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At least 19 recordsLinked to original sources
PubMed2004

Oxidation of 5-hydroxy-2'-deoxyuridine into isodialuric acid, dialuric acid, and hydantoin products.

Oxidation products of cytosine, including 5-hydroxycytosine and 5-hydroxyuracil, are highly susceptible to subsequent oxidation. Here, the oxidation products of 5-hydroxy-2'-deoxyuridine have been studied by NMR and MS analyses. The initial products were diastereomers of isodialuric acid nucleoside. These products subsequently decomposed into corresponding dialuric acid derivatives at neutral pH. The position of the carbonyl and hydroxyl groups, at C5 and C6 for isodialuric acid and at C6 and C5 for dialuric acid derivatives, respectively, was determined by 1H- and 13C NMR analyses. In addition, these analyses revealed that the carbonyl groups of both isodaluric and dialuric acid derivatives exist in their fully hydrated form in aqueous solution. Finally, the dialuric acid derivatives were observed to undergo subsequent decomposition into the corresponding 5-hydroxyhydantoin derivatives. Studies of a trinucleotide containing 5-hydroxyuracil suggest that the reactions described herein for the monomer can be extrapolated to DNA.

Barbiturates↗
PubMed1989

Release of iron from ferritin by divicine, isouramil, acid-hydrolyzed vicine, and dialuric acid and initiation of lipid peroxidation.

Release of iron from ferritin by the polyhydroxypyrimidines, dialuric acid, isouramil, divicine, and acid-hydrolyzed vicine, was measured. Iron was released at fast initial rates which gradually declined to zero in 10 min. All the compounds were better reductants for ferritin-iron under nitrogen than in air. The effects of superoxide dismutase, catalase, and glutathione on both initial rates and total iron released over 30 min in air were determined. Major effects were inhibition by superoxide dismutase for divicine and isouramil and enhancement for dialuric acid and acid-hydrolyzed vicine. Glutathione promoted increased iron release that was further enhanced by superoxide dismutase. These increases were particularly striking over the longer time period. Catalase, in all cases, gave modest enhancement. Enhanced iron release correlated with inhibition of pyrimidine oxidation. The results indicate that the reduced form of each pyrimidine releases ferritin iron directly, and the effects of the antioxidants are mainly to maintain or regenerate the reduced pyrimidines. A combination of each pyrimidine and ferritin caused peroxidation of phopholipid liposomes, above that seen with the pyrimidines and adventitious iron. Glutathione, superoxide dismutase, and catalase modulated lipid peroxidation in a way consistent with their effects being mainly on ferritin-iron release. On the basis of our findings, we propose that the release and subsequent reactions of ferritin-iron may contribute to the toxicity of these compounds. Although glutathione and superoxide dismutase together efficiently inhibit redox cycling and H2O2 production from the pyrimidines, this combination maximized iron release from ferritin and ferritin-dependent lipid peroxidation.

Barbiturates↗
PubMed1989

Auto-oxidation of dialuric acid, divicine and isouramil. Superoxide dependent and independent mechanisms.

The toxicity of dialuric acid to pancreatic beta cells, and the haemolytic action of divicine and isouramil involve auto-oxidation and redox cycling reactions. Divicine and isouramil are produced on hydrolysis of the fava bean glycosides, vicine and convicine. The mechanism of auto-oxidation of the three compounds as well as the acid hydrolysis product of vicine (provisionally assigned the structure 2-amino-4,5,6-trihydroxypyrimidine) has been studied. All four pyrimidines auto-oxidized rapidly at neutral pH, generating H2O2 by an O2-dependent chain mechanism. Superoxide dismutase inhibited the initial oxidation, but inhibition was transitory, and after a lag period rapid oxidation occurred. The lag period varied with pH, temperature and pyrimidine concentration, and was much shorter for isouramil and divicine than for dialuric acid and acid-hydrolysed vicine. The initial rate of dialuric acid oxidation was greater and the acceleration less pronounced than with the other pyrimidines. A mechanism common to all four pyrimidines has been shown by kinetic analysis to account for nearly all the observations in the presence and absence of superoxide dismutase. Autocatalysis in the latter case is attributed mainly to the reactions reduced pyrimidine + oxidized pyrimidine in equilibrium 2 pyrimidine radical pyrimidine radical + O2----oxidized pyrimidine + O2- Rate constants for these and other reactions are reported. At pH 7.4 and 37 degrees the lag period before 100 microM acid-hydrolysed vicine underwent rapid oxidation was approx. 15 min. Isouramil and divicine at an equivalent concentration gave lags of less than 1 min, which became less at higher concentrations. Thus intracellular superoxide dismutase should provide only transitory protection against the oxidation products of dialuric acid, divicine or isouramil. Prolonged protection should only be achieved if accumulation of oxidized pyrimidine is also prevented.

Alloxan↗
PubMed2006

Mechanistic aspects of alloxan diabetogenic activity: a key role of keto-enol inversion of dialuric acid on ionization.

