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At least 19 recordsLinked to original sources
PubMed1990

[Effect of alloxans on pancreatic B-cells with special regard to the alloxan-metal-complex theory. I. Effects of alloxan, alloxan-zinc chelates, dilauric acid and colchicine on blood sugar and rate of mitosis of B-cell Langerhans islets].

Alloxan, alloxan-zinc-chelate, sodium salt of dialuric acid, and colchicine significantly raised the blood sugar level under the previously mentioned experimental conditions 28 h after the application. The typical three-phase blood sugar curve development after alloxan (initial hyperglycemia, hypoglycemia, permanent hyperglycemia) was only approximately reached by dialuric acid which initiated, however, instead of the initial hyperglycemia a more pronounced hypoglycemic phase within the first 6 h. Alloxan-zinc-chelate protractedly and significantly made the blood sugar's increase up to the 7th d post injectionem, without being able to maintain a permanent hyperglycemia with half-normal dosage in comparison with alloxan. Non-diabetogenic alloxan doses (19 mg/kg i. v.) and the appropriate alloxan-zinc-chelate dosage (35 mg/kg) led to a significant increase of the blood sugar only in the chelate group with the long-term test up to 10 d, suggesting an increased and prolonged effect of the metal-chelates by stabilization of alloxan. The tested substances differently acted on the mitotic frequency of B-cells. The mitosis did not increase in the alloxan-zinc- and dialuric acid treated animals and was similar to normal animals far below the fractions of 1/10(6). A 4- and 5-fold increase of the mitotic frequency in the colchicine or alloxan treated animals as well as an accumulation of delayed metaphases suggest an impeded transition to the anaphase and include alloxan among the mitotic poisons.

Alloxan↗
PubMed1990

[Mechanism of action of alloxan on pancreatic B-cells with special regard to the alloxan-metal-complex theory. II. Actions of alloxan, alloxanic acid, Zn2+ and ethyleneglycol-bis-(beta-aminoethylether)-N,N'tetraacetic acid (EGTA) on the assembly of microtubule proteins (MTP) into microtubules or MPT sheets in vitro].

Analyses of the cell structures in the islets of Langerhans revealed the presence of 2 predominant cations, calcium (beta-granules and saccules, mitochondria, sac membranes, and cell membranes) and zinc (secretory granules, encasing membraneous sacs) in association with organelles which involve directional secretion. Both elements are known to interact with microtubules influencing their structural and functional properties, e.g. movement of secretory granules. Influences of Zn2+ on microtubules are investigated with a view to interactions in vitro with and without diabetogenic substances. Turbidimetry and electron microscopic investigations showed that under the conditions mentioned above, alloxan of a concentration of 2 x 10(-5) mol/l (alloxan/tubulin 1:1) inhibits the formation of microtubules and increases the portion of microtubules stabilized of 4 degrees C. The Zn2(+)-induced formation of MTP sheets is not influenced by alloxan and the metal complex forming agent EGTA, if the molar concentrations of the substance and Zn2+ are equally high. With a molar proportion of 2:1 (EGTA:Zn2+), the formation of sheets does not longer occur and only microtubules are formed, whereas neither sheets nor microtubules were assembled by alloxan with this molar proportion. However, neither the assembly of microtubules nor the formation of Zn2(+)-induced sheets are influenced by alloxanic acid in both molar proportions. It is shown that the diabetogenic alloxan influences the formation of microtubules and that performed microtubules are destroyed. This result of alloxan corresponds to its antimitotic activity analogously to the wellknown effect of colchicine (s. Schmidt et al. 1990).(ABSTRACT TRUNCATED AT 250 WORDS)

Alloxan↗
PubMed1975

The mechanism of alloxan toxicity: an indication for alloxan complexes in tissues and alloxan inhibition of 4-acetamido-4'-isothiocyanato-stilbene-2,2'-disulphonic acid (SITS) binding for the liver cell membrane.

It is shown that alloxan inhibits binding of SITS to liver cells. This indicates the cell membrane as a site of alloxan action. Alloxan is found to react with tissues to form complexes that are detectable up to 3 hrs after alloxan treatment. On the basis of the present findings, an assumption is made that alloxan inhibits a cell membrane processes by blockade of functionally importnat groups.

