.g., Tat, are integral in AIDS-KS cellular proliferation. Further, both experimental and clinical evidence is accumulating to link reactive oxygen intermediates (ROI) with both cytokine induction (primarily via nuclear factor-kappa B[NF-kappa B] dependent routes) as well as the subsequent cytokine, tumor necrosis factor alpha (TNF alpha) stimulation of HIV replication. Features of AIDS-KS patients, such as retention of phagocytes, presence of sustained immunostimulation, and a frequent history of KS lesions arising at traumatized sites, make oxidant stress a viable clinical factor in AIDS-KS development. Time course nucleotide profile analyses show that AIDS-KS cells have an inherent, statistically significant, biochemical deficit, even prior to oxidant stress, due to 1) a more glycolytic bioenergetic profile, resulting in lower levels of high energy phosphates (impairing capacity for glutathione [GSH] synthesis and DNA repair); 2) lower levels of NADPH (compromising the activities of GSSG reductase and peroxidase function of catalase); and 3) reduced levels of GSH (impeding both GSH peroxidase and GSH-S-transferases). Following exposure to physiologically relevant levels of H2O2, only the human microvascular endothelial cells (a putative AIDS-KS progenitor cell) responded with bioenergetic adaptations that reflected co-ordination of energy generating and cytoprotective pathways, e.g., retention of the cellular energy charge, increased NAD+, and an accentuation of the ATP, NADPH, and total adenine nucleotide differences relative to AIDS-KS cells. Also, some of the AIDS-KS strains retained intracellular GSSG subsequent to oxidant challenge, inviting the formation of deleterious protein mixed disulfides. While the results of our study address some AIDS-KS issues, they also raise an etiological question, i.e., Does the inability to tolerate oxidant stress arise in conjunction with AIDS-KS neoplastic development, or is it pre-existing in the population at risk? Regardless, use of antioxidant therapy (low risk/ potentially high benefit) in both the "at risk" population as well as in those individuals with active disease may prove a useful preventative and/or treatment modality.
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PMID:Cultured AIDS-related Kaposi's sarcoma (AIDS-KS) cells demonstrate impaired bioenergetic adaptation to oxidant challenge: implication for oxidant stress in AIDS-KS pathogenesis. 856 50

The response of Schizosaccharomyces pombe to oxidative stresses has been examined. On challenging Schiz. pombe for 60 min at early exponential phase with either 40 mM H2O2 or 6 mM menadione (MD), a superoxide-generating agent, less than 10% of the cells survived. Pretreating Schiz. pombe cells with 0.2 mM H2O2 or 0.2 mM MD for 1 h significantly increased survival of these lethal doses of each oxidant, indicating the existence of an adaptive response to oxidative stress. Furthermore, cells pretreated with a low dose of MD became resistant to a lethal dose of H2O2. However, cells pretreated with H2O2 became only partially resistant to a lethal dose of MD. Adaptation was accompanied by the induction of several oxidative defence enzymes. The presence of 0.2 mM H2O2 induced catalase by 2.8-fold and peroxidase by 2.0-fold The presence of 0.2 mM MD induced catalase by 2.0-fold, glucose-6-phosphate dehydrogenase by 1.9-fold, glutathione reductase by 2.7-fold, peroxidase by 3.0-fold, and superoxide dismutase (SOD) by 2.1-fold. The higher induction of these defence enzymes by MD may explain why MD-pretreated cells were better adapted to lethal doses of oxidants than H2O2-pretreated ones. All these enzymes except SOD and peroxidase increased more than 5.0-fold as cells proceeded into stationary phase. The GSH/GSSG ratio also increased by 60%. These changes accord with the observation that stationary phase cells survive oxidant treatment better than cells in vegetative growth.
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PMID:Adaptive response of Schizosaccharomyces pombe to hydrogen peroxide and menadione. 857 6

