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)

It is well known that aminoguanidine (AG) can diminish advanced glycosylation of proteins, which might be beneficial in preventing chronic diabetic complications. Recent reports suggested an inter-relationship between glycosylation of protein and free radical damage. In the present study, we examined the free radical scavenging properties of AG. Electron paramagnetic resonance using the spin-trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was performed to determine the superoxide and hydroxyl radical scavenging abilities of AG. These experiments revealed that AG was an effective hydroxyl radical scavenger even though it expressed a direct inhibitory effect on the xanthine oxidase activity at high concentrations (AG > or = 5 mM). In the second part of the study, allophycocyanin was used as an indicator of free radical mediated protein damage. In the assay, 2,2'-azobis(2-amidinopropane) hydrochloride (AAPH) was used as a peroxyl radical generator, and the loss of allophycocyanin fluorescence was monitored. The antioxidant effect of AG was expressed in oxygen-radical absorbing capacity (ORAC), where one ORAC unit equals the net protection produced by 1 microM Trolox (a water soluble analogue of vitamin E) as a control standard. AG exhibited a significant dose-dependent effect against free radical damage. These radical scavenging properties of AG may contribute to protective effects during glycation and explain the prevention of diabetic complications.
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PMID:Antioxidant properties of aminoguanidine. 1052 Jul 25

We present a flow cytometry technique to evaluate the antioxidative properties of molecules on living cells, using a stable murine-murine hybridoma (Mark 3) cell line routinely cultured. Using this technique, intracellular superoxide anions and peroxides were evaluated with dihydrorhodamine (DHR-123) and dichlorofluorescein diacetate (DCFH-DA), respectively. When cells were first incubated for 10 min with either H(2)O(2) or the xanthine (X)/xanthine oxidase (XO) system, this flow cytometric technique was capable of evaluating the oxidative stress on cells. Twenty-one new analogues of ellipticine were synthesized and tested for their antioxidative properties compared to vitamin E and Ebselen used as references. A good statistical reflection of the antioxidative activities of these molecules was achieved by analyzing 35 000 cells in each experiment. Among them, the selenated molecule 18 was found to be 10 times more active than Ebselen but 10 000 times less active than vitamin E. Moreover, eight compounds showed glutathione peroxidase-like activities.
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PMID:Screening of new antioxidant molecules using flow cytometry. 1079 93

Activities of hepatic xanthine oxidase (XO) and xanthine dehydrogenase (XD), serum liver enzymes, and reduced glutathione (GSH) were determined in livers of chronic cholestatic rats. The common bile duct was ligated (CBDL) and rats were randomized to either an untreated group or to treatment with allopurinol, a competitive XO inhibitor, or received a tungsten-supplemented diet to inactivate XO and XD, or received antioxidants vitamin C and vitamin E. One group underwent only sham laparotomy. After 4 weeks, in untreated CBDL animals serum aspartate aminotransferase and bilirubin concentrations were significantly elevated and hepatic GSH was significantly decreased when compared with the sham-operated group. Histochemical and enzymatic determinations of XD and XO showed a significant increase in hepatic XO activity after CBDL. Treatment with allopurinol and a tungsten-supplemented, molybdenum-free diet significantly attenuated serum liver enzymes, hepatic XO activity, and improved hepatic GSH levels, whereas vitamins C and E had a positive effect only on hepatic GSH levels. Our results support the hypothesis that cholestasis-induced hepatocellular injury is partially triggered by oxidative processes derived from increased hepatic XO activity. Inhibition and inactivation of XO exerts a hepatocellular protective effect in chronic cholestasis.
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PMID:The impact of hepatic xanthine oxidase and xanthine dehydrogenase activities on liver function in chronic cholestasis. 1089 33