Alloxan↗
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↗
PubMed2002

[Alloxan radical-induced generation of reactive oxygen species in the reaction system of alloxan with ascorbate].

The diabetogenic action of alloxan is thought to be initiated by generation of reactive oxygen species (ROS). Ascorbate can be an antioxidant in a predominantly aqueous environment, such as plasma and extracellular fluids. We have investigated the generation of ROS in the interaction of alloxan with ascorbate. Rapid oxygen consumption was observed in the reactin system of alloxan with ascorbate. The oxygen consumption was suppressed by superoxide dismutase and catalase, suggesting that superoxide and hydrogen peroxide could be generated in the reaction system. In addition, the generation of alloxan radical, an electron reductance of alloxan, and ascorbate free radical (AFR), an electron oxidant of ascorbate, was observed using electron spin resonance (ESR). Under anaerobic conditions, the ESR signal intensity of alloxan radical was significantly increased in comparison with that under aerobic conditions, whereas the intensity of AFR was significantly decreased. These results suggest that alloxan radical and AFR were generated in the reaction system of alloxan with ascorbate, and that the alloxan radical but not AFR reacted with molecular oxygen, resulting in the generation of ROS.

Alloxan↗
PubMed1984

The effect of alloxan, and alloxan-induced diabetes on the kidney.

Alloxan is known to induce diabetic renal changes as well as causing nephrotoxic alterations. However, no ultrastructural study has been performed to differentiate diabetic verses toxic affects of alloxan to the tubule and/or glomerulus. Therefore the present study used the "protected" kidney model to prevent one kidney from being exposed to the alloxan while allowing the other to receive the drug immediately. In all experimental animals the right renal hilum was gently occluded for 5 minutes and then released. This was performed prior to the injection of alloxan. Subsequently, the left renal hilum was occluded at the time of, and for 5 minutes after, alloxan administration (40 mg/kg i.v.). The experimental rats were divided into three groups: untreated diabetics, diabetics treated with protamine-zinc-insulin, and alloxan-treated rats that failed to become diabetic. Three groups of controls were included: one group received an equal volume of saline diluent as the experimental rats but no clamping of either renal hilum; another group received the saline and had the left renal hilum occluded for 5 minutes; and a third group had both the right and left renal hila occluded. All animals were followed and sacrificed after 9 weeks. Endogenous creatinine clearance did not change among groups. Alloxan-treated nondiabetic rats displayed marked interstitial nephritis in unprotected kidneys, while protected kidneys were normal. The diabetic state resulted in mesangial proliferation and focal glomerular basement membrane thickening as well as glomerular capillary endothelial abnormalities and visceral epithelial foot-process fusion. The endothelial changes consisted of focal areas showing a reduction in the size of endothelial fenestrae. All glomerular changes were ameliorated by insulin treatment. We conclude: 1) alloxan per se is distinctly nephrotoxic; and 2) the glomerular endothelium and epithelium are involved early in the course of experimental diabetes.

Alloxan↗
PubMed1989

Alloxan-induced alterations in composition and dynamics of red blood cell membranes. I. Effect of alloxan on intact red blood cells and isolated erythrocyte membranes.

Changes of dynamics and chemical composition in membranes of intact red blood cells and isolated erythrocyte membranes treated with alloxan were investigated in order to assess whether alloxan-induced generation of active forms of oxygen may be critical for erythrocyte destroying. In vitro incubation of native red blood cells or prepared erythrocyte membrane ghosts with various concentrations of alloxan gave rise both to levels of membrane TBA-reacting substance and lipid membrane microviscosity both in the deeper and surface regions of lipid bilayer, as evidenced by fluorescence polarization technique. The amount of membrane phospholipid decreased upon alloxan action and that of membrane cholesterol remained rather unchangeable, thus resulting in significant elevation of membrane cholesterol:phospholipid (C:PL) ratio. Both time course and concentration effect of alloxan were found to change exponentially with the different rates of the reaction. There was a linear correlation between 1,6-diphenylhexatriene-1,3,5 (DPH) and 1-anilinonaphthalene-8-sulfonate (ANS) anisotropy coefficients and C:PL ratio (respectively r = 0.697 and r = 0.580) as well as TBARS levels (r = 0.386 for rDPH and r = 0.324 for rANS), thus implying the possible effect of membrane dialdehydes on bilayer components immobilization. Regression coefficients significance testing showed reaction rates of TBARS and C:PL changes to be significantly parallel, contrary to those of fluorescence anisotropy coefficients assessing considerably slower dynamics of alloxan-induced changes. The relevance of changes induced by alloxan in isolated erythrocyte ghosts and intact red blood cells and the compatibility of the present results with several previous studies support the widespreading idea pointing the cell membrane as a main target of damage during alloxan action.

