Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04040 (Catalase)
 3,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This investigation examined the effect of the anthracycline antitumor agents on reactive oxygen metabolism in rat heart. Oxygen radical production by doxorubicin, daunorubicin, and various anthracycline analogues was determined in heart homogenate, sarcoplasmic reticulum, mitochondria, and cytosol, the major sites of cardiac damage by the anthracycline drugs. Superoxide production in heart sarcosomes was significantly increased by anthracycline treatment; for doxorubicin, the reaction appeared to follow saturation kinetics with an apparent Km of 112.62 microM, required NADPH as cofactor, was accompanied by the accumulation of hydrogen peroxide, and probably resulted from the transfer of electrons to molecular oxygen by the doxorubicin semiquinone after reduction of the drug by sarcosomal NADPH:cytochrome P-450 reductase (NADPH:ferricytochrome oxidoreductase, EC 1.6.2.4). Superoxide formation was also significantly enhanced by the anthracycline antibiotics in the mitochondrial fraction. Doxorubicin stimulated mitochondrial superoxide formation in a dose-dependent manner that also appeared to follow saturation kinetics (apparent Km of 454.55 microM); however, drug-related superoxide production by mitochondria required NADH rather than NADPH and was significantly increased in the presence of rotenone, which suggested that the proximal portion of the mitochondrial NADH dehydrogenase complex [NADH:(acceptor) oxidoreductase, EC 1.6.99.3] was responsible for the reduction of doxorubicin at this site. In heart cytosol, anthracycline-induced superoxide formation and oxygen consumption required NADH and were significantly reduced by allopurinol, a potent inhibitor of xanthine oxidase (xanthine:oxygen oxidoreductase, EC 1.2.3.2). Reactive oxygen production was detected in all of our studies despite the presence of both superoxide dismutase (superoxide:superoxide oxidoreductase, EC 1.15.1.1) and glutathione peroxidase (glutathione:hydrogen peroxide oxidoreductase, EC 1.11.1.9) in each cardiac fraction. These results suggest that free radical formation by the anthracycline antitumor agents, which occurs in the same myocardial compartments that are subject to drug-induced tissue injury, may damage the heart by exceeding the oxygen radical detoxifying capacity of cardiac mitochondria and sarcoplasmic reticulum.
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PMID:Effect of anthracycline antibiotics on oxygen radical formation in rat heart. 629 97

Purified ferredoxin-(cytochrome c)-NADP+ oxidoreductase and xanthine oxidase were found to catalyse the reduction of nitrofurantoin to the free radical. Under aerobic conditions, the nitrofurantoin radical underwent autoxidation to regenerate the parent compound with the concomitant production of superoxide and eventually hydrogen peroxide. The nitrofurantoin radical was also shown to react with hydrogen peroxide to generate a highly reactive species which was capable of oxidising methionine to ethylene. This active oxygen radical appeared to be identical with the crypto-OH . radical, previously proposed as being formed from the analogous reaction of the methyl viologen radical with hydrogen peroxide [R.J. Youngman and E.F. Elstner, FEBS Lett. 129, 265 (1981)]. Catalase inhibited nitrofurantoin-dependent ethylene formation in both enzyme systems, whereas superoxide dismutase was only inhibitory in the xanthine oxidase mediated reaction. Although the primary function of the respective enzyme systems is to generate the nitrofurantoin radical, the xanthine oxidase reaction is markedly more complex than that of ferredoxin-(cytochrome c)-NADP+ oxidoreductase. The differences between the two enzyme reactions appear to be due to the endogenous autoxidation of xanthine oxidase. The aerobic activation of nitrofurantoin by xanthine oxidase involved the superoxide anion as an intermediate, whereas the nitrofuran was directly reduced by ferredoxin-(cytochrome c)-NADP+ oxidoreductase without a requirement for active oxygen species.
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PMID:Mechanisms of oxygen activation by nitrofurantoin and relevance to its toxicity. 629 96