Diethyl maleate (DEM) (5 mM) and ethyl methanesulfonate (EMS) (35 mM) treatments rapidly depleted cellular reduced glutathione (GSH) below detectable levels (1 nmol/10(6) cells), and induced lipid peroxidation and necrotic cell death in freshly isolated rat hepatocytes. In hepatocytes incubated with 2.5 mM DEM and 10 mM EMS, however, the complete depletion of cellular GSH observed was not sufficient to induce lipid peroxidation or cell death. Instead, DEM- and EMS-induced lipid peroxidation and cell death were dependent on increased reactive oxygen species (ROS) production as measured by increases in dichlorofluorescein fluorescence. The addition of antioxidants (vitamin E succinate and deferoxamine) prevented lipid peroxidation and cell death, suggesting that lipid peroxidation is involved in the sequence of events leading to necrotic cell death induced by DEM and EMS. To investigate the subcellular site of ROS generation, the cytochrome P450 inhibitor, SKF525A, was found to reduce EMS-induced lipid peroxidation but did not protect against the loss of cell viability, suggesting a mitochondrial origin for the toxic lipid peroxidation event. In agreement with this conclusion, mitochondrial electron transport inhibitors (rotenone, thenoyltrifluoroacetone and antimycin A) increased EMS-induced lipid peroxidation and cell death, while the mitochondrial uncoupler, carbonyl cyanide m-chlorophenylhydrazone, blocked EMS- and DEM-mediated ROS production and lipid peroxidation. Furthermore, EMS treatment resulted in the significant loss of mitochondrial alpha-tocopherol shortly after its addition, and this loss preceded losses in cellular alpha-tocopherol levels. Treatment of hepatocytes with cyclosporin A, a mitochondrial permeability transition inhibitor, oxypurinol, a xanthine oxidase inhibitor, or BAPTA-AM, a calcium chelator, provided no protection against EMS-induced cell death or lipid peroxidation. Our results indicate that DEM and EMS induce cell death by a similar mechanism, which is dependent on the induction of ROS production and lipid peroxidation, and mitochondria are the major source for this toxic ROS generation. Cellular GSH depletion in itself does not appear to be responsible for the large increases in ROS production and lipid peroxidation observed.
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PMID:Glutathione depletion and the production of reactive oxygen species in isolated hepatocyte suspensions. 1096 18

Multiple sclerosis (MS) has a much higher incidence among caucasians that in any other race. Furthermore: females are much more susceptible than males and white females living in colder, wetter areas are much more susceptible than those living in warmer areas. On the other hand, menstruating women have increased copper (Cu) absorption and half-life, so they tend to accumulate more Cu than males. Moreover, rapidly growing girls have an increased demand for zinc (Zn), but their rapidly decreasing production of melatonin results in impaired Zn absorption, which is exacerbated by the high Cu levels. The low Zn levels result in deficient CuZnSuperoxide dismutase (CuZnSOD), which in turn leads to increased levels of superoxide. Menstruating females also often present with low magnesium (Mg) and vitamin B6 levels. Vitamin B6 moderates intracellular nitric oxide (NO) production and extracellular Mg is required for NO release from the cell, so that a deficiency of these nutrients results in increased NO production in the cell and reduced release from the cell. The trapped NO combines with superoxide to form peroxinitrite, an extremely powerful free radical that leads to the myelin damage of MS. Iron (Fe), molybdenum (Mo) and cadmium (Cd) accumulation also increase superoxide production. Which explains MS in males, who tend to accumulate Fe much faster and Cu much less rapidly than females. Since vitamin D is paramount for Mg absorption, the much reduced exposure to sunlight in the higher latitudes may account for the higher incidence in these areas. Moreover, vitamin B2 is a cofactor for xanthine oxidase, and its deficiency exacerbates the low levels of uric acid caused by high Cu levels, resulting in myelin degeneration. Finally Selenium (Se) and vitamin E prevent lipid peroxidation and EPA and DHA upregulate CuZnSOD. Therefore, supplementation with 100 mg MG, 25 mg vit B6, 10 mg vit B2, 15 mg Zn and 400 IU vit D and E, 100 microg Se, 180 mg EPA and 120 mg DHA per day between 14 and 16 years of age may prevent MS.
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PMID:The possible role of gradual accumulation of copper, cadmium, lead and iron and gradual depletion of zinc, magnesium, selenium, vitamins B2, B6, D, and E and essential fatty acids in multiple sclerosis. 1098 16

Following hypoxia/reoxygenation (6h/96h), cultured neurons from the embryonic rat forebrain undergo delayed apoptosis. To evaluate the participation of oxidative stress and defense mechanisms, temporal evolution of intraneuronal free radical generation was monitored by flow cytometry using dihydrorhodamine 123, in parallel with the study of transcriptional, translational, and activity changes of the detoxifying enzymes Cu/Zn-SOD and Mn-SOD. Two distinct peaks of radical generation were depicted, at the time of reoxygenation (+ 27%) and 48 h later (+ 25%), respectively. Radical production was unaffected by caspase inhibitors YVAD-CHO or DEVD-CHO, which prevented neuronal damage, suggesting that caspase activation is not an upstream initiator of radicals in this model. Cell treatment by vitamin E (100 microM) displayed significant neuroprotection, whereas the superoxide generating system xanthine/xanthine oxidase induced apoptosis. Transcript and protein levels of both SODs were reduced 1 h after the onset of hypoxia, but activities were transiently stimulated. Reoxygenation was associated with an increased expression (139%), but a decreased activity (21%) of the inducible Mn-SOD, whereas Cu/Zn-SOD protein and activity were low and progressively increased until 48 h post-hypoxia, when the second rise in radicals occurred. In spite of a temporal regulation of SODs, which parallels radical formation, oxidative stress might account for neurotoxicity induced by hypoxia.
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PMID:Free radical production and changes in superoxide dismutases associated with hypoxia/reoxygenation-induced apoptosis of embryonic rat forebrain neurons in culture. 1111 19