Adult↗
PubMed1989

Generation of alloxan free radicals in chemical and biological systems: implication in the diabetogenic action of alloxan.

Electron spin resonance (ESR) studies that on reaction with NADPH, alloxan was reduced forming labile anion radicals giving a 7-line signal with g = 2.005. These radicals were also produced on incubation of alloxan with rat liver subcellular fractions and their production was greatly enhanced by NADPH. Alloxan effectively scavenged superoxide anion generated by a xanthine-xanthine oxidase (XOD) system in association with its reduction to these anion radicals. These radicals were also formed during incubation of alloxan with rat pancreatic beta-cells. These results suggest that the cytotoxicity of alloxan is related to the formation of alloxan anion radicals.

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↗
PubMed1954

The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. IV. The effect of insulin therapy on the inhibition of atherosclerosis in the alloxan-diabetic rabbit.

Experiments were undertaken to ascertain whether the previously demonstrated inhibition of the development of experimental aortic atherosclerosis in alloxan-diabetic rabbits fed cholesterol was due to the injection of alloxan per se or to the existence of the diabetic state produced by alloxan. It was established that, by treating the diabetic state with insulin, the diabetic state could be ameliorated and the inhibitory effect obviated. It was therefore concluded that the inhibitory phenomenon was not due to the injection of alloxan per se but that it was associated with one or more factors that characterize the alloxan diabetic state in the rabbit and that are reversible by insulin therapy. In the course of the experiment it was demonstrated that the inhibitory effect was apparent in cholesterol-fed diabetic rabbits whether or not their diet was supplemented with vegetable oil. The previously reported metabolic abnormalities of the diabetic animals were confirmed. It was established that suitable treatment of the cholesterol-fed diabetic animals with insulin would bring all the metabolic aberrations, including those of the serum lipids, into reasonably close correspondence with those observed in non-diabetic rabbits fed cholesterol.

Alloxan↗
PubMed1995

Effect of ferritin on lambda DNA strand breaks in the reaction system of alloxan plus NADPH-cytochrome P450 reductase: ferritin's role in diabetogenic action of alloxan.

The incubation of lambda DNA in the reaction system of alloxan plus NADPH-cytochrome P450 reductase (fp2) in the presence of ferritin caused strand breaks after a lag time of about 5 min. Addition of ferritin to the reaction system at concentrations below 50 micrograms/ml caused the strand breaks of DNA in a concentration-dependent fashion. Catalase, scavengers of hydroxyl radicals (HO.) and iron-chelators almost completely inhibited the DNA strand breaks, but superoxide dismutase (SOD) did not, suggesting that the strand breaks are induced by the generation of HO. via the reaction of H2O2 and Fe(II), namely, the Fenton reaction. When the ferritin was incubated in the reaction system of alloxan plus fp2, the iron release from ferritin increased with incubation time depending on the amount of fp2. The addition of increasing concentrations of ferritin to the reaction system resulted in progressive increase in the iron release and a decrease in the electron spin resonance signal intensity of alloxan radical (HA.), the one electron reduced form of alloxan, suggesting that HA. generated in the reaction system is capable of releasing iron from ferritin. These results support the possibility that the iron released from ferritin may be involved in the diabetogenic action of alloxan.

Alloxan↗
PubMed1993

The relationship between the physicochemical properties and the biological effects of alloxan and several N-alkyl substituted alloxan derivatives.