Uninduced rat liver microsomes and NADPH-Cytochrome P-450 reductase, purified from phenobarbital-treated rats, catalyzed an NADPH-dependent oxidation of hydroxyl radical scavenging agents. This oxidation was not stimulated by the addition of ferric ammonium sulfate, ferric citrate, or ferric-adenine nucleotide (AMP, ADP, ATP) chelates. Striking stimulation was observed when ferric-EDTA or ferric-diethylenetriamine pentaacetic acid (DTPA) was added. The iron-EDTA and iron-DTPA chelates, but not unchelated iron, iron-citrate or iron-nucleotide chelates, stimulated the oxidation of NADPH by the reductase in the absence as well as in the presence of phenobarbital-inducible cytochrome P-450. Thus, the iron chelates which promoted NADPH oxidation by the reductase were the only chelates which stimulated oxidation of hydroxyl radical scavengers by reductase and microsomes. The oxidation of aminopyrine, a typical drug substrate, was slightly stimulated by the addition of iron-EDTA or iron-DTPA to the microsomes. Catalase inhibited potently the oxidation of scavengers under all conditions, suggesting that H2O2 was the precursor of the hydroxyl radical in these systems. Very high amounts of superoxide dismutase had little effect on the iron-EDTA-stimulated rate of scavenger oxidation, whereas the iron-DTPA-stimulated rate was inhibited by 30 or 50% in microsomes or reductase, respectively. This suggests that the iron-EDTA and iron-DTPA chelates can be reduced directly by the reductase to the ferrous chelates, which subsequently interact with H2O2 in a Fenton-type reaction. Results with the reductase and microsomal systems should be contrasted with results found when the oxidation of hypoxanthine by xanthine oxidase was utilized to catalyze the production of hydroxyl radicals. In the xanthine oxidase system, ferric-ATP and -DTPA stimulated oxidation of scavengers by six- to eightfold, while ferric-EDTA stimulated 25-fold. Ferric-desferrioxamine consistently was inhibitory. Superoxide dismutase produced 79 to 86% inhibition in the absence or presence of iron, indicating an iron-catalyzed Haber-Weiss-type of reaction was responsible for oxidation of scavengers by the xanthine oxidase system. These results indicate that the ability of iron to promote hydroxyl radical production and the role that superoxide plays as a reductant of iron depends on the nature of the system as well as the chelating agent employed.
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PMID:The role of iron chelates in hydroxyl radical production by rat liver microsomes, NADPH-cytochrome P-450 reductase and xanthine oxidase. 633 21

During renal ischemia, ATP is degraded to hypoxanthine. When xanthine oxidase converts hypoxanthine to xanthine in the presence of molecular oxygen, superoxide radical (O-2) is generated. We studied the role of O-2 and its reduction product OH X in mediating renal injury after ischemia. Male Sprague-Dawley rats underwent right nephrectomy followed by 60 min of occlusion of the left renal artery. The O-2 scavenger superoxide dismutase (SOD) was given 8 min before clamping and before release of the renal artery clamp. Control rats received 5% dextrose instead. Plasma creatinine was lower in SOD treated rats: 1.5, 1.0, and 0.8 mg/dl vs. 2.5, 2.5, and 2.1 mg/dl at 24, 48, and 72 h postischemia. 24 h after ischemia inulin clearance was higher in SOD treated rats than in controls (399 vs. 185 microliter/min). Renal blood flow, measured after ischemia plus 15 min of reflow, was also greater in SOD treated than in control rats. Furthermore, tubular injury, judged histologically in perfusion fixed specimens, was less in SOD treated rats. Rats given SOD inactivated by prior incubation with diethyldithiocarbamate had plasma creatinine values no different from those of control rats. The OH X scavenger dimethylthiourea (DMTU) was given before renal artery occlusion. DMTU treated rats had lower plasma creatinine than did controls: 1.7, 1.7, and 1.3 mg/dl vs. 3.2, 2.2, and 2.4 mg/dl at 24, 48, and 72 h postischemia. Neither SOD nor DMTU caused an increase in renal blood flow, urine flow rate, or solute excretion in normal rats. The xanthine oxidase inhibitor allopurinol was given before ischemia to prevent the generation of oxygen free radicals. Plasma creatinine was lower in allopurinol treated rats: 2.7, 2.2, and 1.4 mg/dl vs. 3.6, 3.5, and 2.3 mg/dl at 24, 48, and 72 h postischemia. Catalase treatment did not protect against renal ischemia, perhaps because its large size limits glomerular filtration and access to the tubular lumen. Superoxide-mediated lipid peroxidation was studied after renal ischemia. 60 min of ischemia did not increase the renal content of the lipid peroxide malondialdehyde, whereas ischemia plus 15 min reflow resulted in a large increase in kidney lipid peroxides. Treatment with SOD before renal ischemia prevented the reflow-induced increase in lipid peroxidation in renal cortical mitochondria but not in crude cortical homogenates. In summary, the oxygen free radical scavengers SOD and DMTU, and allopurinol, which inhibits free radical generation, protected renal function after ischemia. Reperfusion after ischemia resulted in lipid peroxidation; SOD decreased lipid peroxidation in cortical mitochondria after renal ischemia and reflow. We concluded that restoration of oxygen supply to ischemic kidney results in the production of oxygen free radicals, which causes renal injury by lipid peroxidation.
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PMID:Oxygen free radicals in ischemic acute renal failure in the rat. 643 91