Organophosphates are known primarily as neurotoxins. However, reactive oxygen species (ROS) caused by organophosphates may be involved in the toxicity of various pesticides. Therefore, in this study we aimed to examine how an organophosphate insecticide, chlorpyrifos-ethyl (CE) [0,0-diethyl 0 (3,5,6-trichloro-2-pyridyl) phosphorothioate], affects lipid peroxidation and the antioxidant defense system in vitro. For this purpose, four experiments were carried out. In experiment 1, erythrocyte packets obtained from six (three male, three female) volunteers were divided into six portions, and to each was added CE in both a high concentration range (0, 0.4, 2, 10, 50, 100 g/l) and a low concentration range (0, 0.01, 0.1 g/l). Additionally, each concentration group was divided into five tubes, and incubated at +4 degrees C for 0, 30, 60, 120, and 240 min. After incubation, the levels of malondialdehyde (MDA) and the activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) were determined in the erythrocytes in all tubes. In experiment 2, to examine the effect of CE (or its main metabolites) on the activity of purified, commercially available enzymes, CE at concentrations of 0. 0.01, 0.1, 0.4, and 10 g/l was incubated with purified SOD, GSH-Px and CAT at the concentrations observed in control group at the 0 CE concentration level in experiment 1 for 1 h at room temperature (25 degrees C). In experiment 3, the xanthine-xanthine oxidase system was used to determine whether the activities of SOD, GSH-Px and CAT were inactivated other than by CE, for example by superoxide radicals inducing lipid peroxidation in erythrocytes. Samples with xanthine and xanthine oxidase were mixed and incubated for 1 h at room temperature (25 degrees C). In experiment 4, to determine whether enzyme activities were still inhibited if lipid peroxidation was prevented by exogenous antioxidants, experiment 1 was repeated with the CE concentrations of 0.01, 0.1, 0.4, and 10 g/l by adding butylated hydroxytoluene and vitamin E to the medium. The MDA levels were determined spectrophotometrically. Enzymatic methods were used for the determination of SOD, GSH-Px, and CAT activities. The Friedman test and Wilcoxon's Signed Ranks test were used to compare paired groups. MDA values and GSH-Px activities increased with increasing CE concentration and incubation period (P<0.05), but SOD and CAT activities decreased with increasing CE concentration and incubation period (P<0.01). From these results, it can be concluded that in vitro administration of CE resulted in the induction of erythrocyte lipid peroxidation and significant changes in antioxidant enzyme activities, suggesting that ROS and/or free radicals may be involved in the toxic effects of CE.
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PMID:The effect of organophosphate insecticide chlorpyrifos-ethyl on lipid peroxidation and antioxidant enzymes (in vitro). 1113 Oct 33

Endothelial function is abnormal in a variety of diseased states such as hypercholesterolemia and atherosclerosis. This may be secondary to decreased synthesis of nitric oxide (NO) and/or increased degradation of NO due to interaction with superoxide anions. More recent experimental observations demonstrate increased production of superoxide in hyperlipidemia, suggesting that endothelial dysfunction in these states is in part secondary to increased NO metabolism. Enzymes proposed to be involved in increased superoxide production may include xanthine oxidase, the NO synthase, and the NAD(P)H oxidase. Superoxide rapidly reacts with NO to form peroxynitrite (ONOO-), a highly reactive intermediate with cytotoxic properties. Despite experimental evidence for the oxidative stress concept in causing endothelial dysfunction, the results of recent randomized trials to test the influence of antioxidants on coronary event rates and prognosis in patients with coronary artery disease were very disappointing. In all of these studies the use of vitamins such as vitamin E failed to improve the prognosis. In contrast, treatment with angiotensin converting enzyme inhibitors or cholesterol- lowering drugs improved endothelial dysfunction, prevented the activation of superoxide-producing enzymes in cholesterol-fed animals, reduced coronary event rates, and improved prognosis in patients with coronary artery disease. Therefore, inhibition of superoxide production at the enzymatic level rather than symptomatic superoxide scavenging may be the better choice of treatment.
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PMID:Antioxidants and endothelial dysfunction in hyperlipidemia. 1117 9

