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 combined effects of ethanol and hypoxia on the conversion of xanthine dehydrogenase (D form) to xanthine oxidase (O form) and on the leakage of the enzyme from isolated rat hepatocytes was studied. Time-dependent death of cells occurred during incubation in hypoxic conditions. Ethanol (40 mM) had only a moderate effect on viability in aerobiosis, but accelerated the loss of hypoxic cells, which was 96% after 3 h of incubation. In hypoxic conditions, the xanthine oxidase was gradually converted from D into O form. The conversion was complete in 3 h, and was accelerated by 1 mM xanthine or by ethanol, in a concentration-related manner. Hypoxia brought about a progressive leakage of xanthine oxidase from hepatocytes, which was accelerated by ethanol in a concentration-dependent manner. The enzyme found outside hepatocytes was mostly in its O form. The xanthine oxidase of hepatocytes cytosol was converted from D into O form by human plasma or serum. In all cases the conversion could be completely reverted by treatment of the extract with dithiothreitol.
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PMID:Effects of hypoxia and ethanol on xanthine oxidase of isolated rat hepatocytes: conversion from D to O form and leakage from cells. 164 70

Anaerobic reduction of hydrogen peroxide in a xanthine/xanthine oxidase system by adriamycin semiquinone in the presence of chelators and radical scavengers was investigated by direct electron paramagnetic resonance and spin trapping techniques. Under these conditions, adriamycin semiquinone appears to react with hydrogen peroxide forming the hydroxyl radical in the presence of chelators such as ethylenediaminetetraacetic acid and diethylenetriaminepentaacetic acid. In the absence of chelators, a related, but unknown oxidant is formed. In the presence of desferrioxamine, adriamycin semiquinone does not disappear in the presence of hydrogen peroxide at a detectable rate. The presence of adventitious iron is therefore implicated during adriamycin semiquinone-catalyzed reduction of hydrogen peroxide. Formation of alpha-hydroxyethyl radical and carbon dioxide radical anion from ethanol and formate, respectively, was detected by spin trapping. Both the hydroxyl radical and the related oxidant react with these scavengers, forming the corresponding radical. In the presence of scavengers from which reducing radicals are formed, the rate of consumption of hydrogen peroxide in this system is increased. This result can be explained by a radical-driven Fenton reaction.
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PMID:An electron paramagnetic resonance study of the interactions between the adriamycin semiquinone, hydrogen peroxide, iron-chelators, and radical scavengers. 165 78

We investigated the role of singlet oxygen (generated from photoactivation of rose bengal) on the calcium transport and Ca(2+)-ATPase activity of cardiac sarcoplasmic reticulum (SR). Isolated cardiac SR exposed to rose bengal (10 nM) irradiated at 560 nm resulted in significant inhibition of Ca2+ uptake (from 2.27 +/- 0.05 to 0.62 +/- 0.05 mumol Ca2+/mg.min [mean +/- SEM], p less than 0.01) and Ca(2+)-ATPase activity (from 2.08 +/- 0.05 to 0.28 +/- 0.04 mumol Pi/min.mg [mean +/- SEM], p less than 0.01). The inhibition of calcium uptake and Ca(2+)-ATPase activity by rose bengal-derived activated oxygen (singlet oxygen) was dependent on the duration of exposure and intensity of light. Singlet oxygen scavengers ascorbic acid and histidine significantly protected SR Ca(2+)-ATPase against rose bengal-derived activated oxygen species, but superoxide dismutase and catalase did not attenuate the inhibition. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of SR exposed to photoactivated rose bengal for up to 14 minutes demonstrated complete loss of the Ca(2+)-ATPase monomer band, which was significantly protected by histidine. The addition of dithiothreitol (5 mM) had a slight protective effect, showing that new disulfide bond formation was not a major cause of aggregation. The results were also confirmed by high-performance liquid chromatography of the SR exposed to irradiated rose bengal. Irradiation of rose bengal also caused an 18% loss of total sulfhydryl groups of SR. On the other hand, superoxide radical (generated from xanthine oxidase action on xanthine) and hydroxyl radical (in the presence of Fe(3+)-EDTA or 0.5 mM H2O2 plus Fe(2+)-EDTA) as well as H2O2 (0.25-12 mM) were without any effect on the 97,000-d Ca(2+)-ATPase band of SR. Generation of radical species (superoxide and hydroxyl radical) from rose bengal was studied by electron paramagnetic resonance spectroscopy using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). The results showed that irradiation of rose bengal formed a 1:2:2:1 quartet, characteristic of the DMPO-OH adduct, which was scavenged by ethanol but not by superoxide dismutase, catalase, or histidine. No radical species could be detected from irradiated rose bengal or irradiated DMPO under the assay conditions used. Peroxy adducts of DMPO might be produced but would be observed only at very low temperatures. Similarly, we could not detect any measurable.O2- anion from irradiation of rose bengal as indicated by either cytochrome c reduction at 550 nm or nitro blue tetrazolium reduction at 560 nm. These results show that SR is damaged most likely by singlet oxygen derived from rose bengal.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Singlet oxygen interaction with Ca(2+)-ATPase of cardiac sarcoplasmic reticulum. 165 35