Alloxan causes diabetes in experimental animals through its ability to destroy the insulin-secreting B-cells of the pancreas. Alloxan is hydrophilic and chemically unstable; it is reactive toward thiols, undergoing redox cycling in the presence of glutathione and oxidizing protein-bound thiol groups, as reflected by inhibition of the thiol enzymes, hexokinase and glucokinase. It is apparently also selectively taken up by the GLUT-2 glucose transporter in the pancreatic B-cell membrane. In order to investigate which, if any, of these physicochemical properties are important in the toxic action of alloxan, we have examined seven N-alkyl substituted alloxan derivatives of various diabetogenic activity. Hydrophilicity was identified as a factor essential for diabetogenicity. Stability, rate of redox cycling and reactivity toward thiol groups were not correlated with diabetogenicity. Selective uptake by the GLUT-2 glucose transporter is not a prerequisite for the diabetogenicity of alloxan derivatives.

Alloxan↗
PubMed1989

Generation of free radicals by alloxan in the presence of bovine serum albumin: a role of protein sulfhydryl groups in alloxan cytotoxicity.

The interaction of alloxan with bovine serum albumin was studied. When alloxan was incubated with bovine serum albumin, oxygen consumption, H2O2 formation, and diminution of sulfhydryl groups of the protein were observed. During the reaction of alloxan with the protein, superoxide radicals were generated; and under anaerobic conditions, ESR signal of alloxan free radicals was observed. These results strongly suggest that alloxan mediates electron transfer from the protein sulfhydryl groups to oxygen.

Alloxan↗
PubMed1977

The endocrine pancreas in early alloxan diabetes. Including study of the alloxan inhibitory effect of feeding and some hexoses.

Starved animals were sensitive to alloxan, whereas a more or less inhibitory effect towards alloxan was observed in fed animals, and in starved animals pretreated with glucose, mannose or fructose, but not in those pretreated with galactose. The islets of starved controls possessed larger B-cell mitochondria than those of fed ones. The earliest B-cell changes in the alloxan-treated animals were localized to the mitochondria which showed swelling, and disruption of inner and occasionally outer membranes. Later, many mitochondria were disintegrated, and the endoplasmic reticulum and Golgi complex disorganized. The secretory granules were preserved, although sometimes with atypical configuration, in degenerating but non-necrotic B-cells, suggesting that insulin stored in granules is not released until the cells are necrotic. Finally, frank necrosis was seen in some B-cells, whereas others were unaffected. The Ca2+-precipitation studied by pyroantimonate technique and x-ray analysis differed in the B-cells of the alloxan-treated animals from that in the controls; the former animals exhibited no or only sparse precipitation in mitochondria and secretory granules, but a rich precipitation in the cytoplasmic ground substance, whereas the precipitation in the controls mainly was localized to mitochondria and secretory granules. The primary site of alloxan action in the B-cells is believed to be localized to the mitochondria.

Animals↗
PubMed1983

Loss of a priming effect of glucose on A and D cell secretion in perfused pancreases from alloxan-diabetic rats: role of insulin and alloxan.

Under normal conditions, glucose acutely influences pancreatic islet B, A and D cell secretion. In addition, prior exposure to glucose modulates the secretory responsiveness of these cells (priming effect). We have tested whether alloxan diabetes influences priming effects of glucose on A and D cell secretion. Rat pancreases were perfused 72 h after alloxan treatment. A 20 min infusion of 27.7 mmol/l of glucose failed to induce priming effects, i.e. it did not inhibit the glucagon nor amplify the somatostatin response to a subsequent (15 min later) infusion of 8 mmol/l of arginine. Insulin treatment in vivo for 48 h restored a priming effect of glucose on glucagon secretion in the perfused pancreas, i.e. exposure to 27.7 mmol/l of glucose now inhibited subsequent arginine-induced glucagon secretion by 48% relative to a stimulation period with arginine preceding the glucose pulse (from 5.0 +/- 0.7 to 2.6 +/- 0.5 ng/min, p less than 0.01). Conversely, insulin treatment in vivo did not restore a priming effect of glucose on somatostatin secretion. Other effects noted were failure of 27.7 mmol/l glucose to stimulate, during its presence, the release of somatostatin from pancreases of the diabetic rats whether untreated or insulin-treated. Furthermore, insulin treatment abolished the arginine-induced somatostatin secretion observed in pancreases from untreated rats. It is concluded that short-term alloxan diabetes leads to loss of a priming effect of glucose on glucagon secretion and that this abnormality is secondary to direct or indirect effects of insulinopenia. Concomittant abnormalities of glucose regulation of somatostatin secretion may, in part, be secondary to a cytotoxic effect of alloxan on the D cell.