It is generally accepted that the protection effect of biological tissues by vitamin E is due to its radical scavenging potency in membranes, thereby being transformed to a vitamin E radical. A deficiency of appropriate reductants, which recycle vitamin E radicals back to its antioxidative active form, causes an irreversible degradation of vitamin E leading to tocopheryl quinone (TQ). TQ-like compounds were shown to result from both vitamin E and corresponding hydrophilic analogues of this antioxidant in vitro. In vivo elevated concentrations of tocopheryl quinones were detected after oxidative stress and TQ supplementation as well. Quinones in general are known to be efficient one-electron donors and acceptors. Therefore the question arises whether TQ-like compounds can undergo redox-cycling in conjunction with redox-active enzymes in the heart, thereby producing harmful oxygen radicals, or whether these compounds exhibit antioxidant properties. In order to elucidate this question we focused our interest on the interaction of TQ and a corresponding short-chain homologue (TQ(0)) with xanthine oxidase and heart mitochondria. Furthermore, we tested the influence of TQ on the recovery of isolated perfused rat hearts after ischemia/reperfusion. Our experiments revealed that hydrophilic TQ(0) was univalently reduced by xanthine oxidase (XOD) yielding semiquinone radicals in the absence of oxygen. However, under aerobic conditions TQ(0) enhanced the O(2)(*)(-) radical output of XOD. In the mitochondrial respiratory chain TQ was shown to interact with high potential cytochrome b in the bc(1) complex specifically. In contrast to the system XOD/TQ(0), lipophilic TQ in submitochondrial particles decreased the O(2)(*)(-) radical release during regular respiration possibly due to its interaction with b-cytochromes in the mitochondrial respiratory chain. In isolated rat hearts perfused with liposomes containing lipophilic TQ, it was efficiently accumulated in the heart tissue. When hearts were subjected to conditions of ischemia/reperfusion, infusion of TQ prior to ischemia significantly improved the recovery of hemodynamic parameters. Our results demonstrate that TQ derivatives may induce pro-oxidative and antioxidative effects depending on the distribution of TQ derivatives in the heart tissue and the interacting redox system.
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PMID:Effects of tocopheryl quinone on the heart: model experiments with xanthine oxidase, heart mitochondria, and isolated perfused rat hearts. 1129 29

3-Hydroxyanthranilic acid (3-HAA), a metabolite of L-tryptophan, accumulates in monocyte-derived cells (THP-1), but not in other cell lines tested (MRC-9, H4, U373MG, Wil-NS), following immune stimulation that induces indoleamine-2,3-dioxygenase (IDO), a rate-limiting enzyme in the L-tryptophan kynurenine pathway. We examined whether metabolites of the L-tryptophan-kynurenine pathway act to induce apoptosis in monocytes/macrophages. Of the L-tryptophan metabolites tested, only 3-HAA at a concentration of 200 micromol/L was found to induce apoptosis in THP-1 and U937 cells. The addition of ferrous or manganese ions further enhanced apoptosis and free radical formation by 3-HAA in these two types of cells. The apoptotic response induced by 3-HAA was significantly attenuated by the addition of antioxidant, alpha-tocopherol or Trolox (a water-soluble analogue of vitamin E), and the xanthine oxidase inhibitor, allopurinol. In addition, the 3-HAA-induced apoptotic response was slightly attenuated by catalase, but not by superoxide dismutase (SOD), indicating that generation of hydrogen peroxide is involved in this response. Interferon-gamma (IFN-gamma), an inducer of IDO, potently induced apoptosis in THP-1 cells, but not in U937 cells, in the presence of ferrous or manganese ions. This different susceptibility to apoptosis inducer between THP-1 and U937 cells may depend on the capacity of the cells for 3-HAA synthesis following IDO induction by IFN-gamma. Furthermore, apoptosis was suppressed by cycloheximide in THP-1 cells, suggesting that newly synthesized proteins may be essential for apoptotic events. These results suggest that 3-HAA induces apoptosis in monocytes/macrophages under inflammatory or other pathophysiological conditions.
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PMID:3-Hydroxyanthranilic acid, an L-tryptophan metabolite, induces apoptosis in monocyte-derived cells stimulated by interferon-gamma. 1139 99


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