Release of iron from ferritin by xanthine oxidase. Role of the superoxide radical.
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ABSTRACT:
SUBMITTER: Bolann BJ
PROVIDER: S-EPMC1147813 | biostudies-other | 1987 Apr
REPOSITORIES: biostudies-other
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Project description: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.
| S-EPMC1147255 | biostudies-other
Project description:In this study, we evaluated the abilities of a series of chalcones to inhibit the activity of the enzyme xanthine oxidase (XO) and to scavenge radicals. 20 mono- and polyhydroxylated chalcone derivatives were synthesized by Claisen-Schmidt condensation reactions and then tested for inhibitory potency against XO, a known generator of reactive oxygen species (ROS). In parallel, the ability of the synthesized chalcones to scavenge a stable radical was determined. Structure-activity relationship analysis in conjunction with molecular docking indicated that the most active XO inhibitors carried a minimum of three hydroxyl groups. Moreover, the most effective radical scavengers had two neighboring hydroxyl groups on at least one of the two phenyl rings. Since it has been proposed previously that XO inhibition and radical scavenging could be useful properties for reduction of ROS-levels in tissue, we determined the chalcones' effects to rescue neurons subjected to ROS-induced stress created by the addition of β-amyloid peptide. Best protection was provided by chalcones that combined good inhibitory potency with high radical scavenging ability in a single molecule, an observation that points to a potential therapeutic value of this compound class.
| S-EPMC4738094 | biostudies-literature
Project description: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.
| S-EPMC1137092 | biostudies-other
Project description:The inhibitory effect of xanthine oxidase (XO) reactions with stilbene compounds, 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging by stilbene compounds and superoxide anion (O2-) scavenging activity were examined. The inhibition of the O2- generation catalyzed by XO by stilbene compounds is stronger than the effect on uric acid formation. The suppression of the O2- generation with resveratrol was diminished by the addition of flavin adenine dinucleotide (FAD). The water-solubility and visible spectra (VIS) of the stilbene compounds in the presence of water-soluble flavin compounds indicated a π-π interaction between the stilbene compounds and the isoalloxazine in flavin compounds. These results indicate that stilbene compounds specifically bind the FAD site in XO so as to inhibit the O2- generation. In the case of piceatannol, it is deduced that the suppression of O2- generation is induced by this specific binding to the FAD site and the subsequent reduction of XO.
| S-EPMC8566757 | biostudies-literature
Project description:Although folate deficiency and increased requirements for folate are observed in most alcoholics, the possibility that acetaldehyde generated from ethanol metabolism may increase folate catabolism has not been previously demonstrated. Folate cleavage was studied in vitro during the metabolism of acetaldehyde by xanthine oxidase, measured as the production of p-aminobenzoylglutamate from folate using h.p.l.c. Acetaldehyde/xanthine oxidase generated superoxide, which cleaved folates (5-methyltetrahydrofolate greater than folinic acid greater than folate) and was inhibited by superoxide dismutase. Cleavage was increased by addition of ferritin and inhibited by desferrioxamine (a tight chelator of iron), suggesting the importance of catalytic iron. Superoxide generated from the metabolism of ethanol to acetaldehyde in the presence of xanthine oxidase in vivo may contribute to the severity of folate deficiency in the alcoholic.
| S-EPMC1135567 | biostudies-other
Project description:Nitration of arachidonic acid (AA) to nitroarachidonic acid (AANO2) leads to anti-inflammatory intracellular activities during macrophage activation. However, less is known about the capacity of AANO2 to regulate the production of reactive oxygen species under proinflammatory conditions. One of the immediate responses upon macrophage activation involves the production of superoxide radical (O2(•-)) due to the NADPH-dependent univalent reduction of oxygen to O2(•-) by the phagocytic NADPH oxidase isoform (NOX2), the activity of NOX2 being the main source of O2(•-) in monocytes/macrophages. Because the NOX2 and AA pathways are connected, we propose that AANO2 can modulate macrophage activation by inhibiting O2(•-) formation by NOX2. When macrophages were activated in the presence of AANO2, a significant inhibition of NOX2 activity was observed as evaluated by cytochrome c reduction, luminol chemiluminescence, Amplex red fluorescence, and flow cytometry; this process also occurs under physiological mimic conditions within the phagosomes. AANO2 decreased O2(•-) production in a dose- (IC50=4.1±1.8 μM AANO2) and time-dependent manner. The observed inhibition was not due to a decreased phosphorylation of the cytosolic subunits (e.g., p40(phox) and p47(phox)), as analyzed by immunoprecipitation and Western blot. However, a reduction in the migration to the membrane of p47(phox) was obtained, suggesting that the protective actions involve the prevention of the correct assembly of the active enzyme in the membrane. Finally, the observed in vitro effects were confirmed in an in vivo inflammatory model, in which subcutaneous injection of AANO2 was able to decrease NOX2 activity in macrophages from thioglycolate-treated mice.
