Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P47989 (xanthine oxidase)
 8,633 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron kinetics, absorption and storage were studied by means of 59Fe and deferoxamine (Desferal-Ciba) in eight patients with porphyria cutanea tarda at the time of clinical activity and after allopurinol treatment. At the time of clinical manifestations, a significant impairment of erythrocyte-iron turnover and of radio-iron utilization was demonstrable in a half of the patients and a significant increase in iron absorption and turnover in patients out of 8. The measurements of surface activity in vivo showed a significant increase in storage iron. This was confirmed by the excessive urinary excretion of deferoxamine-iron, attaining three- to four-fold figures of the normal values (251 +/- 85 mg). The increased absorption of iron coupled with an abnormal porphyrin metabolism is suggestive of a double genetic defect. As a result of allopurinol treatment, normalization of iron kinetics and a moderate decrease in iron storage were demonstrable. The abnormal excretion of uroporphyrin and coproporphyrin were also brought under control. The success of treatment is attributed to the inhibitory effect of allopurinol on xanthine oxidase.
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PMID:Iron metabolism and its responses to allopurinol treatment in porphyria cutanea tarda. 74 38

We investigated the peroxidative effect of paraquat and active oxygens on detergent-dispersed linolenic acid in phosphate buffer (pH 7.5) from the malondialdehyde (MDA) level. Our complete system and further inclusion of catalase were effective in stimulating MDA formation. On the other hand, xanthine oxidase (XOD) or paraquat omission, superoxide dismutase (SOD) inclusion or anaerobic incubation inhibited the formation of MDA. Ferrous ion was weakly associated with phosphate of the buffer, forming a complex, and the release of ferrous ion from the complex intensified the MDA levels with the complete and catalase inclusion systems. The electron paramagnetic resonance (EPR) spectra using 5,5-dimethyl-1-pyrroline N-oxide (DMPO) showed that superoxide, produced immediately after the addition of XOD, played a crucial role. We could obtain a DMPO-OOH signal at the starting stage whenever MDA stimulation was observed. The omission of paraquat, however, produced no increase in MDA level in spite of an appearance of DMPO-OOH signal, indicating that paraquat also plays an important role. On the other hand, Desferal, a ferric chelator, showed a concentration-dependent inhibition effect. There was an immediate strong intensity of DMPO-OOH and paraquat signals. We did not, however, observe MDA stimulation at 250 microM Desferal, which confirms that ferrous ion plays an essential role in the lipid peroxidation. These results indicate a combined action of paraquat (or its radical) and superoxide on the accessibility of ferrous ion, including its release from the complex with phosphate, which may be an endogenous chelator. The possibility of ternary complex participation is also discussed.
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PMID:Combined action of paraquat and superoxide on the peroxidation of detergent-dispersed linolenic acid. 132 74

Cardiac mitochondrial function as measured by oxidative phosphorylation is impaired by ischemia; and, this deteriorates even further on reperfusion of the heart. Free oxygen radicals, especially the formation of hydroxyl radicals via the iron-catalyzed Haber-Weiss and Fenton reactions have been implicated in the reperfusion injury. In this study, the effect of desferrioxamine (desferal) in the perfusate on mitochondrial function of isolated rat hearts during different periods of normothermic ischemic cardiac arrest (NICA), and subsequent reperfusion was investigated. Mitochondrial functions measured were the QO2 (state 3); ADP/O ratio and oxidative phosphorylation; the mitochondrial, loosely bound (chelateable) iron (LB-iron); the xanthine dehydrogenase and xanthine oxidase activities. Inclusion of desferal in the perfusion solution significantly improved mitochondrial function during the different NICA periods, and prevented the deterioration of mitochondrial function resulting from reperfusion. Desferal did not significantly affect the LB-iron content of the mitochondria or the ratio of xanthine dehydrogenase/xanthine oxidase activities in the mitochondria during NICA or reperfusion. Our experiments suggest that iron, which is free to be chelated by desferal, plays a role in this injury to the rat myocardium.
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PMID:The effect of desferal on rat heart mitochondrial function, iron content, and xanthine dehydrogenase/oxidase conversion during ischemia-reperfusion. 228 9