The inversion of the keto-enol stability order of dialuric acid on ionization was calculated and verified experimentally. The radical cations in both forms were characterized. The spectrum of the keto form was observed upon direct ionization of dialuric acid under matrix conditions, whereas the enol form was formed upon a sequential electron-proton-proton attachment to alloxan under acidic aqueous condition. Facilitation of the one-electron oxidation of dialuric acid upon its enolization can result in a more effective formation of superoxide radical anion in the process of its auto-oxidation. This process is discussed in reference to the alloxan diabetogenic action. Both neutral keto and enol forms are energetically close, and under favorable conditions, the auto-oxidation of dialuric acid could involve participation of the enol form.

Alloxan↗
PubMed1982

The desolvation and oxidation of crystals of dialuric acid monohydrate.

Examination of the influence of the solvent of crystallization on the solid-state oxidation of dialuric acid (I) monohydrate to alloxantin (II) is reported. This reaction was investigated at low and high humidities using photomicrography, X-ray crystallography, and IR and mass spectrometry. Crystals of dialuric acid desolvated somewhat anisotropically; this behavior was consistent with crystal packing. The desolvated crystals of dialuric acid monohydrate had approximately the same crystal structure as the monohydrate and were stable in air at room temperature at low humidities. At high humidity, these crystals rehydrated and rapidly oxidized to alloxantin. These studies showed for the first time that desolvation was not a necessary prerequisite to solid-state oxidation and that solid-state oxidation reactions could be accelerated by high humidity.

Barbiturates↗
PubMed1988

Dialuric acid autoxidation. Effects of transition metals on the reaction rate and on the generation of "active oxygen" species.

The autoxidation of dialuric acid, a process which is believed to be of crucial importance in the diabetogenic action of alloxan, was found to be strongly catalysed by copper, iron and manganese. Superoxide radical and hydrogen peroxide were generated in both the uncatalysed and the metal-catalysed reactions. In contrast, hydroxyl radical was formed during dialuric acid autoxidation only in the presence of added iron salts. Production of the latter radical was strongly inhibited by catalase but only weakly by superoxide dismutase, implying that the metal-catalysed Haber-Weiss reaction is of comparatively little importance in hydroxyl radical generation from dialuric acid.

Animals↗
PubMed2006

Relative importance of cellular uptake and reactive oxygen species for the toxicity of alloxan and dialuric acid to insulin-producing cells.

The diabetogenic agent alloxan is selectively accumulated in insulin-producing cells through uptake via the GLUT2 glucose transporter in the plasma membrane. In the presence of intracellular thiols, especially glutathione, alloxan generates "reactive oxygen species" (ROS) in a cyclic reaction between this substance and its reduction product, dialuric acid. The cytotoxic action of alloxan is initiated by free radicals formed in this redox reaction. Autoxidation of dialuric acid generates superoxide radicals (O(2)(*-)) and hydrogen peroxide (H(2)O(2)), and finally hydroxyl radicals ((*)OH). Thus, while superoxide dismutase (SOD) only reduced the toxicity, catalase, in particular in the presence of SOD, provided complete protection of insulin-producing cells against the cytotoxic action of alloxan and dialuric acid due to H(2)O(2) destruction and the prevention of hydroxyl radical ((*)OH) formation, indicating that it is the hydroxyl radical ((*)OH) which is the ROS ultimately responsible for cell death. After selective accumulation in pancreatic beta cells, which are weakly protected against oxidative stress, the cytotoxic glucose analogue alloxan destroys these insulin-producing cells and causes a state of insulin-dependent diabetes mellitus through ROS-mediated toxicity in rodents and in other animal species, which express this glucose transporter isoform in their beta cells.

Alloxan↗
PubMed1975

Bactericidal activity of superoxide anion and of hydrogen peroxide: investigations employing dialuric acid, a superoxide-generating drug.

The addition of dialuric acid (a superoxide-generating drug) to a suspension of resting human neutrophils resulted in a stimulation of cellular hexose monophosphate shunt activity. Measurement of oxygen consumption demonstrated a rapid rate of oxygen uptake by the drug alone in aqueous solution. The subsequent addition of catalase (but not of superoxide dismutase) resulted in a substantial release of oxygen, indicating that H(2)O(2) was accumulating in the media. The generation of O(2) (-) by the drug was verified by measuring the rate of reduction of cytochrome c by the drug in the presence and absence of authentic superoxide dismutase. The growth of Escherichia coli B and Staphylococcus aureus was inhibited in vitro by addition of the drug to a suitable culture media; the degree of inhibition was dose dependent. This inhibition of bacterial growth could be completely reversed by the addition of as little as 5 mug of purified catalase, but was not affected by concentrations of superoxide dismutase that were 2,000-fold higher. These results suggest that the dialuric acid-induced stimulation of hexose monophosphate shunt activity in neutrophils is due to accumulated H(2)O(2). Further, the contribution of superoxide to the bactericidal activity towards E. coli and S. aureus is probably minimal compared with that of H(2)O(2).

Barbiturates↗
PubMed2001

Simultaneous quantitative determination of alloxan, GSH and GSSG by HPlc. Estimation of the frequency of redox cycling between alloxan and dialuric acid.