| S-EPMC3622795 | biostudies-literature
Project description:Anticancer agent 6-mercaptopurine (6MP) has been in use since 1953 for the treatment of childhood acute lymphoblastic leukemia (ALL) and inflammatory bowel disease. Despite being available for 60 years, several aspects of 6MP drug metabolism and pharmacokinetics in humans are unknown. Molybdoflavoenzymes such as aldehyde oxidase (AO) and xanthine oxidase (XO) have previously been implicated in the metabolism of this drug. In this study, we investigated the in vitro metabolism of 6MP to 6-thiouric acid (6TUA) in pooled human liver cytosol. We discovered that 6MP is metabolized to 6TUA through sequential metabolism via the 6-thioxanthine (6TX) intermediate. The role of human AO and XO in the metabolism of 6MP was established using the specific inhibitors raloxifene and febuxostat. Both AO and XO were involved in the metabolism of the 6TX intermediate, whereas only XO was responsible for the conversion of 6TX to 6TUA. These findings were further confirmed using purified human AO and Escherichia coli lysate containing expressed recombinant human XO. Xanthine dehydrogenase (XDH), which belongs to the family of xanthine oxidoreductases and preferentially reduces nicotinamide adenine dinucleotide (NAD(+)), was shown to contribute to the overall production of the 6TX intermediate as well as the final product 6TUA in the presence of NAD(+) in human liver cytosol. In conclusion, we present evidence that three enzymes, AO, XO, and XDH, contribute to the production of 6TX intermediate, whereas only XO and XDH are involved in the conversion of 6TX to 6TUA in pooled HLC.
| S-EPMC4109211 | biostudies-literature
Project description:Xanthine oxidase activation occurs in sepsis and results in the generation of uric acid (UrAc) and reactive oxygen species (ROS). We aimed to evaluate the effect of xanthine oxidase inhibitors (XOis) in rats stimulated with lipopolysaccharide (LPS). LPS (10 mg/kg) was administered intraperitoneally (i.p.) immediately after allopurinol (Alo, 2 mg/kg) or febuxostat (Feb, 1 mg/kg) every 24 h for 3 days. To increase UrAc levels, oxonic acid (Oxo) was administered by gavage (750 mg/kg per day) for 5 days. Animals were divided into the following 10 groups (n = 6 each): (1) Control, (2) Alo, (3) Feb, (4) LPS, (5) LPSAlo, (6) LPSFeb, (7) Oxo, (8) OxoLPS, (9) OxoLPSAlo, and (10) OxoLPSFeb. Feb with or without Oxo did not aggravate sepsis. LPS administration (with or without Oxo) significantly decreased the creatinine clearance (ClCr) in LPSAlo (60%, P < 0.01) versus LPS (44%, P < 0.05) and LPSFeb (35%, P < 0.05). Furthermore, a significant increase in mortality was observed with LPSAlo (28/34, 82%) compared to LPS treatment alone (10/16, 63%) and LPSFeb (11/17, 65%, P < 0.05). In addition, increased levels of thiobarbituric acid reactive substances (TBARS), tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-10 were observed at 72 h compared to the groups that received LPS and LPSFeb with or without Oxo. In this study, coadministration of Alo in LPS-induced experimental sepsis aggravated septic shock, leading to mortality, renal function impairment, and high ROS and proinflammatory IL levels. In contrast, administration of Feb did not potentiate sepsis, probably because it did not interfere with other metabolic events.
| S-EPMC5967155 | biostudies-literature
Project description:Iron uptake and release by ferritin molecules of different iron contents show similar profiles. These are discussed in relation to the structure of the ferritin molecule. Two models of iron uptake and release are considered. One involves iron oxidation-reduction sites on the protein. The other allows direct interaction of reagents with the iron-core crystallites. It is concluded that the second model accounts better for the experimental results presented now and in previous publications.
| S-EPMC1168401 | biostudies-other
Project description:Xanthine oxidase (XO) catalyzes the catabolism of hypoxanthine to xanthine and xanthine to uric acid, generating oxidants as a byproduct. Importantly, XO activity is elevated in numerous hemolytic conditions including sickle cell disease (SCD); however, the role of XO in this context has not been elucidated. Whereas long-standing dogma suggests elevated levels of XO in the vascular compartment contribute to vascular pathology via increased oxidant production, herein, we demonstrate, for the first time, that XO has an unexpected protective role during hemolysis. Using an established hemolysis model, we found that intravascular hemin challenge (40 μmol/kg) resulted in a significant increase in hemolysis and an immense (20-fold) elevation in plasma XO activity in Townes sickle cell phenotype (SS) sickle mice compared to controls. Repeating the hemin challenge model in hepatocyte-specific XO knockout mice transplanted with SS bone marrow confirmed the liver as the source of enhanced circulating XO as these mice demonstrated 100% lethality compared to 40% survival in controls. In addition, studies in murine hepatocytes (AML12) revealed hemin mediates upregulation and release of XO to the medium in a toll like receptor 4 (TLR4)-dependent manner. Furthermore, we demonstrate that XO degrades oxyhemoglobin and releases free hemin and iron in a hydrogen peroxide-dependent manner. Additional biochemical studies revealed purified XO binds free hemin to diminish the potential for deleterious hemin-related redox reactions as well as prevents platelet aggregation. In the aggregate, data herein reveals that intravascular hemin challenge induces XO release by hepatocytes through hemin-TLR4 signaling, resulting in an immense elevation of circulating XO. This increased XO activity in the vascular compartment mediates protection from intravascular hemin crisis by binding and potentially degrading hemin at the apical surface of the endothelium where XO is known to be bound and sequestered by endothelial glycosaminoglycans (GAGs).
| S-EPMC10025133 | biostudies-literature