The role of iron-loaded transferrin in xanthine-xanthine oxidase (X-XO) induced cardiac injury in isolated perfused rat hearts was examined. X (2 mM) - XO (10 U/L) perfusion resulted in contractile failure, a rise in resting tension, an increase in lipid peroxidation, and myocardial cell damage. The addition of transferrin (2.4 microM) into the X-XO medium had a protective effect, as indicated by an increase in time to contractile failure, a lesser rise in resting tension, a decrease in MDA values, and lesser damage compared with the X-XO perfused controls. Ultrastructural studies revealed localization of transferrin along the capillary basement membrane. In contrast, addition of transferrin and Desferal (desferrioxamine mesylate, 3 mM, an iron chelator) into X-XO medium caused a rapid contractile failure as well as a rise in resting tension, and in these hearts transferrin was localized inside the myocytes. These findings suggest that a vascular supply of iron protein chelators may have a beneficial effect against myocardial cell injury caused by a vascular source of oxygen radicals.
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PMID:Transferrin delays oxygen radical induced cardiac-contractile failure. 232 50

Even when cytoplasmic scavenging activities are plentiful, yeast cells (S. cerevisiae) remain particularly sensitive towards reactive oxygen species generated in the extracellular space (either by the xanthine/xanthine oxidase reaction or by the redox cycling of menadione). A sharp reduction of the extent of cellular alterations when SOD and/or catalase were supplemented in the incubation buffer, points to a contribution of both O-.2 and H2O2 in the toxic process. Although oxygen metabolites as well as t-butylhydroperoxide (tBH), a highly toxic organic peroxide, may be directly responsible for cellular damage, their toxicity is largely reduced in the presence of Desferal. A role of metal ions in potentiating the toxicity points to the involvement of OH. radicals, actually produced in the medium. With tBH, metal cations would be rather active in promoting peroxidative chain reactions. In the case of an extracellular oxidative attack, it may be foreseen that the plasma membrane will form a preferential target. An increased permeability of the plasma membrane towards ionized molecules and uncharged polycarboxylic acids is indeed observed after an oxidative treatment. The loss of selective permeability is, as a rule, correlated with a drop in viability. Early alterations, disrupting the functional organization of the plasma membrane have been sought. The permease involved in the active transport of purine(s) has appeared to be an appropriate marker for checking its functional integrity. This transport function appears to be very sensitive to damage induced by O-.2 generators, particularly under conditions in which the resulting lethality is still kept low and in which the energization of active transport processes remains unimpaired.
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PMID:Sensitivity of yeast cells to reactive oxygen species generated in the extracellular space. 302 7

We evaluated whether supplemental pharmacologic interventions that altered formation or degradation of reactive oxygen metabolites, when added to hypothermic crystalloid cardioplegic solution (procaine-free St. Thomas' Hospital solution), alter postischemic function of isolated rabbit hearts. Hypoxic, substrate-free cardioplegic solutions cooled to 27 degrees C were perfused through isolated rabbit hearts for 5 minutes before and after an uninterrupted 2 hour period of global ischemia at 27 degrees C. Hearts were then reperfused with standard buffer for 1 hour at 37 degrees C. In some experiments, the cardioplegic solution was supplemented with the following: superoxide dismutase (30 micrograms/ml; degrades superoxide anion); catalase (1.7 micrograms/ml; degrades hydrogen peroxide); allopurinol (1 mmol/L; inhibits xanthine oxidase); or deferoxamine (Desferal, 0.5 mmol/L; selectively chelates ferric iron). Postreperfusion contractile parameters of supplemented hearts, including left ventricular pressure development and its first derivative, left ventricular compliance, spontaneous heart rate, and coronary vascular resistance, were statistically compared to data obtained from hearts arrested with unsupplemented cardioplegic solution. Catalase supplementation provided statistically significant improvement of most functional parameters; somewhat less protection was obtained with allopurinol. Deferoxamine provided little added protection except for the ability to prevent ischemia-induced increases of coronary vascular resistance. There was no evidence of added protection by superoxide dismutase. The data suggest that an important component of ischemia-induced cardiac cell damage in an asanguineous setting is hydrogen peroxide-dependent, and interventions that either inhibit production of superoxide anion or degrade hydrogen peroxide offer best protection. They may be clinically efficacious additives to crystalloid cardioplegic solutions.
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PMID:Effects of supplementing hypothermic crystalloid cardioplegic solution with catalase, superoxide dismutase, allopurinol, or deferoxamine on functional recovery of globally ischemic and reperfused isolated hearts. 394 95