Fotemustine is a clinically used DNA-alkylating 2-chloro-ethyl-substituted N-nitrosourea, which sometimes shows signs of haematotoxicity and reversible liver and renal toxicity as toxic side-effects. Mechanistic data on these side-effects are scarce and incomplete. In this study, firstly the cytotoxicity of fotemustine in freshly isolated rat hepatocytes was investigated and secondly the metabolism of fotemustine and possible mechanisms involved in the observed cytotoxicity. Fotemustine caused concentration- and time-dependent cytotoxic effects in rat hepatocytes. Extensive GSH-depletion and formation of GSSG were first observed, followed by lipid peroxidation and finally by cell death measured as LDH-leakage. 2-Chloroethyl analogues of fotemustine, which in contrast to fotemustine have no carbamoylating potency, were not toxic to rat hepatocytes. The data suggest that the cytotoxicity of fotemustine is resulting from its reactive decomposition product, DEP-isocyanate. GSH-conjugation of DEP-isocyanate was shown to protect against the cytotoxicity of fotemustine, however, only temporary and not completely. Synthetical DEP-SG, the GSH-conjugate of DEP-isocyanate, was also toxic to rat hepatocytes, albeit to a significantly lesser extent than fotemustine. In rat liver microsomes, no fotemustine-induced LPO was observed, suggesting that reactive decomposition products of fotemustine do not directly cause peroxidation of cellular membranes. Fotemustine did not affect the antioxidant enzymes superoxide dismutase, catalase, GSH-peroxidase, GSSG-reductase and GSH S-transferases. Thus, direct effects on these antioxidant enzymes are not likely to explain the cytotoxic effects of fotemustine in hepatocytes. In conclusion, it is proposed that the cytotoxicity of fotemustine in rat hepatocytes is caused by rapid and extensive depletion of GSH by DEP-isocyanate, a reactive decomposition product of fotemustine, consequently hampering the endogenous protection against its own toxicity. Knowledge of molecular mechanisms of the cytotoxicity of fotemustine may contribute to a more rational design of selective protection against toxic side-effects which occur upon therapy of patients with fotemustine.
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PMID:Molecular mechanisms of toxic effects of fotemustine in rat hepatocytes and subcellular rat liver fractions. 862 82

All organisms are protected from harmful reactive oxygen which is produced also under physiological conditions by a complex antioxidative system. Our work was aimed at the ascertainment of the level of reduced and oxidated glutathione in erythrocytes of healthy people, the concentrations of ceruloplasmin (GSH) and transferrin (GSSG) in the serum, as well as the investigation of the relationship to antioxidative enzymes ---Cu, Zn-superoxide dismutase (SOD), catalase (CAT) and Se-glutathione-peroxidase (GPx) in erythrocytes. We discovered a mutual direct linear correlation between the levels of GSH, GSSG, CPL and TRF, indirect linear relation between the concentrations of TRF, GSH, GSSG and activities of SOD and GPx, between the concentrations of CPL and GPx activities, and a direct linear relation between concentrations of GSH and TRF with CAT activity. The results indicate to a mutual dependence of investigated nonenzymatic antioxidative factors and antioxidative enzymes. (Tab2, Fig. 4, Ref.13.).
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PMID:[Levels of erythrocyte glutathione and ceruloplasmin and transferrin in the serum and their role in antioxidant protection]. 868 24