Polymorphonuclear leukocytes and other inflammatory cells release superoxide anion and additional oxidant species following stimulation. Corneal endothelial cells were exposed to a flux of chemically generated superoxide anion (oxygen-free radical) produced by the combination of 1 mM hypoxanthine and 0.06 U/ml xanthine oxidase. Exposure of endothelial cells to the combination of hypoxanthine and xanthine oxidase resulted in anatomic disruption of the cells with interference in the function of endothelial water movement and resultant swelling of the corneal stroma. Catalase reduced the corneal swelling caused by exposure of endothelium to the oxygen-free radical generating system, whereas superoxide dismutase, ascorbic acid, D-mannitol, and ethanol did not prevent damage. The data suggest that hydrogen peroxide produced during the dismutation reaction of the superoxide anion is one of the toxic species, whereas the superoxide anion itself and the hydroxyl-free radical probably do not participate. The data suggest that corneal endothelial cells are susceptible to physiologic and anatomic damage induced by the products of reactive oxygen species, which, from previous studies, are known to be generated by inflammatory cells. The development of therapeutic modalities directed at the prevention of damage produced by hydrogen peroxide and other oxidant species may be of benefit in reducing corneal endothelial cell damage secondary to ocular inflammatory disease processes.
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PMID:Hydrogen peroxide-mediated corneal endothelial damage. Induction by oxygen free radical. 643 89

We have studied the effect of oxidant stress on the lymphocyte membrane and lymphocyte functions. Lymphocyte cultures were incubated with xanthine oxidase and xanthine, an enzyme system known to generate several highly reactive oxygen compounds. We demonstrated that these lymphocytes were viable after exposure to an in vitro oxidant stress. However, there was a marked reduction in their ability to bind SRBCs and to form caps after Con A stimulation. These lymphocytes also demonstrated a delay in PHA-induced LBT, with maximal response occurring at 5 days instead of 3 days. Catalase, a hydrogen peroxide scavenger, protected lymphocytes from this injury, implicating hydrogen peroxide as the causative agent. Another lymphocyte membrane-related function, the ability to stimulate or respond in MLC, was not impaired after oxidant injury. These results demonstrate that after in vitro oxidant injury, lymphocytes may have alterations in the cell membrane and impaired function.
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PMID:The effect of oxidant injury on the lymphocyte membrane and functions. 645 85

The murine malaria parasite Plasmodium yoelii was killed in vitro when incubated with glucose and glucose oxidase, a system generating hydrogen peroxide, or with xanthine and xanthine oxidase, a system which produces the superoxide anion and subsequently other products of the oxidative burst. Catalase blocked the killing in both cases; superoxide dismutase and scavengers of hydroxyl radicals or singlet oxygen were ineffective in the xanthine oxidase system. Thus, hydrogen peroxide appears to be the main reactive oxygen species killing P. yoelii.
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PMID:Killing of Plasmodium yoelii by enzyme-induced products of the oxidative burst. 654 75

Mechanisms of H2O2-induced cell injury were explored in primary cultures of rat hepatocytes. Cells prepared from male rats and cultured for 1 day prior to treatment were killed by H2O2 either added directly to the medium at 0.25-2 mM or generated in situ by glucose oxidase (0.25-2 U/ml) or xanthine oxidase (20-120 mM/ml) and 2 mM xanthine. Catalase protected the cells in each case. Lipid peroxidation as measured by the accumulation of malondialdehyde (MDA) preceded the cell death due to H2O2 added directly to the cultures or generated in the medium. The antioxidants N,N'-diphenyl-p-phenylenediamine (DPPD) and promethazine prevented the accumulation of MDA in both cases and protected the cells treated with H2O2 directly. DPPD and promethazine did not react directly with H2O2. Other antioxidants including butylated hydroxytoluene, vitamin E, and N-propylgallate had varied protective activity against the addition of H2O2 in proportion to their ability to reduce MDA accumulation. In glucose oxidase-treated cultures, DPPD and promethazine prevented the cell killing during the first hour but failed to protect between 1 and 3 h despite prevention of lipid peroxidation. The cell killing between 1 and 3 h in the presence of DPPD was prevented by catalase indicating its dependence upon continued generation of H2O2. Further addition of H2O2 in the presence of DPPD also increased the number of dead cells without lipid peroxidation. The data are consistent with at least two mechanisms of hepatocyte killing by H2O2. The first pathway is prevented by the antioxidants DPPD and promethazine and is very likely related to the peroxidation of membrane phospholipids. The second is independent of lipid peroxidation yet dependent upon the continued presence of H2O2.
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PMID:Mechanisms of the killing of cultured hepatocytes by hydrogen peroxide. 669 41