Alloxan↗
PubMed1982

Superoxide dismutase-inhibitible reduction of cytochrome c by the alloxan radical. Implications for alloxan cytotoxicity.

Cytochrome c was reduced when superoxide was generated from xanthine oxidase in the presence of alloxan, and by the reaction of alloxan and with reduced glutathione. In each case, most of the reduction was inhibited by superoxide dismutase, but considerably more enzyme was required than with superoxide alone. This indicates that the superoxide dismutase-inhibitible cytochrome c reduction was mainly due to a direct reaction with the alloxan radical, and implies that other reactions that are inhibited by superoxide dismutase could be due to either alloxan radicals or superoxide.

Alloxan↗
PubMed1995

Protection against alloxan diabetes by low-dose 60Co gamma irradiation before alloxan administration.

We evaluated the protective effects of a single low-dose whole body 60Co gamma irradiation against alloxan-induced hyperglycemia in rats. i) In rats that did not receive alloxan, the superoxide dismutase (SOD) activity in the pancreas significantly increased after irradiation at a dose of 0.5 or 1.0 Gy. ii) In rats that received alloxan, plasma lipid peroxide levels, pancreatic lipid peroxide levels and blood glucose were increased. However, the increase in pancreatic lipid peroxide level was prevented by irradiation at a dose of 0.5 or 1.0 Gy; and the increase in blood glucose, by irradiation at 0.5 Gy. iii) After alloxan administration, degranulation was observed in beta cells, but this was prevented by low-dose irradiation at 0.5 Gy.

Animals↗
PubMed1950

The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. III. The mechanism of the inhibition of experimental cholesterol atherosclerosis in alloxan-diabetic rabbits.

A study of the serum lipids in normal and alloxan-diabetic rabbits during the course of cholesterol feeding is presented, particular attention being paid to the factors considered to be responsible for the stability of the serum lipids; namely, (1) their interrelations and (2) their association with the serum proteins. As far as the interrelations of the lipids were concerned a definite correlation was found between the development of atherosclerosis and an increase of serum cholesterol that was out of all proportion to the increase of serum lipid phosphorus and neutral fat. When these last two lipid constituents rose almost parallel with the serum cholesterol (as they did in some alloxan-diabetic rabbits), then the development of atherosclerosis was inhibited. This correlation was independent of the diabetic state, per se. It appeared likely that the marked elevation of serum neutral fat and lipid phosphorus in the diabetic animals was due to mobilization of body fat because of the disturbed carbohydrate metabolism. Because of their hydrophilic and emulsifying properties, it was thought probable that the elevation of the phospholipids was the important factor responsible for the stability of serum cholesterol. That neutral fat played a role, however, could not be denied. In normal rabbit sera, as we have previously shown, only small proportions of the lipid phosphorus and cholesterol are "readily extractable" (i.e., unattached or only loosely attached to protein). On the other hand, in every case in which the serum lipids were elevated, the greater proportion of the lipid phosphorus and cholesterol was "readily extractable," irrespective of whether atherosclerosis developed or was inhibited. Analysis of the lipid content of the aorta of rabbits not fed cholesterol, whether diabetic or non-diabetic, and from alloxan-diabetic rabbits fed cholesterol but protected from the development of atherosclerosis, showed that there was no significant difference in lipid content or composition among the animals of these groups. When atherosclerosis developed following cholesterol feeding, the lipid composition of the aortas was essentially the same in both control and diabetic animals. The deposited lipid consisted predominantly of cholesterol with small and fairly constant proportions of other lipids that did not vary significantly regardless of the quantities of these other lipids present in the circulating blood. In the less severe lesions the proportion of ester cholesterol was greater than that of free cholesterol, but in advanced lesions the reverse was true. The following conclusions are drawn concerning the pathogenesis of experimental cholesterol atherosclerosis in the rabbit: 1. Instability of cholesterol in the blood rather than hypercholesterolemia, per se, is the general condition responsible for the deposition of this substance in the arterial walls. 2. Of the two factors considered to be responsible for the stability of the lipids in the blood, the interrelations of the lipids appear to be more important than their relation to the serum proteins, at least in so far as the development of experimental cholesterol atherosclerosis is concerned. The importance of these conclusions in relation to the pathogenesis of human atherosclerosis is discussed.

Alloxan↗