Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Current dogma associates reperfusion injury with the introduction of reactive oxygen species (ROS) into the ischemic tissue. The sources of ROS under discussion are xanthine oxidase in the endothelium of small vessels and/or invaded polymorphonuclear leukocytes (PMN). The beneficial effects of both superoxide dismutase and catalase suggest an involvement of superoxide anions and hydrogen peroxide in this pathophysiological process, without describing the targets of their action. In our work we demonstrate that these two ROS effectively interact with two enzymes. Superoxide anions inhibit soluble guanylate cyclase. Its product, cGMP, is considered to antagonize platelet activation and to cause smooth muscle relaxation. Thus O2- can intensify platelet aggregability and small vessel occlusion. Similar effects are elicited by H2O2, which shifts the dose response curve of several agonists towards smaller concentrations by activating cyclooxygenase. This enzyme provides the substrate for thromboxane synthase which generates TxA2, the most potent physiologically occurring platelet aggregating and smooth muscle contacting agonist. These results lead us to the suggestion that the influence of the oxidative burst of PMN in the phenomenon of reperfusion injury should be reconsidered.
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PMID:Physiological targets of superoxide anion and hydrogen peroxide in reperfusion injury. 257 64

Incubation of a number of ferric ion chelates with H2O2 at pH 7.4 generated a reactive species able to produce chemical modifications of the bases in DNA that are very similar to those produced in DNA by the hypoxanthine/xanthine oxidase system (Aruoma, O.I., Halliwell, B., and Dizdaroglu, M. (1989) J. Biol. Chem. 264, 13024-13028). Products were identified and quantitated by the use of gas chromatography-mass spectrometry with selected-ion monitoring. Compared with other complexes used, ferric ion-nitrilotriacetic acid produced by far the largest amount of the base products. Typical hydroxyl radical scavengers and superoxide dismutase provided significant decreases in the yields of the products. On this basis, it is proposed that ferric ion complexes react with H2O2 to produce hydroxyl radical; this was also shown using the deoxyribose assay. Inhibition of product formation by superoxide dismutase suggests the involvement of superoxide radical in this reaction. It is likely that hydroxyl radical generated by reaction of the ferric ion-nitrilotriacetic acid complex with H2O2 contributes to the carcinogenicity and nephrotoxicity associated with this chelating agent.
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PMID:Damage to the bases in DNA induced by hydrogen peroxide and ferric ion chelates. 258 27

The mono-electronic reduction of oxygen in the hypoxanthine-xanthine oxidase system led to the formation of active species eliciting an evident and highly reproducible mutagenic response in strain TA104 of S. typhimurium. Similar effects were observed by generating oxy radicals either extracellularly or inside bacterial cells. Mutagenicity was selectively detected in TA104 and not in other Salmonella strains, which points out the importance of the hisG428 mutation and of the deletion excising the uvrB gene, as far as sensitivity to oxy radicals is concerned. The mutagenicity of the system was further enhanced in the presence of superoxide dismutase. Catalase did not affect the mutagenicity of hypoxanthine plus xanthine oxidase, whereas it inhibited the mutagenicity induced by the mixture of hypoxanthine with xanthine oxidase and superoxide dismutase. This demonstrates that not only hydrogen peroxide but also the superoxide radical anion is positive in this system. Glutathione and 2 synthetic thiols, i.e., N-acetylcysteine and alpha-mercaptopropionylglycine, besides decreasing the high spontaneous mutagenicity of TA104, efficiently prevented the mutagenicity of active oxygen species.
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PMID:Mutagenicity of active oxygen species in bacteria and its enzymatic or chemical inhibition. 267 96

Although oxygen has been known to be toxic for more than 200 years, the clinical importance of oxygen toxicity was not appreciated until an epidemic of retrolental fibroplasia occurred in the early 1950s. Oxygen at high partial pressures is toxic to the respiratory, cardiovascular, nervous, and gastrointestinal systems. Toxicity results from the formation of oxygen-free radicals. These arise within mitochondria as oxygen is reduced to water, as byproducts of prostaglandin and thromboxane synthesis, and by the xanthine oxidase catalyzed reduction of xanthine or hypoxanthine. They are also produced by activated macrophages as part of the immune response. Superoxide anion is the radical most commonly produced. It dismutes to hydrogen peroxide, which is able to diffuse through lipid membranes. Hydrogen peroxide reacts with transition metals to produce the highly reactive hydroxyl radical which can initiate chain reactions of lipid peroxidation leading to cell rupture. Oxygen radical scavengers such as superoxide dismutase and catalase protect the body against normal levels of oxygen-free radicals. Oxygen toxicity can result from either reperfusion of ischemic tissue or prolonged exposure to high concentrations of oxygen. Limiting hyperoxia to maintain arterial oxygen percent saturation (SaO2) greater than or equal to 90% is recommended.
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PMID:Oxygen toxicity: an introduction. 267 91