Experiments were carried out to determine if the difference in rates of cell proliferation between normal and neoplastic cells may be related to altered levels of oxidative enzymes. Assays were performed using homogenates from hepatocellular carcinoma HC-252, a rapidly growing and moderately well-differentiated tumor; from normal liver; and from the liver of the tumor-bearing ACI rat. Results of the mitochondrial enzymes indicated that the activities of cytochrome oxidase and succinate dehydrogenase were 3-fold lower in tumor homogenates than in liver homogenates. Monoamine oxidase activity could not be detected in HC-252; mixing experiments indicated no inhibitor was present in HC-252. Activities of th peroxisomal enzymes, urate oxidase, D-amino acid oxidase, and L-alpha-hydroxy acid oxidase were either undetected in the tumor or were 12-fold lower than in liver homogenates. The activity of xanthine oxidase, a cytoplasmic enzyme, was 5- to 6-fold lower in the tumor. Catalase activity in the tumor was also lower than in liver; this may be indicative of a lower oxidative environment at the cellular level. These enzyme activities of the liver of tumor-bearing rats were in the same range as those of normal rat liver, except that D-amino acid oxidase activity was slightly lower, and catalase activity was markedly lower and varied in a wide range. These results show an inverse correlation between the activities of oxygen-utilizing enzymes and rates of proliferation of one tumor line and its control. The possible implications of these results in neoplasia, cell proliferation, and cellular aging are discussed.
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PMID:Oxidoreductase activities in normal rat liver, tumor-bearing rat liver, and hepatoma HC-252. 689 80

This study demonstrates that the promastigote form of virulent Leishmania donovani and Leishmania tropica are both deficient in endogenous enzymatic scavengers of H(2)0(2) (catalase, glutathione peroxidase) and susceptible to low fluxes of H(2)O(2) in a cell-free model. In addition, the killing of promastigotes by H(2)0(2) is markedly enhanced in the presence of a peroxidase and halide. Promastigotes also readily trigger the macrophage oxidative burst including the generation of H(2)0(2), and most intracellular promastigotes are killed within 18 h by unstimulated normal resident cells. Catalase, but not scavengers or quenchers of O(2)(-), OHx, or (1)O(2), protected promastigotes in a cell-free xanthine oxidase microbicidal system, and catalase also partially inhibited the leishmanicidal activity of resident macrophages. Thus, amongst various oxygen intermediates, H(2)0(2) alone appeared to be both necessary and sufficient for promastigote killing. Depriving macrophages of exogenous glucose, which inhibits the generation of oxygen intermediates, achieved effects similar to catalase treatment. These observations directly contrast with the intracellular parasite, T. gondii which is richly endowed with catalase and glutathione peroxidase, highly resistant to H(2)0(2), and requires products of O(2)(-)-H(2)0(2) interaction for effective oxidative killing. Toxoplasmas also fail to trigger the respiratory burst of normal macrophages, and readily multiply within these cells (1-5). Macrophages first activated by in vivo or in vitro immunologic stimuli, however, display an enhanced capacity to generate oxygen intermediates beyond O(2)(-) and H(2)0(2), and are able to kill toxoplasmas or inhibit their intracellular replication (1, 2). These studies illustrate the wide spectrum of susceptibility to oxidative products which appears to exist for virulent intracellular protozoans, and indicate that such differences may be reflected in contrasting fates of parasites within cell-free oxidative environments and the cytoplasm of normal resident macrophages. In addition, these observations also demonstrate that nonactivated phagocytes may display effective microbicidal activity against certain intracellular pathogens utilizing an oxygen-dependent mechanism.
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PMID:Susceptibility of Leishmania to oxygen intermediates and killing by normal macrophages. 725 18


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