This investigation examines the contribution of glutathione peroxidase (GSHPx-1) in degrading H2O2 in lens preparations. Rabbit (N/N1003A) and normal and GSHPx-1 transfected mouse (alpha TN4-1) lens epithelial cell lines and normal and GSHPx-1 transgenic and knockout mouse lenses were utilized. GSHPx-1 activity in the cell lines was increased from two-fold to about four-fold, in the lenses from transgenics more than four-fold and the lenses from knockouts had less than 3% of normal GSHPx-1 activity. The transgenic and knockout mice as well as their lenses appeared normal for up to 3 to 4 months, the longest period of observation. The preparations were subjected to oxidative stress by placing them either in a medium containing 120 or 300 microM H2O2 or utilizing photochemical stress where the H2O2 levels normally rise to about 100 microM over a few hours in the presence of a normal lens. With all preparations, it was found that either markedly increasing or eliminating GSHPx-1 activity had only a small effect on the system's ability to metabolize H2O2, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), an inhibitor of GSSG reductase (GSSG Red) and 3-aminotriazole (3-AT), an inhibitor of catalase, also had little effect. However, the addition of both inhibitors caused a marked decrease in H2O2 degradation. Examination of the distribution of GSHPx-1 in the lens indicated that the activity per milligram of protein was evenly distributed between the epithelium and the remainder of the lens in the normal lens and was about 1.7-fold greater in the epithelium of transgenic lenses than in the remainder of the lens. Surprisingly, the distribution of GSSG Red was quite different with eight- to ten-fold more activity in the epithelium. Catalase was also found to be concentrated in the epithelium. With H2O2 exposure, a rapid loss of non-protein thiol (NP-thiol) was found in cell cultures and in the epithelia of cultured lenses. However, the remainder of the lens showed little change in NP-thiol. The variation of GSHPx-1 activity did not influence the NP-thiol changes which occurred more rapidly and to a greater extent in the presence of BCNU. The addition of BCNU also caused a decrease in total lens NP-thiol. Examination of thymidine incorporation and choline transport, indicators of nuclear and membrane function, also reflects the H2O2 degradation data, showing little difference in the degree to which H2O2 effects these parameters in lenses from normal and transgenic animals. Catalase activity is four- to six-fold greater than GSHPX-1 activity in the alpha TN4-1 cell lines, about three-fold lower in the rabbit cell line and, remarkably, about 18-fold lower than the peroxidase in the normal mouse lens. In spite of such observations, the consistent overall conclusion is that GSHPx-1 and catalase function together but when GSHPx-1 is knocked out or GSSG Red is inhibited, catalase is able to protect the system from H2O2 stress. Indeed, the young mouse does not appear to require GSH Px-1 for normal function.
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PMID:Variation in cellular glutathione peroxidase activity in lens epithelial cells, transgenics and knockouts does not significantly change the response to H2O2 stress. 875 21

HOC1-induced one-electron oxidation of Fe(CN)(6)4- was used as a reference reaction to investigate the stoichiometry of interaction of HOCl with a variety of biological substrates. GSH and GSSG were both found capable of reacting with four and 2-mercaptoethanol with three HOCl molecules. Stopped-flow investigations, with HOCl in excess, indicate that very fast primary reactions of HOCl with GSH and DTPA are followed by slower secondary reactions. In the case of GSH we propose that one HOCl reacts at the terminal alpha-amino-group and three HOCl react at the -SH group to generate the sulfonylchloride GSO2Cl. This assignment is supported by the finding that reaction of HOCl (in excess) with 2-mercaptonaphthalene generates the absorption spectrum of authentic naphthalene-2-sulfonylchloride. NADH reacts with at least two HOCl molecules. A very fast primary reaction of HOCl was followed by a slower secondary reaction at HOCl/NADH > 2, but neither the primary nor the secondary reaction led to NAD+. Stopped-flow investigations of reactions of HOCl with nucleotides indicate that HOCl reacts slowly with the amino-groups of AMP, CMP, and GMP but very fast with the heterocyclic NH-groups of GMP, inosine, and TMP. AMP and CMP promote, but GMP, inosine, and TMP retard HOCl-induced oxidation of Fe(CN)(6)4-. At present we have no convincing evidence, however, that products of interaction of HOCl with nucleotides are capable of one-electron oxidation of Fe(CN)6(-4), with generation of free radical intermediates. HOCl causes slow but very efficient denaturation of native DNA, in our opinion not by oxidative fragmentation, but due to chlorination of amino- and heterocyclic NH-groups of the DNA-bases, which leads to dissociation of the double strand by the loss of hydrogen bonding. HOCl-induced oxidation of Fe(CN)(6)4- is promoted very efficiently by catalytic amounts of Cu2+. Catalysis is explainable by formation of a CuIFeIII(CN)(6)2- complex, with CuI acting as electron donor in a propagating Fenton-like reaction, CuIFeIII(CN)(6)2- +HOCl-->Cu2+ + Fe(CN)(6)3- + Cl- + OH, the rate constant of which was estimated as k = 1.8 x 10(5) M-1 s-1. HOCl is inactivated by Tris, but Hepes promotes HOCl-induced oxidation of Fe(CN)(6)4- very efficiently; this is a warning against application of such buffers in investigations of HOCl- or myeloperoxidase-induced reactions. Anthranilic acid was found to interact with four HOCl molecules to yield highly reactive (unidentified) one-electron oxidants.
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PMID:Hypochlorous acid interactions with thiols, nucleotides, DNA, and other biological substrates. 880 15