The oxidative demethylenation reactions of (methylendioxy)phenyl compounds (MDPs), (methylenedioxy)benzene (MDB), (methylenedioxy)amphetamine (MDA), and (methylenedioxy)methamphetamine (MDMA), were evaluated by using two hydroxyl radical generating systems, the autoxidation of ascorbate in the presence of iron-EDTA and the iron-catalyzed Haber-Weiss reaction conducted by xanthine/xanthine oxidase with iron-EDTA. Reaction products generated when MDB, MDA, and MDMA were incubated with the ascorbate or xanthine oxidase system were catechol, dihydroxyamphetamine (DHA), and dihydroxymethamphetamine (DHMA), respectively. The reaction required the presence of either ascorbic acid or xanthine oxidase. Levels of each catechol increased in proportion to ferric ion concentration and were suppressed by desferrioxamine B methanesulfonate (desferal). Catalase (CAT) inhibited the oxidation by the ascorbate system whereas superoxide dismutase (SOD) had little effect. The addition of hydrogen peroxide to the reaction mixture stimulated the oxidation, but the reaction was not initiated by hydrogen peroxide alone, suggesting that hydrogen peroxide acts as a precursor of hydroxyl radical. SOD and CAT suppressed the demethylenation reactions in the xanthine oxidase system. Hydroxyl radical scavenging agents such as ethanol, benzoate, DMSO, and thiourea effectively inhibited the oxidation by both systems. Urea, which has little effect on hydroxyl radical, was without any effect. These results indicated that hydroxyl radical can effect the cleavage of methylenedioxy group on MDPs.
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PMID:Hydroxyl radical mediated demethylenation of (methylenedioxy)phenyl compounds. 168 Apr 77

Acetaldehyde (AA), the first product of ethanol metabolism, has been suggested as an important mediator in alcoholic pancreatitis, but experimental evidence has not been convincing. Prior work using the isolated perfused canine pancreas preparation has suggested that toxic oxygen metabolites generated by xanthine oxidase (XO) may mediate the early injury in pancreatitis. Xanthine oxidase is capable of oxidizing AA, and during this oxidation free radicals are released. The hypothesis that acute alcoholic pancreatitis may be initiated by AA in the presence of active XO (converted from xanthine dehydrogenase [XD]) was tested in the authors' experimental preparation by converting XD to XO by a period of ischemia, and infusing AA. Control preparations remained normal throughout the 4-hour perfusion (weight gain, 7 +/- 4 g; amylase activity, 1162 +/- 202 U/dL). One hour of ischemia or infusion of AA at 25 mg/hr or at 50 mg/hr without ischemia did not induce changes in the preparation. Acetaldehyde at 250 mg/hr induced minimal edema and weight gain (16 +/- 4 g; p less than 0.05), but not significant hyperamylasemia. Changes also were not observed when 1-hour ischemia was followed by a bolus of ethanol (1.5 g) or sodium acetate (3.0 g), or by infusion of 25 mg/hr of AA. One hour of ischemia followed by infusion of AA at 50 mg/hr or at 250 mg/hr induced edema, hemorrhage, weight gain (22 +/- 7 g [p less than 0.05] and 26 +/- 17 g [p less than 0.05]) and hyperamylasemia (2249 +/- 1034 U/dL [p less than 0.05] and 2602 +/- 1412 U/dL [p less than 0.05]). Moreover infusion of AA at 250 mg/hr after 2 hours of ischemia potentiated the weight gain (62 +/- 20 g versus 30 +/- 14 g [p less than 0.05]), but not the hyperamylasemia (3404 +/- 589 U/dL versus 2862 +/- 1525 U/dL) as compared with 2 hours of ischemia alone. Pancreatitis induced by 1 hour of ischemia followed by AA at 50 mg/hr could be inhibited by pretreatment with the free radical scavengers superoxide dismutase and catalase and ameliorated with the XO inhibitor allopurinol. The authors conclude that AA, in the presence of active XO, can initiate acute pancreatitis in the isolated canine pancreas preparation and may be important in the initiation of acute alcoholic pancreatitis in man. Toxic oxygen metabolites appear to play an important intermediary role.
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PMID:The role of acetaldehyde in the pathogenesis of acute alcoholic pancreatitis. 172 Jun 11

