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:1.17.3.2 (xanthine oxidase)
8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Xanthine oxidase is able to mobilize iron from ferritin. This mobilization can be blocked by 70% by superoxide dismutase, indicating that part of its action is mediated by superoxide (O2-). Uric acid induced the release of ferritin iron at concentrations normally found in serum. The O2(-)-independent mobilization of ferritin iron by xanthine oxidase cannot be attributed to uric acid, because uricase did not influence the O2(-)-independent part and acetaldehyde, a substrate for xanthine oxidase, also revealed an O2(-)-independent part, although no uric acid was produced. Presumably the amount of uric acid produced by xanthine oxidase and xanthine is insufficient to release a measurable amount of iron from ferritin. The liberation of iron from ferritin by xanthine oxidase has important consequences in ischaemia and inflammation. In these circumstances xanthine oxidase, formed from xanthine dehydrogenase, will stimulate the formation of a non-protein-bound iron pool, and the O2(-)-produced by xanthine oxidase, or granulocytes, will be converted by 'free' iron into much more highly toxic oxygen species such as hydroxyl radicals (OH.), exacerbating the tissue damage.
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PMID:Superoxide-dependent and -independent mechanisms of iron mobilization from ferritin by xanthine oxidase. Implications for oxygen-free-radical-induced tissue destruction during ischaemia and inflammation. 302 67

Evidence in alcoholics as well as in experimental models support the role of hepatic lipid peroxidation in the pathogenesis of alcohol-induced liver injury, but the mechanism of this injury is not fully delineated. Previous studies of the metabolism of ethanol by alcohol dehydrogenase revealed iron mobilization from ferritin that was markedly stimulated by superoxide radical generation by xanthine oxidase. Peroxidation of hepatic lipid membranes (assessed as malondialdehyde production) was studied during in vitro alcohol metabolism by alcohol dehydrogenase. Peroxidation was initiated by acetaldehyde-xanthine oxidase, stimulated by ferritin, and inhibited by superoxide dismutase or chelation or iron with desferrioxamine. In conclusion, lipid peroxidation may be initiated during the metabolism of ethanol by alcohol dehydrogenase by an iron-dependent acetaldehyde-xanthine oxidase mechanism.
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PMID:Acetaldehyde-mediated hepatic lipid peroxidation: role of superoxide and ferritin. 303 92

Mobilization of iron from ferritin by xanthine oxidase was studied under aerobic and anaerobic conditions. Aerobic iron release amounted to approx. 3.7 nmol/ml in 10 min. This amount was decreased by approx. 30% under anaerobic conditions. Aerobic iron mobilization involved two mechanisms. About 70% was released by O2.- generated by xanthine oxidase. The rest was released by O2(.-)-independent mechanisms, which also accounted for the total iron release when O2 was absent. A possible transfer of reducing equivalents directly from xanthine oxidase to ferritin is discussed. The results imply that, in pathological conditions with increased formation of O2.-, iron may be released from ferritin. Furthermore, in hypoxic tissues xanthine oxidase can release iron from ferritin by an O2(.-)-independent process. Free iron is liable to catalyse the formation of the extremely reactive and damaging OH. radical.
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PMID:Release of iron from ferritin by xanthine oxidase. Role of the superoxide radical. 303 86

Lipid peroxidation has been invoked as a mechanism of alcoholic liver injury but its role has been controversial and the mechanism by which it occurs is unclear. Catalytic iron is known to play an important role in cellular injury and is produced during mobilization of ferritin iron. In vivo administration of a large acute dose of ethanol (5 g/kg) which produces hepatic lipid peroxidation in chow-fed rats resulted in mobilization of non-heme iron. The generation of NADH from alcohol metabolism via ADH or superoxide from acetaldehyde-xanthine oxidase mobilized iron from horse spleen ferritin in vitro. Chronic feeding of alcohol as 36% of energy for 6 weeks does not itself produce peroxidation in the rat but potentiates acute effects of ethanol. It produced microsomal induction which enhanced iron-stimulated lipid peroxidation and increased hepatic non-heme iron. Carbon monoxide increased rather than decreased accumulation of microsomal peroxidation products in vitro suggesting that cytochrome P-450 reductase mediates peroxidation but cytochrome P-450 may metabolize products. Incubation at lowered oxygen tensions equivalent to those observed in the perivenular zone (pO2 = 24 mmHg) enhanced in vitro iron mobilization but decreased peroxidation. Lipid peroxidation and its stimulation by iron mobilization and microsomal induction may be an important contributory mechanism of alcohol-induced liver injury.
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PMID:Lipid peroxidation as a mechanism of alcoholic liver injury: role of iron mobilization and microsomal induction. 313 9

Compelling evidence has been accumulated which indicates that myocardial tissue damage occurring during reperfusion after an ischaemic period may partly be due to the formation of oxygen free radicals and subsequent peroxidative processes. It has been well established that the actual toxicity of free radicals is dependent on the presence of free iron in the heart tissue. Based upon the hypothesis of McCord et al., proposing xanthine oxidase mediated formation of superoxide (O2-.) during the conversion of ATP-breakdown product(s) (hypo)xanthine to urate, we studied whether xanthine oxidase was able to mobilize free iron from the intra- and extracellular iron-binding proteins, ferritin and transferrin. It appeared that there was an O2-.-dependent and O2-.-independent mechanism by which xanthine oxidase could mobilize iron from ferritin while no iron mobilization from transferrin was detectable. The capacity of xanthine oxidase to mobilize iron from ferritin by an O2-.-independent mechanism implies that already during the anoxic/ischaemic period, iron may become available in the tissue which, upon the re-entrance of O2, catalyzes the formation of the very reactive OH radicals. The interaction between endothelial cells and cardiocytes in free radical homeostasis is discussed with the emphasis on the tissue localization of xanthine oxidase. The latter is located in endothelial cells implying an interaction between xanthine oxidase-induced endothelial cells initiated lipid peroxidation and the actual overall myocardial tissue damage.
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PMID:Lipid peroxidation and myocardial ischaemic damage: cause or consequence? 331 Oct 8