1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -CH3, -C2H5, -iC3H7) have been determined with beta-naphthoflavone (beta NF)-induced rat liver microsomes and produced reverse type I spectral changes. Ks,app varied from 0.14 mM for 3,5-diiC3H7-paracetamol to 2.8 mM for paracetamol. 2. All seven analogues underwent rat liver microsomal cytochrome P450-dependent oxidation, as reflected by the formation of GSSG in the presence of GSH. The GSSG-formation was increased in all cases upon pretreatment of rats by beta-naphthoflavone (beta NF) and was generally decreased upon pretreatment by phenobarbital (PB). 3. Rat liver microsomal cytochrome P450 as well as horseradish peroxidase catalysed the formation of 3,5-disubstituted NAPQI analogues from the corresponding parent compounds, as identified by UV-spectrophotometry of the NAPQI analogues and by GC/MS detection of the following GSH-conjugates: 2-glutathione-S-yl-3,5-dimethyl-1,4-dihydroxybenzene, 2-glutathione-S-yl-3,5-dichloro-paracetamol, and 2-glutathione-S-yl-3,5-dibromo-paracetamol. 4. In liver microsomal (beta NF-induced) incubations, apparent K(m) values, as determined for the cytochrome P450 catalysis-dependent oxidation of GSH, for seven 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -CH3, -C2H5, iC3H7) varied from 0.07 to 0.64 mM. Paracetamol exhibited an apparent K(m) of 0.73 mM. Apparent Vmax values for the cytochrome P450 catalysis dependent oxidation of GSH varied from 0.66 nmol min-1 mg-1 protein for paracetamol to 3.0 nmol min-1 mg-1 protein for 3,5-dimethyl-paracetamol.
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PMID:Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol. 881 35

For evaluation of the effects of different free-radical scavengers on biochemical changes in lens-induced uveitis (LIU), ten male Wistar rats were sensitized for 8 weeks using bovine lens protein and Freund's adjuvant. The uveitis was induced by disruption of the lens capsule. One group of animals received superoxide dismutase and catalase (SOD/CAT); a second group of animals was treated with vitamin E. Lipid peroxides (LPO) of the retinal tissue and aqueous humor served as parameter of oxidative tissue damage. Glutathione (GSH/GSSG) of the aqueous humor was evaluated as a parameter of the tissue's redox state. For evaluation of the inflammatory response, myeloperoxidase activity (MPO) was determined in the iris/ciliary-body complex. SOD/CAT produced no improvement in the significantly (P < 0.05) elevated MPO and LPO values recorded for untreated control animals. Following vitamin E treatment the GSH/GSSG and LPO values in aqueous humor were markedly improved as compared with controls. Retinal LPO values were significantly (P < 0.05) reduced as compared with controls. No change in MPO levels was observed. The results demonstrate that enzymes such as SOD and CAT do not influence tissue damage at a significant level, whereas radical chain breakers such as vitamin E can do so. However, the inflammatory response itself is not reduced. To achieve global results, drugs are necessary that act on both free radicals produced by noninflammatory pathways and those originating from inflammation.
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PMID:Effects of different antioxidants on lens-induced uveitis. 885