The administration of allopurinol significantly increased resistance to repeated hypobaric hypoxia, while hypoxanthine decreased it. The administration of adenine or inosine (25 mg/kg) was without effect. The results show pathogenic significance of xanthine oxidase-dependent production of free oxygen radicals in posthypoxic damage. In other experiments, the administration of 50% ethanol (12 ml/kg) by gastric catheter increased plasma xanthine oxidase activity in both rats and hamsters.
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PMID:Plasma xanthine oxidase and resistance to hypoxia: effect of purines and alcohol administration. 182 84

It is demonstrated that the perhydroxyl radical (HOO., the conjugate acid of superoxide (O2-], initiates fatty acid peroxidation (a model for biological lipid peroxidation) by two parallel pathways: fatty acid hydroperoxide (LOOH)-independent and LOOH-dependent. Previous workers (Gebicki, J. M., and Bielski, B. H. J. (1981) J. Am. Chem. Soc. 103, 7020-7025) demonstrated that HOO., generated by pulse radiolysis, initiates peroxidation in ethanol/water fatty acid dispersions by abstraction of the bis-allylic hydrogen atom from a polyunsaturated fatty acid. Addition of O2 to the fatty acid radicals forms peroxyl radicals (LOO.s), the chain-propagating species of lipid peroxidation. In this work it is demonstrated that HOO., generated either chemically (KO2) or enzymatically (xanthine oxidase), is a good initiator of fatty acid peroxidation in linoleic acid ethanol/water dispersions; O2- serves only as the source of HOO., and HOO. initiation can be observed at physiologically relevant pH values. In contrast to the previous results, the initiating effectiveness of HOO. is related directly to the initial concentrations of LOOHs in the lipids to be peroxidized. This defines a LOOH-dependent mechanism for fatty acid peroxidation initiation by HOO., which parallels the previously established LOOH-independent pathway. Since the LOOH-dependent pathway is much more facile than the LOOH-independent pathway, LOOH is the kinetically preferred site of HOO. attack in these systems. Experiments comparing HOO./LOOH-dependent fatty acid peroxidation with transition metal- and peroxyl radical-initiated peroxidation rule out the participation of the latter two species as initiators, which defines the HOO./LOOH initiation system as mechanistically unique. LOOH product studies are consistent with either a direct or indirect hydrogen atom transfer between LOOH and HOO. to yield LOO.s, which propagate peroxidation. The LOOH-dependent pathway of HOO.-initiated fatty acid peroxidation may be relevant to mechanisms of lipid peroxidation initiation in vivo.
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PMID:Perhydroxyl radical (HOO.) initiated lipid peroxidation. The role of fatty acid hydroperoxides. 186 44

Caffeine was used as a metabolic probe to screen healthy subjects for their activities of two enzymes, deduced to be CYP1A2 (an inducible cytochrome P450) and xanthine oxidase. A longitudinal study revealed modest effects of caffeine dose, ethanol intake, and time-of-day on the CYP1A2 index, without any effect on the xanthine oxidase index. The coefficients of intraindividual variation not accounted for were 5.0% for the xanthine oxidase and 17.2% for the CYP1A2 index. In a population study, both indexes showed a log normal distribution, with CYP1A2 values of most subjects covering a 6.3-fold range but only a 1.7-fold range with xanthine oxidase. The CYP1A2 index was 33% decreased in women who used oral contraceptives and substantially increased in cigarette smokers. Neither the CYP1A2 nor the xanthine oxidase index differed between volunteers of Chinese and European extraction. Four of 178 subjects showed unexplained low xanthine oxidase values (i.e., values several standard deviations below the mean).
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PMID:Use of caffeine metabolite ratios to explore CYP1A2 and xanthine oxidase activities. 193 64