Three lipophilic, membrane-active "stabilizing agents," cepharanthine, chlorpromazine, and trifluoperazine, were found to protect myocardial membrane phospholipid from peroxidative injury. The compounds prevented, in a concentration-dependent manner, the cardiac phospholipid peroxidation which resulted from lipid exposure to superoxide-dependent, iron-promoted oxygen-radical chemistry of the type thought to be a causative factor in ischemic-reperfusion tissue damage. Chlorpromazine's antiperoxidant IC50 (i.e., concentration at which peroxidation was inhibited by 50%) was 180 microM; the antiperoxidant potencies of cepharanthine (IC50 = 90 microM) and trifluoperazine (IC 50 = 100 microM) were some two-fold greater. These agents, at effective antiperoxidant concentrations, did not inhibit the enzymatic superoxide source, xanthine oxidase, scavenge superoxide radical, or act like a chain-breaking antioxidant. The data raise a possibility that the these three membrane-active compounds, as lipophilic anesthetics, may exert antiperoxidant effects by inducing structural changes in the lipid-rich (membrane or liposome) target of free radical attack.
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PMID:Prevention of oxidative injury to cardiac phospholipid by membrane-active "stabilizing agents". 271 Oct 24

Ischemia-reperfusion injury has been associated with intracellular H2O2 and superoxide radical production from accumulated hypoxanthine (HX) and xanthine oxidase (XO). The effect of H2O2 and superoxide radical on mitochondrial Ca2+ efflux was characterized in isolated renal mitochondria using a HX-XO system. Mitochondria were suspended in buffered medium containing 200 microM HX. Extramitochondrial Ca2+ was monitored kinetically at 660-685 nm using the Ca2+ indicator arsenazo III. After preloading mitochondria with 18-25 nmol Ca2+/mg protein, addition of XO to the medium caused a rapid oxidation of mitochondrial NAD(P)H followed by Ca2+ release. Ca2+ efflux was attributed to mitochondrial metabolism of H2O2 because efflux could be prevented with catalase but not superoxide dismutase. The Ca2+ efflux rate (r = 0.995) and lag time to Ca2+ efflux (r = 0.987) both correlate well with the NAD(P)H oxidation rate. Exogenous ATP prevents Ca2+ efflux in a dose-dependent fashion (Km = 35 microM ATP) without affecting NAD(P)H oxidation; ATP plus oligomycin, however, had no effect. The protective effect of ATP on Ca2+ efflux was diminished by ruthenium red (RR). XO-induced Ca2+ efflux increased state 4 respiration 148% via a futile Ca2+ cycle involving the Ca2+ uniport. The increase in state 4 respiration could be reversed with RR (alpha less than 0.001) or ATP (alpha less than 0.01); ATP plus oligomycin, however, had no effect. The results are discussed in relation to the oxygen free radical theory of reperfusion injury.
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PMID:Potential role of mitochondrial calcium metabolism during reperfusion injury. 273 95

Superoxide anion (O2-) generated from xanthine oxidase/xanthine has been used to decrease the half life of endothelium derived relaxing factor (EDRF). However, by itself, xanthine oxidase causes endothelium dependent relaxation. This relaxation is unrelated to the oxidative property of the enzyme since it is not inhibited by allopurinol. In addition, the relaxation is not inhibited by the cyclooxygenase inhibitor, indomethacin, or the phospholipase A2 inhibitor, p-bromophenacyl bromide. On the other hand the relaxation is inhibited by the trypsin inhibitor (TI) from chicken egg white. A similar endothelium dependent relaxation elicited by pancreatin and trypsin is also inhibited by TI. Pancreatin used in the preparation of xanthine oxidase contains trypsin, chymotrypsin and carboxypeptidase. When compared to trypsin both chymotrypsin and carboxypeptidase elicit little relaxation. Thus the endothelium dependent relaxation elicited by xanthine oxidase is likely due to contamination with trypsin. Our results emphasize that when the superoxide generating system, xanthine oxidase/xanthine is used to study the effect of oxygen radicals on EDRF, it is advantageous to ensure that only purified preparations of xanthine oxidase are used.
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PMID:Xanthine oxidase and endothelium dependent relaxation. 282 Apr 11