Oxygen free radicals generated by xanthine oxidase are able to depolymerize hyaluronic acid in the presence of ferritin-bound iron. This suggests that ferritin can catalyse the Haber-Weiss reaction, leading to the formation of highly damaging hydroxyl radicals.
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PMID:Xanthine oxidase induced depolymerization of hyaluronic acid in the presence of ferritin. 609 41

Xanthine oxidase exhibits ferroxidase activity and previously has been shown to catalyze the oxidative incorporation of iron into apotransferrin, the iron transport protein of plasma. These studies demonstrate that xanthine oxidase also efficiently promotes the oxidative incorporation of iron into apoferritin, the major iron storage protein of vertebrates, and that the ferroxidase activity of intestinal xanthine oxidase could be important in determining the fraction of iron within the intestinal mucosa cell partitioned to ferritin versus the iron that remains in a transient pool for rapid transport to plasma.
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PMID:Xanthine oxidase: an efficient promoter of the iron loading of apoferritin. 795 Oct 57

Iron chelators have been reported to protect tissues against reperfusion injury. This implies that iron is being released into the plasma or is made accessible in tissues for oxidation-reduction reactions. It has been postulated that ferritin is a likely source for this iron. This report demonstrates that adrenergic agents with the catechol structure, which includes the endogenous catecholamines norepinephrine and epinephrine, are capable of releasing iron from ferritin. It is shown that the net release of iron from ferritin by epinephrine is significantly enhanced under anaerobic conditions. The findings suggest that catecholamines can mediate iron release from ferritin under conditions that can occur during ischemia/reperfusion. Catecholamines are also shown to interact with the released iron and xanthine oxidase to produce highly reactive hydroxyl radicals. The implications of this interaction for ischemia/reperfusion are discussed.
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PMID:Catechol adrenergic agents enhance hydroxyl radical generation in xanthine oxidase systems containing ferritin: implications for ischemia/reperfusion. 798 63

The influence of the superoxide-generating system, xanthine oxidase, on the release of iron from various vertebrate ferritins was determined both in the presence and absence of superoxide dismutase. The initial rate of iron release in the presence of this system was higher for ferritins from human, trout and rat liver than for those from lamprey liver and horse spleen. The proportion of this iron release that was superoxide-dependent in the case of rat, human and trout ferritins was 92, 86 and 84% respectively, whereas no such superoxide-dependent iron release occurred from the ferritins of lamprey liver and horse spleen. On the other hand, the rate of superoxide-independent iron release was of comparable magnitude for all of the species examined. The rate of superoxide-dependent iron release was related neither to the iron: protein ratios nor to the subunit size of the ferritins. However, it is significant that the ferritins with a high rate of superoxide-dependent iron release came from tissues known to be susceptible to iron damage. It is thus proposed that the resistance of lamprey liver ferritin to the mobilization of iron by superoxide ions accounts in part for the tolerance of the lamprey liver to high iron loads.
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PMID:Iron release from ferritin and its sensitivity to superoxide ions differs among vertebrates. 804 81

Cellular iron homeostasis is regulated by the cytoplasmic iron regulatory protein (IRP), which binds to iron-responsive elements (IRE) of mRNAs, modulating iron uptake and sequestration, respectively. When iron is scarce, IRP binds to IRE and coordinately increases the synthesis of transferrin receptor and decreases that of ferritin, thus providing the cell with readily available free iron. When iron is in excess, IRP does not bind and iron sequestration prevails over iron uptake. We have found that incubation of rat liver lysates with xanthine oxidase (XO), which generates superoxide (O2-.) and hydrogen peroxide (H2O2), caused a remarkable but reversible inhibition of IRP activity, as the formation of IRE-IRP decreased by 70-80% but returned to baseline values upon exposure to a reducing agent like 2-mercaptoethanol. IRP inhibition was prevented by separate or simultaneous addition of superoxide dismutase and catalase, showing that both O2-. and H2O2 were involved. By contrast, iron chelators and hydroxyl radical scavengers did not impede the inhibition of IRP, suggesting that O2-. and H2O2 acted independently of free iron sources. Ferritin enhanced IRP inhibition, but this process involved tightly bound iron centers that shunted reducing equivalents from XO and returned them to oxygen, thus increasing the formation of O2-. In agreement with the exclusive role of O2-. and H2O2, XO also inhibited recombinant human IRP in the absence of iron. These results demonstrate that O2-. and H2O2 can directly but reversibly down-regulate the RNA-binding activity of IRP, causing transient decrease of free iron that otherwise would convert them into more potent oxidants such as hydroxyl radicals or equally aggressive iron-peroxo complexes. This establishes a novel protective stratagem against oxidative injury under pathophysiologic conditions characterized by the excessive generation of O2-. and H2O2.
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PMID:Superoxide and hydrogen peroxide-dependent inhibition of iron regulatory protein activity: a protective stratagem against oxidative injury. 914 4


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