Defenses against free radical damage were determined in red blood cells and plasma from 40 patients with dementia of the Alzheimer-type (DAT) and 34 aged control subjects with normal cognitive function. No crude significant difference in erythrocyte copper-zinc superoxide dismutase (E-CuZnSOD), seleno-dependent glutathione peroxidase (E-GSH-Px), glutathione reductase (E-GSSG-RD) activities, and selenium (Se) concentration was found between DAT cases and control subjects. The peroxidation products evaluated in plasma by the thiobarbituric-reactive material (TBARS) were at the same level in the DAT group as compared to controls. In the DAT group, plasma GSH-Px (P-GSH-Px) activity and plasma Se (P-Se) were negatively correlated with age (r = -0.58; p < 0.001 and r = -0.63; p < 0.001 respectively). Moreover, erythrocyte GSH-Px activity and Se were also negatively correlated with age (r = -0.40; p < 0.01 and r = -0.46; p < 0.01, respectively). No significant correlation with age was observed in the controls. When controlling for age, a significant increase for P-GSH-Px activity and P-Se was observed in DAT patients as compared to controls. These significant differences mostly appeared in DAT subjects under 80 years. Some correlations were only observed in the DAT group such as P-GSH-Px and E-GSH-Px (r = +0.68; p < 0.001); P-GSH-Px and E-Se (r = +0.79; p < 0.001). Correlations between P-GSH-Px and P-Se, E-GSH-Px and P-Se, and P-Se with E-Se are greater in the DAT group (r = +0.84; p < 0.001; r = +0.76; p < 0.001 and r = 0.75; p < 0.001) than in the control group (r = 0.54, pI < 0.01; r = 0.43, p < 0.01 and r = +0.34, p < 0.05 respectively). The fact that first -- a significant increase in P-GSH-Px and P-Se, second -- some modifications in the relationships between antioxidant parameters, and third -- age-dependent decreases of glutathione-peroxidase activities and their cofactor, appeared only in the DAT group suggest that DAT is associated with an oxidative stress due to an imbalance between reactive oxygen species and the peripheral antioxidant opposing forces.
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PMID:Peripheral antioxidant enzyme activities and selenium in elderly subjects and in dementia of Alzheimer's type--place of the extracellular glutathione peroxidase. 890 99

A mouse embryo culture model was used to determine whether embryonic prostaglandin H synthase (PHS)-catalyzed bioactivation and resultant oxidative damage to embryonic protein and DNA may constitute a molecular mechanism mediating phenytoin and benzo[a]pyrene teratogenesis. Embryos were explanted from CD-1 mouse dams on gestational day 9.5 (vaginal plug = day 1) and incubated for either 4 h (biochemistry) or 24 h (embryotoxicity) at 37 degrees C in medium containing either phenytoin (20 micrograms/ml, 80 microM), benzo[a]pyrene (10 microM), or their respective vehicles. As previously observed with phenytoin (Mol. Pharmacol.48: 112-120, 1995), embryos incubated with benzo[a]pyrene showed decreases in anterior neuropore closure, turning, yolk sac diameter, and somite development (p < .05). Addition of the antioxidative enzyme superoxide dismutase (SOD) substantially enhanced embryonic SOD activity (p < .05) and completely inhibited benzo[a]pyrene embryotoxicity (p < .05). Substantial PHS was detected in day 9.5 embryos using SDS/PAGE, anti-PHS antibody, and alkaline phosphatase-conjugated donkey anti-goat IgG. Embryonic protein oxidation was detected by the reaction of 0.5 mM 2,4-dinitrophenylhydrazine with protein carbonyl groups. This method was first validated by using a known hydroxyl radical-generating system consisting of vanadyl sulfate and H2O2, with bovine serum albumin or embryonic protein as the target. Embryonic proteins were characterized by SDS/PAGE, anti-dinitrophenyl antisera, and peroxidase-labeled goat anti-donkey IgG. Using enhanced chemiluminescence, the number and content of oxidized protein bands detected between 25 and 200 kDa were substantially increased by both phenytoin and benzo[a]pyrene. Addition of the reducing agent dithiothreitol, or SOD or catalase, decreased protein oxidation in phenytoin-exposed embryos. Both phenytoin (Mol. Pharmacol.48: 112-120, 1995) and benzo[a]pyrene enhanced embryonic DNA oxidation, determined by the formation of 8-hydroxy-2'-deoxyguanosine, as measured by high-performance liquid chromatography (HPLC) (p < .05). Phenytoin also enhanced the oxidation of embryonic glutathione (GSH) to its GSSG disulfide, as measured by HPLC (p < .05). These results provide direct evidence that, in the absence of maternal or placental processes, embryonic PHS-catalyzed bioactivation and reactive oxygen species-mediated oxidation of embryonic protein, thiols, and DNA may constitute a molecular mechanism mediating phenytoin and benzo[a]pyrene teratogenesis.
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PMID:Evidence for embryonic prostaglandin H synthase-catalyzed bioactivation and reactive oxygen species-mediated oxidation of cellular macromolecules in phenytoin and benzo[a]pyrene teratogenesis. 901 24


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