Doxorubicin is an antineoplastic drug which undergoes oxidation-reduction cycling and produces toxicity to some cancer cell lines. Since oxidation-reduction cycling requires reducing equivalents and because ethanol metabolism via alcohol dehydrogenase (ADH) increases NADH, the effect of ethanol on doxorubicin toxicity was examined in cultured cells. Since some cells exhibit resistance to anthracyclines such as doxorubicin, two different Chinese hamster ovary cell lines were used, one sensitive (AUX B1) and one resistant (CHRC5) to doxorubicin. Studies were designed to determine if ethanol could decrease resistance to doxorubicin. Cells were treated for 24 h with doxorubicin in the presence or absence of ethanol, and the number of live cells was estimated spectrophotometrically. Ethanol (60-150 mM) potentiated the doxorubicin-induced decrease in cell number in both cell lines. In AUX B1 cells the concentration of doxorubicin required for half-maximal inhibition of cell survival was reduced 20-fold by ethanol, and a completely nontoxic concentration of doxorubicin decreased the number of surviving cells to 30% in the presence of ethanol. Addition of ethanol to the medium also increased doxorubicin-induced inhibition of cell survival in CHRC5 cells, but the effect was less dramatic than in AUX B1 cells. The effect of ethanol on cell number was concentration related; the half-maximal response was observed with about 1 mM ethanol. The hypothesis that ethanol potentiates doxorubicin toxicity by generation of NADH during metabolism by ADH was strengthened by the observations that both cell lines possess ADH activity (30-400 units/10(12) cells) and that ethanol (0.1-0.5 mM) increased NADH fluorescence 15-80% over basal values in cultured cells. Further, the effect of doxorubicin on cell number was also potentiated by another substrate for ADH, 2-ethylhexanol. Desferrioxamine, an iron chelator, increased survival in cells treated with doxorubicin plus ethanol by up to 60% (half-maximal effect, 1 mM), and (+)-catechin, a radical scavenger, abolished the decrease in cell number due to doxorubicin plus ethanol at concentrations greater than 0.1 mM. Allopurinol, an inhibitor of xanthine oxidase with radical scavenging properties, diminished the effect of doxorubicin plus ethanol on cell number by 60% (P less than 0.05). Taken together, these data are consistent with the hypothesis that ethanol potentiates toxicity due to doxorubicin by providing reducing equivalents for oxidation-reduction cycling which produce toxic reduced oxygen species.
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PMID:Ethanol potentiates doxorubicin-induced inhibition of cell survival in cultured Chinese hamster ovary cells. 200 22

Incubation of rat liver microsomes with 1-propanol and 1-butanol in the presence of NADPH and of the spin trapping agent 4-pyridyl-1-oxide-t-butyl nitrone (4-POBN) allowed the detection of free radical intermediates tentatively identified as 1-hydroxypropyl and 1-hydroxybutyl radical, respectively. Microsomes isolated from rats treated chronically with ethanol (EtOH) or with the combination of starvation and acetone treatment (SA), exhibited a two-fold increase in the ESR signal intensity as compared to untreated controls, whereas no increase was observed in phenobarbital-induced (PB) microsomes. Consistently, in reconstituted membrane vesicles, ethanol-inducible cytochrome P450IIE1 was twice as active as phenobarbital-inducible P450IIB1 in producing 1-butanol free radicals. In the microsomal preparations from EtOH and SA pretreated rats the addition of antibodies against cytochrome P450IIE1, but not of preimmune IgGs, lowered the ESR signal of 1-butanol radicals by more than 50%. The same antibodies decreased the free radical production by untreated microsomes by 35-40%, but were ineffective on microsomes from PB-treated animals. This indicated that cytochrome P450IIE1 is the major enzyme responsible for the free radical activation of alcohols in control and ethanol-fed rats. The generation of 1-hydroxybutyl radicals by EtOH microsomes was inhibited by 40, 48 and 68%, respectively, by the addition of isoniazid, tryptamine and octylamine, compounds known to specifically affect the NADPH oxidase activity of this isoenzyme. This effect was not due to the scavenging of the alcohol radical since none of these compounds affected the ESR signals originated from 1-butanol in a xanthine-xanthine oxidase system. When added to reconstituted membrane vesicles isoniazid, tryptamine and octylamine also decreased 1-butanol radical formation by P450IIE1 by 54, 38 and 66%, respectively. Such an inhibition corresponded to the effect exerted by the same compounds on O2- release from P450IIE1 containing vesicles. These results indicate that the capacity of cytochrome P450IIE1 to reduce oxygen is related to its ability to generate alcohol free radicals and suggest that ferric cytochrome P450-oxygen complex might act as oxidizing species toward alcohols.
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PMID:Role of ethanol-inducible cytochrome P450 (P450IIE1) in catalysing the free radical activation of aliphatic alcohols. 203 43


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