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)

The hypothesis that posthypoxic renal injury is mediated by xanthine oxidase-derived oxygen free radical production was tested in an in vitro model of rat proximal tubule epithelial cells in primary culture subjected to 60 min of hypoxia and 30 min of reoxygenation. Hypoxia-reoxygenation-induced injury, measured as lactate dehydrogenase (LDH) release, was 54.0 +/- 7.1%. Inhibition of xanthine oxidase by 10(-4) M allopurinol attenuated injury (LDH release = 35.5 +/- 3.7%; P less than 0.01). Oxypurinol was similarly effective. Alternatively, cells were treated with 50 or 100 microM tungsten to inactivate xanthine oxidase. Tungsten prevented hypoxia-reoxygenation-induced superoxide radical production (basal = 97 +/- 8, hypoxia-reoxygenation = 172 +/- 12, and plus tungsten = 73 +/- 8 nmol/micrograms protein) and attenuated hypoxia-reoxygenation-induced injury (LDH release: basal = 18.8 +/- 3.0%, hypoxia-reoxygenation = 62.0 +/- 4.8%, plus 50 microM tungsten = 24.8 +/- 5.0%, and plus 100 microM tungsten = 6.0 +/- 0.7%). In addition, hypoxia and reoxygenation increased the ratio of xanthine oxidase to total activity (xanthine oxidase + xanthine dehydrogenase) from 73 to 100%. Therefore xanthine oxidase was responsible for hypoxia-reoxygenation-induced superoxide radical formation and hypoxia-reoxygenation-induced injury. Xanthine oxidase is likely to be the major source of oxygen free radicals during renal ischemia and reperfusion.
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PMID:Xanthine oxidase produces O2-. in posthypoxic injury of renal epithelial cells. 132 7

The role of xanthine oxidase and oxygen free radicals in postischemic reperfusion injury in the rat kidney remains controversial. Proximal tubules, the focal segment affected by ischemic renal injury, were isolated in bulk, assayed for xanthine oxidase activity, and subjected to 60 min of anoxia or hypoxia and 60 min of reoxygenation to evaluate the participation of xanthine oxidase and oxygen radicals in proximal tubule reoxygenation injury. The total xanthine oxidase in isolated rat proximal tubules was 1.1 mU/mg of protein, approximately 30% to 40% of the activity found in rat intestine and liver. Lactate dehydrogenase release, an indicator of irreversible cell damage, increased substantially during anoxia (39.8 +/- 2.3 versus 9.8 +/- 1.8% in controls) with an additional 8 to 12% release during reoxygenation. Addition of 0.2 mM allopurinol, a potent xanthine oxidase inhibitor, and dimethylthiourea, a hydroxyl radical scavenger, failed to protect against the reoxygenation lactate dehydrogenase release. Analysis of xanthine oxidase substrate levels after anoxia and flux rates during reoxygenation indicates that hypoxanthine and xanthine concentrations are in a 15-fold excess over the enzyme Km and 0.3 mU/mg of protein of xanthine oxidase activity exists during reoxygenation. Hypoxic tubule suspensions had a minimal lactate dehydrogenase release during hypoxia and failed to demonstrate accelerated injury upon reoxygenation. In conclusion, although xanthine oxidase is present and active during reoxygenation in isolated rat proximal tubules, oxygen radicals did not mediate reoxygenation injury.
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PMID:Minimal role of xanthine oxidase and oxygen free radicals in rat renal tubular reoxygenation injury. 188 66

Renal reperfusion injury results from oxygen radical generation. During reoxygenation of hypoxic kidney cells, xanthine oxidase produces superoxide radical, which eventuates in hydroxyl radical formation by the Fenton reaction. This reaction, catalyzed by transition metals such as iron, is particularly important because hydroxyl radical is highly reactive with a wide variety of biomolecules. We tested the hypothesis that this catalytic function is fostered by iron released from the heme moiety of cytochrome P-450. Primary cultures of rat proximal tubule epithelial cells studied in a subconfluent stage were subjected to 60 min of hypoxia and 30 min of reoxygenation. When cells were pretreated with one of three cytochrome P-450 inhibitors (piperonyl butoxide, cimetidine, or ketoconazole), lethal cell injury was attenuated. There was the expected increase in O2-. production during hypoxia/reoxygenation that cytochrome P-450 inhibitors did not prevent; on the other hand, inhibitors did prevent reoxygenation-induced hydroxyl radical formation. Analogously, the increase in catalytic iron (bleomycin-detectable iron) that accompanies hypoxia/reoxygenation did not occur in the presence of cytochrome P-450 inhibitors. In vivo studies confirmed a protective effect of cytochrome P-450 inhibition because glomerular filtration rate was better preserved in rats pretreated with cimetidine and then subjected to renal artery occlusion. In summary, several chemically distinct cytochrome P-450 inhibitors reduced iron release, and thereby, hydroxyl radical formation and reoxygenation-induced lethal cell injury, without inhibiting superoxide radical formation. We conclude that highly labile P-450 may act as an Fe-donating catalyst for Fenton reaction production of HO.-mediated reperfusion injury.
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PMID:Cytochrome P-450 mediates tissue-damaging hydroxyl radical formation during reoxygenation of the kidney. 804 36