This in vitro study compares the frequency of redox cycling between alloxan and dialuric acid at different initial ratios of glutathione and alloxan. Alloxan oxidizes GSH to GSSG. The rate of GSH oxidation at a given initial GSH concentration of 2.0 mmol/L depends on the initial concentration of alloxan added. The higher the concentration of alloxan in relation to the initial concentration of GSH, the faster GSH oxidation proceeds, as well as oxygen consumption, and therefore, formation of reactive oxygen species. The highest rates of GSH oxidation, i.e. GSSG formation, were found at concentration ratios of between 2.0 mmol/L GSH and 0.2 and 0.04 mmol/L alloxan, respectively. Because 0.04 mmol/L alloxan oxidizes 2.0 mmol/L GSH completely, a frequency of at least 25 cycles between alloxan and dialuric acid within 3 hours can be assumed. During each redox cycle, two molecules of GSH are oxidized to one molecule of GSSG, and during each cycle one molecule of oxygen is reduced simultaneously to one molecule of hydrogen peroxide. In total, therefore, one molecule of alloxan oxidizes at least 50 molecules of GSH and forms about 25 molecules of hydrogen peroxide.

Alloxan↗
PubMed2005

Influence of oxygen concentration on redox cycling of alloxan and dialuric acid.

Alloxan, a chemical diabetogen, decays in the absence of reductants into alloxanic acid. In the presence of glutathione, it is reduced via the alloxan radical into dialuric acid, which autoxidizes back to alloxan. During this redox cycling process, reactive oxygen species are formed that destroy beta-cells in islets of Langerhans. Previous experiments were conducted with oxygen concentrations about ten times as high as within cells. The aim of our in vitro study was to evaluate the impact of different oxygen concentrations (0, 25, 250 micromol/l) at a given initial ratio of glutathione and alloxan on this redox cycling. Reduction of alloxan, oxidation of glutathione, and the formation of glutathiol (GSSG) were continuously recorded by HPLC for 90 minutes at 25 degrees C in air, calibration gas, or argon. In the absence of reductants, alloxan irreversibly decomposed into alloxanic acid regardless of oxygen presence. When the reaction system contained glutathione, decomposition was significantly retarded and therefore influenced by oxygen. In argon, decay could not be observed due to its reduction and the absence of oxygen. Increasing oxygen concentration enabled a redox cycling and therefore an ongoing decay. The highest decomposition along with the highest consumption of glutathione occurred at 250 micromol/l oxygen. The lower the oxygen, the more dialuric acid could be detected. After calculation, about 33 redox cycles per hour generates an amount of reactive oxygen species sufficient to damage pancreatic beta cells and induce insulin deficiency.

Alloxan↗
PubMed1997

Glutathione dependent reduction of alloxan to dialuric acid catalyzed by thioltransferase (glutaredoxin): a possible role for thioltransferase in alloxan toxicity.

Recombinant pig liver thioltransferase (rPLTT) catalyzes the reduction of alloxan to dialuric acid by glutathione (GSH). This is the second non-disulfide substrate, after dehydroascorbic acid, described for thioltransferase. The reaction kinetics, measured by a coupled assay including glutathione disulfide reductase and NADPH yielded a Km = 82 microM for alloxan, a k(cat) = 37 s(-1), and a k(cat)/Km = 4.5 x 10(5) M(-1) s(-1). The presence of rPLTT suppressed the competitive formation of compound 305, an alloxan-GSH conjugate of unknown structure, and at GSH concentrations between 0.05 mM and 1.5 mM, oxygen consumption was greater than that recorded in the uncatalyzed reaction. Both superoxide dismutase and catalase inhibited oxygen consumption in 1.0 mM GSH and 0.2 mM alloxan in the presence of rPLTT. This study suggests that thioltransferase (glutaredoxin) plays a significant role in the cytotoxicity of alloxan in vulnerable tissues.

Alloxan↗
PubMed1981

Changes of alpha-tocopherol levels in red blood cells and plasma with respect to hemolysis induced by dialuric acid in vitamin E-deficient rats.

The plasma and red blood cell (RBC) levels of alpha-tocopherol in rats were determined in association with hemolysis induced by dialuric acid for a 7-week period of tocopherol deprivation following a 2-week period on tocopherol-containing diet. The patterns of decreases in plasma and RBC levels during the 7-week period were similar, differing in one respect. The RBC levels were characterized by a prompt decrease to non-detectable levels in the 4th week, while at that time a plasma level of 100 microgram/dl, albeit low, was maintained during the subsequent two weeks. Consequently, tocopherol ratios of RBC to plasma lowered throughout the experimental course. As for the relationship between these levels and hemolysis values, non-hemolysis was recorded in animals whose minimum RBC and plasma levels were 40 microgram/dl packed cell and 180 microgram/dl, respectively. This experiment showed that the plasma tocopherol level which has traditionally been accepted as the only index of hemolysis values does not always reflect them, and that in animals with hemolysis, only RBC tocopherol levels were found to reflect hemolysis values.

Animals↗