In eucaryotic cells, immature mRNA is normally restricted to the nucleus, where it is posttranscriptionally processed to mature mRNA. The intranuclear binding site for both the immature and mature mRNA is thought to be the nuclear matrix which serves as a platform for posttranscriptional RNA maturation and transport. The selectivity of nucleocytoplasmic transport for mature mRNA species seems to be due to the selectivity of the ATP-caused release of mature mRNA from the nuclear matrix; the attachment of immature mRNA to the matrix is not altered in the presence of this nucleotide. Here we show that in the presence of superoxide radical anions (O2-), which are very likely one of the causative factors in ageing, the selection mechanism for mature mRNA at the level of nuclear matrix attachment is disturbed. In the presence of a superoxide radical-generating system (xanthine/xanthine oxidase), both the mature ovalbumin mRNA and the immature ovalbumin mRNA precursors were found to be released from the nuclear matrix of hen oviduct cells, in the absence as well as in the presence of ATP. This result was also obtained when whole, isolated nuclei preincubated with xanthine/xanthine oxidase were used. The superoxide radical-caused effect could be partially prevented by co-addition of superoxide dismutase (SOD) which dismutates O2- to H2O2 and O2. On the other hand, in the presence of antibodies against the SOD, the effect of superoxide anions on RNA-matrix attachment was enhanced and its inhibition by SOD was abolished. Our results suggest that cellular ageing may be partially caused by superoxide radical-induced release of immature mRNA from its intranuclear binding site resulting in the appearance of immature messengers in the cytoplasm. This may cause both qualitative and quantitative changes in protein synthesis. Thus, ageing may be associated not only with the expression of genes coding for proteins not characteristic for the proper state of differentiation of a given cell (as suggested by the dysdifferentiative hypothesis of ageing) but also with impaired maturation of the primary gene transcripts due to the interference of superoxide radicals, not sufficiently eliminated by antioxidant mechanisms with age, with RNA-matrix attachment.
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PMID:Superoxide radical-induced loss of nuclear restriction of immature mRNA: a possible cause for ageing. 282 75

A recent study of the mechanism by which oxypurinol inhibits uric acid generation [T. Spector, W. W. Hall and T. A. Krenitsky, Biochem. Pharmac. 35, 3109(1986)] showed that xanthine is ineffective in impeding the binding of oxypurinol to reduced xanthine oxidase. This study prompted the present hypothesis that, at elevated concentrations of substrates, oxypurinol would be superior to allopurinol as an inhibitor of the xanthine oxidase-catalyzed production of superoxide radical. It was found that the potency of allopurinol was attenuated by elevated concentrations of xanthine and hypoxanthine, whereas the potency of oxypurinol was relatively unaffected. Oxypurinol produced immediate inhibition of superoxide radical production as well as progressive inhibition with time. In contrast, allopurinol, which is also a substrate for xanthine oxidase, produced very little immediate inhibition and caused progressive inhibition only after conversion to oxypurinol. The theoretical advantages of treating ischemic tissues with oxypurinol are discussed.
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PMID:Oxypurinol as an inhibitor of xanthine oxidase-catalyzed production of superoxide radical. 282 16

Seven flavonoids and three non-flavonoid antioxidants, i.e. butylated hydroxyanisole, chlorpromazine and BW 755 C, were studied as potential scavengers of oxygen free radicals. Superoxide anions were generated enzymatically in a xanthine-xanthine oxidase system and non-enzymatically in a phenazine methosulphate-NADH system, and assayed by reduction of nitro blue tetrazolium. The generation of malonaldehyde (MDA) by the ascorbate-stimulated air-oxidised boiled rat liver microsomes was considered as an index of the non-enzymatic formation of hydroxyl radicals. Flavonoids but not non-flavonoid antioxidants lowered the concentration of detectable superoxide anions in both enzymic and non-enzymic systems which generated these SOD-sensitive radicals. The most effective inhibitors of superoxide anions were quercetin, myricetin and rutin. Four out of seven investigated flavonoids seemed also to suppress the activity of xanthine oxidase as measured by a decrease in uric acid biosynthesis. All ten investigated compounds inhibited the MDA formation by rat liver microsomes. Non-flavonoid antioxidants were more potent MDA inhibitors than flavonoids. It is concluded that antioxidant properties of flavonoids are effected mainly via scavenging of superoxide anions whereas non-flavonoid antioxidants act on further links of free radical chain reactions, most likely by scavenging of hydroxyl radicals.
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PMID:Flavonoids are scavengers of superoxide anions. 283 Aug 82


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