There is considerable evidence suggesting that reactive oxygen species (ROS) are implicated in the pathogenesis of ischemic, toxic, and immunologically-mediated renal injury. In experimental renal ischemia, ROS sources include the electron transport chain, oxidant enzymes (xanthine oxidase), phagocytes, and auto-oxidation of epinephrine. ROS cause lipid peroxidation of cell and organelle membranes and, hence, disruption of the structural integrity and capacity for cell transport and energy production, especially in the proximal tubule segment. In experimental immune glomerulonephritis, ROS are generated by both infiltrating blood-borne cells (polymorphonuclear leukocytes and monocytes) and resident glomerular cells, mainly mesangial cells. Their formation results in morphologic lesions and in modifications of glomerular permeability to proteins through activation of proteases and reduction of proteoglycan synthesis. Additionally, they promote a reduction in glomerular blood flow and glomerular filtration rate through liberation of vasoconstrictory bioactive lipids (prostaglandins, thromboxane, and platelet activating factor) and, possibly, inactivation of relaxing nitric oxide. Further studies are needed to address the role of ROS in human glomerular diseases.
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PMID:Involvement of reactive oxygen species in kidney damage. 822 Oct 27

This study was designed to investigate the influence of intracellular ionized calcium ([Ca2+]i) on the induction of c-fos, c-jun, c-myc, and hsp70 genes after oxidant stress induced by xanthine/xanthine oxidase (X/XOD) treatment or after heat shock using primary cultures of rat proximal tubule epithelium (PTE). X/XOD (500 microM/25 mU/mL) induced all of these genes; ionomycin also resulted in similar kinetics of induction of all genes. The expression of both c-fos following X/XOD treatment and hsp70 following heat shock was markedly decreased through chelation of [Ca2+]i by Quin 2/AM. The c-fos expression following X/XOD treatment was partly reduced by a protein kinase C inhibitor, staurosporine (ST), and markedly inhibited by another protein kinase inhibitor, 2-aminopurine (2AP), while both ST and 2AP markedly reduced hsp70 expression. The ADP-ribosylation transferase inhibitor 3-aminobenzamide had no effect on either c-fos or hsp70 expression. These results suggest that cell injuries leading to increased [Ca2+]i in PTE result in induction of c-fos, c-jun, c-myc, and hsp70; and that the activation of c-fos and hsp70 genes may be regulated by [Ca2+]i and [Ca2+]i-dependent protein kinases.
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PMID:Induction of immediate early and stress genes in rat proximal tubule epithelium following injury: the significance of cytosolic ionized calcium. 846 83

1. Antioxidant and oxidative enzymes were examined in renal glomeruli and proximal tubules of healthy young rats (10-12 weeks old), and results were related to the superoxide anion generation of these tissues. 2. Activities of superoxide dismutases, catalase, and glutathione peroxidase were 3- to 6-fold higher in proximal tubules than in glomeruli. Similarly, enzyme levels and mRNA levels of superoxide dismutases and catalase were significantly higher in proximal tubules. 3. NADH- and NADPH-dependent oxidase activity and xanthine oxidase activity were not different in glomeruli and proximal tubules. 4. Measurements with lucigenin-enhanced chemiluminescence in vital tissues indicated 10-fold higher rates of superoxide anion in glomeruli than in tubules. 5. Compared with the young rats, tubules of 8-month-old rats had significantly higher superoxide anion rates and lower superoxide dismutase activity, whereas NADH- and NADPH-dependent oxidase activities were unchanged. 6. We conclude that considerable differences in the antioxidant-oxidant balance exist between the glomerulus and proximal tubule. Results from experiments using chemiluminescence in vital tissues suggest that changes in the antioxidant-oxidant balance have an effect on oxygen radical levels. The relevance of the observed differences to glomerular and tubulo-interstitial disease remains to be determined, but a greater susceptibility of the glomerulus to oxidant stress might be anticipated.
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PMID:Antioxidant-oxidant balance in the glomerulus and proximal tubule of the rat kidney. 957 7