The catalysis by iron of the formation of reactive oxygen species in biological systems has been well documented. In this present study, we have investigated the hypothesis that iron-catalyzed formation of hydroxyl radical (.OH) from superoxide anion radical (O-.2) and H2O2 requires the availability of at least one iron coordination site that is open or occupied by a readily dissociable ligand such as water. This hypothesis was tested by measuring the catalytic activity of 12 different iron chelates using hypoxanthine and xanthine oxidase to generate O-.2. In these same chelates, we also determined the presence or absence of coordinated water by UV-visible spectroscopy and 1H NMR relaxation measurements. Of all chelates tested, only Fe3+ coordinated to diethylenetriamine pentaacetic acid; ethylenediamine di(o-hydroxyphenylacetic acid), phytate, and Desferal lacked coordination water; and only these four complexes failed to produce hydroxyl radical. Separate determinations of the two redox half-reactions involved (i.e. Fe3+ + O-.2----Fe2+ + O2 and Fe2+ + H2O2----Fe3+ + .OH + OH-) indicate that an available coordination site is necessary for the latter (Fenton) reaction. This principle governing iron reactivity may help advance our understanding of the mechanism of oxidative damage in biological systems and may also permit the design of more effective chelators for the control of iron in biological systems.
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PMID:Iron-catalyzed hydroxyl radical formation. Stringent requirement for free iron coordination site. 632 33

The degree of DNA damage by the treatment with various molecular species of active oxygen and its inhibition by pretreatment with different scavengers were evaluated using pUC19 plasmid DNA. DNA damage caused by O2-. generated by xanthine-xanthine oxidase system (X-XOD), .OH by Fenton reactions, and OCl- by NaOCl involved the generation of open circle DNA demonstrating single strand breaks. Catalase (Cat), diethylenetriaminepentaacetic acid (DETAPAC), desferroxiamine (Desferal), dimethyl sulfoxide (DMSO) and ethanol (EtOH) all inhibited 60-80% of DNA damage by the generated O2-.. Superoxide dismutase (SOD) inhibited all DNA damages by O2-.. Cat, DETAPAC and Desferal effectively inhibited DNA break by .OH; complete inhibition of .OH-induced DNA break was achieved by addition of DMSO and EtOH. Desferal and EtOH completely inhibited DNA damage by OCl-. These findings suggested that metal ions are associated with the mechanism of DNA damage by all forms of active oxygen species.
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PMID:DNA damage by various forms of active oxygens and its inhibition by different scavengers using plasmid DNA. 783 95

The reaction of the antitumor drugs adriamycin and daunomycin with the self-complementary DNA oligonucleotide (GC)4 to generate DNA-drug adducts was investigated as a function of redox reaction conditions. The redox systems dithiothreitol (DTT)/Fe(III) and xanthine oxidase/ NADH both gave the same distribution of four DNA-anthracycline adducts. In each of these adducts the anthracycline is bonded via a methylene linkage between the 3'-amino group of the drug and the 2-amino group of a deoxyguanosine of the DNA. The methylene linkage results from reaction of the drug and DNA with in situ-generated formaldehyde via Schiff base chemistry [Taatjes, D.J., Gaudiano, G., Resing, K., and Koch, T.H. (1997) J. Med. Chem. 40, 1276-1286]. Formaldehyde production is promoted by iron, inhibited by metal-chelating agents, and does not require drug. Iron enhances formaldehyde production by a factor of 30, EDTA inhibits its formation by a factor of 2, and Desferal inhibits its formation by a factor of more than 20. Hydrogen peroxide accumulates in significant quantities only with xanthine oxidase/NADH in the presence of Desferal. The results are explained in terms of Fenton oxidation of Tris buffer to formaldehyde. Biological reagents also cause DNA-drug adduct formation; reduction of ferric ion with glutathione in phosphate buffer in the presence of spermine produced the same DNA-drug adducts. The observations are discussed in terms of cytotoxicity resulting from iron chelated to adriamycin catalyzing in vivo production of formaldehyde which links adriamycin to DNA and tumor cell resistance resulting from factors which decrease formaldehyde.
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PMID:Production of formaldehyde and DNA-adriamycin or DNA-daunomycin adducts, initiated through redox chemistry of dithiothreitol/iron, xanthine oxidase/NADH/iron, or glutathione/iron. 930 76

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


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