Ischemia/reperfusion (I/R) injury induces both functional and morphological changes in the kidney. Necrosis, predominantly of the proximal tubule (PT), is the hallmark of this model of renal injury, whereas cells of the distal nephron survive, apparently intact. We examined whether differences in cellular outcome of the various regions of the nephron may be due to segmental variation in the activation of the mitogen-activated protein kinases (MAPKs) in response to I/R injury. Whereas c-Jun N-terminal kinase (JNK) is activated in both the cortex and inner stripe of the outer medulla, the extracellular regulated kinase (ERK) pathway is activated only in the inner stripe in which thick ascending limb (TAL) cells predominate. These studies are consistent with the notion that ERK activation is essential for survival. To test this hypothesis directly, we studied an in vitro system in which manipulation of these pathways and their effects on cellular survival could be examined. Oxidant injury was induced in mouse PT and TAL cells in culture by the catabolism of hypoxanthine by xanthine oxidase. PT cells were found to be more sensitive than TAL cells to oxidative stress as assessed by cell counting, light microscopy, propidium iodide uptake, and fluorescence-activated cell sorting (FACS) analysis. Immunoprecipitation/kinase analysis revealed that JNK activation occurred in both cell types, whereas ERK activation occurred only in TAL cells. We then examined the effect of PD-098059, a MAP kinase kinase (MEK)-1 inhibitor of the ERK pathway, on PT and TAL survival. In TAL cells, ERK inhibition reduced cell survival nearly fourfold (P < 0.001) after oxidant exposure. In PT cells, activation of the ERK pathway by insulin-like growth factor I (IGF-I) increased survival by threefold (P < 0.001), and this IGF-I-enhanced cell survival was inhibited by PD-098059. These results indicate that cell survival in the kidney after ischemia may be dependent on ERK activation, suggesting that this pathway may be a target for therapeutic treatment in I/R injury.
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PMID:MAPK activation determines renal epithelial cell survival during oxidative injury. 1044 73

Copper(2)(II)(3,5-ditertiarybutylsalicylate)(4)(ethanol)(4), Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), was synthesized and characterized for evaluation as an anti-apoptotic superoxide dismutase (SOD)-mimetic in an in vitro 50 microM cis-diamminedichloroplatinum(II), [Pt(II)(NH(3))(2)(Cl)(2)]-treated kidney proximal tubule epithelial cell (LLC-PK) preparation. Synthesized Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) was characterized by elemental analysis, FTIR spectrophotometry, and X-ray crystallography. The IC(50) for SOD-mimetic reactivity of Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), determined with the xanthine/xanthine oxidase/nitroblue tetrazolium (NBT) system, was found to be 2.69 microM for the binuclear chelate. Pretreatment of LLC-PK cells with 20 microM Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) prevented 50 microM Pt(II)(NH(3))(2)(Cl)(2)-induced and superoxide-mediated apoptosis. This SOD-mimetic significantly suppressed Pt(II)(NH(3))(2)(Cl)(2)-induced translocation of pro-apoptotic Bax from the cytosol to the inner mitochondrial membrane, prevented Pt(II)(NH(3))(2)(Cl)(2)-induced release of cytochrome c from the inner mitochondrial membrane and the appearance of cytochrome c in the cytosol, and prevented conversion of procaspase-3 to active caspase-3. Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) treatment inhibited Pt(II)(NH(3))(2)(Cl)(2)-mediated tubular cell injury by preventing activation of cellular mechanisms that lead to proximal tubule kidney cell death. Based on these observations, Pt(II)(NH(3))(2)(Cl)(2)- induced O(2)(-)-mediated apoptosis can be mechanistically overcome with a small molecular mass SOD-mimetic, Cu(2)(II)(3,5-DTBS)(4)(Eth)(4). Prior treatment of patients who are to undergo treatment with Pt(II)(NH(3))(2)(Cl)(2) for their neoplastic disease with Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) may be beneficial to these patients.
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PMID:Prevention of cisplatin-induced kidney epithelial cell apoptosis with a Cu superoxide dismutase-mimetic [copper2II(3,5-ditertiarybutylsalicylate)4(ethanol)4]. 1681 79

Mechanistic and therapeutic advances in gout have been moving swiftly in the past decade. Clinically, the disease is changing in character. This review discusses several of the pertinent recent developments in understanding gout and in novel therapeutics for the disease. Subjects addressed include the role of URAT1-mediated renal proximal tubule epithelial cell urate anion reabsorption in hyperuricemia. We discuss the therapeutic limitations of allopurinol and uricosurics and the potential applications of novel xanthine oxidase inhibitors and of recombinant uricase preparations. Last, we summarize understanding of the central role of the early induced innate immune response in gouty inflammation, which has suggested the potential value of new strategies for treating gouty inflammation by targeting caspase-1 or IL-1beta.
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PMID:Gout in 2006: the perfect storm. 1712 96

The approval of febuxostat, a non-purine-analogue inhibitor of xanthine oxidase, by the European Medicines Agency and the US Food and Drug Administration heralds a new era in the treatment of gout. The use of modified uricases to rapidly reduce serum urate concentrations in patients with otherwise untreatable gout is progressing. Additionally, advances in our understanding of the transport of uric acid in the renal proximal tubule and the inflammatory response to monosodium urate crystals are translating into potential new treatments. In this Review, we focus on the clinical trials of febuxostat. We also review results from studies of pegloticase, a pegylated uricase in development, and we summarise data for several other pipeline drugs for gout, such as the selective uricosuric drug RDEA594 and various interleukin-1 inhibitors. Finally, we issue a word of caution about the proper use of the new drugs and the already available drugs for gout. At a time of important advances, we need to recommit ourselves to a rational approach to the treatment of gout.
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PMID:Gout therapeutics: new drugs for an old disease. 2121 69


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