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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↗
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↗
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↗
PubMed1978

Alloxan uptake by isolated rat islets of Langerhans.

Alloxan inhibits subsequent glucose-induced insulin release from isolated rat islets of Langerhans maintained in vitro. Several agents (D-glucose, D-mannose, 3-0-methyl-D-glucose, caffeine, and cytochalasin B) when present during the alloxan exposure protect against alloxan inhibition of insulin release. To examine the mechanism of alloxan inhibition, the uptake of [2-14C]alloxan was measured in isolated islets. [2-14C]Alloxan was rapidly accumulated by the islets in a time- and temperature-dependent manner. The radio-activity from islets incubated with [2-14C]alloxan was isolated and shown by thin layer chromatography to comigrate with alloxan and alloxanic acid, an alloxan decomposition product. As no uptake of radioactivity occurred in the presence of medium containing the radioactive decomposition product, it was concluded that alloxan enters the intracellular space of the islet and undergoes a subsequent internal decomposition. Some of the protective agents (3-0-methyl-D-glucose, caffeine, and cytochalasin B) partially inhibited alloxan uptake, whereas others (D-glucose and D-mannose) increased the uptake of alloxan. These and other results suggest that the experimental agents do not provide protection against alloxan inhibition by preventing the entry of alloxan into the intracellular space of the islet. The possibility of D-glucose and alloxan competing for a common binding site on the cell membrane is discussed.

Alloxan↗
PubMed1992

Protection of B cells against the effect of alloxan.

Alloxan induces diabetes in laboratory animals through the destruction of the endocrine pancreatic B cells. The mechanism of alloxan toxicity is still obscure. This study was conducted to investigate the effects of superoxide dismutase (SOD) or reduced nicotinamide adenine dinucleotide (NADPH) treatment on the B cells in isolated rat islets prior to alloxan treatment. Islets were treated with SOD (1000 U) or 0.1 mM NADPH for 10 min followed by alloxan treatment (0.18 mg) for 5 min. Insulin secretion was studied in samples incubated for 60 min in media supplemented with glucose (1.8 mg/ml). Morphological examinations were conducted on fixed samples after the alloxan treatment. SOD significantly protected the islets from the cytotoxic effect of alloxan. Although alloxan decreased insulin secretion to 35% of the control, SOD increased this level to 73% of the control values. NADPH did not provide any protection to the islets. Insulin secretion from islets treated with NADPH and alloxan was not different from that after alloxan treatment alone. Morphological changes were observed in the islets treated with alloxan alone or alloxan in the presence of NADPH. Islets exhibited multiple cellular necrosis, marked degranulation and extensive vesiculation of the endoplasmic reticulum and Golgi complex. Mitochondrial enlargement with disrupted cristae and mitochondrial ruptures were prominent. However, islets treated with SOD and alloxan were similar to the control except for the enlarged mitochondria. The increased insulin secretion from islets treated with SOD and alloxan reinforces the free radical hypothesis of alloxan toxicity. The markedly enlarged mitochondria was one of the targets through which alloxan destroyed the B cells.

Alloxan↗
PubMed1992

Effects of alloxan and ninhydrin on mitochondrial Ca2+ transport.

Alloxan at millimolar concentrations slightly inhibited the velocity of Ca2+ uptake by isolated rat liver mitochondria irrespective of the free Ca2+ concentration between 1 and 10 microM and was an effective concentration-dependent stimulator of mitochondrial Ca2+ efflux. Ninhydrin also slightly inhibited the velocity of mitochondrial Ca2+ uptake but only at free Ca2+ concentrations above 5 microM. However, ninhydrin was a strong stimulator of mitochondrial Ca2+ efflux even at micromolar concentrations, 10-50 times more potent than alloxan. The mitochondrial membrane potential was reduced 10-20% at most by alloxan and ninhydrin. Alloxan and ninhydrin also stimulated Ca2+ efflux from isolated permeabilized liver cells. When isolated intact liver cells had been pre-incubated with alloxan or ninhydrin before permeabilization of the cells the ability of spermine to induce mitochondrial Ca2+ uptake was abolished. Glucose provided the typical protection against the effects of alloxan on mitochondrial Ca2+ transport only in experiments with intact cells but not in experiments with permeabilized cells or isolated mitochondria. Therefore glucose protection is apparently due to inhibition of alloxan uptake into the cell. Glucose provided no protection against effects of ninhydrin under any of the experimental conditions. Thus both alloxan and ninhydrin are potent stimulators of Ca2+ efflux by isolated mitochondria but very weak inhibitors of the velocity of mitochondrial Ca2+ uptake. The direct effects of ninhydrin on mitochondrial Ca2+ efflux may contribute to the cytotoxic action of this agent whereas the direct effects of alloxan on mitochondrial Ca2+ transport require concentrations which are too high to be of relevance for the induction of the typical pancreatic B-cell toxic effects of alloxan. However, the effects on mitochondrial Ca2+ transport during incubation of intact cells which may result from the generation of cytotoxic intermediates during alloxan xenobiotic metabolism may well contribute to the pancreatic B-cell toxic effect of alloxan.

Alloxan↗
PubMed1991

Interactions of diabetogenic compounds: cyproheptadine and alloxan.

Pretreatment with an oral dose (45 mg/kg) of cyproheptadine (CPH), a drug that inhibits secretion and synthesis of insulin. 3 hr before alloxan (100 mg/kg, iv) protects mice from the permanent diabetes produced by alloxan. Pretreated animals at the time of alloxan administration were hyperglycemic. Therefore, the possibility that CPH-induced hyperglycemia protected mice from alloxan was investigated. This was accomplished by giving mannoheptulose (a glucose antagonist) or insulin (to lower blood glucose) after CPH and before alloxan. These interventions eliminated CPH-induced protection from alloxan, indicating a role for CPH-induced hyperglycemia in the protective effect. To confirm that CPH does not protect mice from alloxan-induced diabetes by a direct action, in vitro experiments using isolated pancreatic islets were conducted. Mouse islets were pretreated with CPH, its metabolite desmethylcyproheptadine (DMCPH), or an equal mixture of the two and/or various concentrations of glucose prior to an acute exposure to a toxic concentration of alloxan. Glucose-stimulated insulin release was used as a measure of pancreatic beta-cell function after alloxan exposure. CPH or DMCPH (alone or in combination) pretreatment did not provide protection against alloxan-induced inhibition of insulin release nor did pretreatments potentiate the protective action of glucose against in vitro alloxan toxicity. The results indicate that the protective action of CPH when given to mice before alloxan is due to drug-induced hyperglycemia and not to a direct effect of CPH or its metabolite.

Alloxan↗
PubMed1992

Inhibition of aconitase by alloxan and the differential modes of protection of glucose, 3-O-methylglucose, and mannoheptulose.

Alloxan inhibited aconitase with a half maximal inhibitory concentration of 0.5 mM in sonically disrupted and 2.3 mM in intact isolated liver mitochondria. For dialuric acid the half maximal inhibitory concentrations were 1.1 mM and 2.5 mM, respectively. Ninhydrin and N-ethylmaleimide (NEM) also inhibited aconitase with half maximal inhibitory concentrations in the submillimolar range and t-butylhydroperoxide (BuOOH) in the millimolar range, which, however, were not different for disrupted and intact mitochondria. Only the aconitase substrate citrate, but not glucose provided protection of the enzyme against inhibition. In intact liver cells the half maximal inhibitory concentration for alloxan was 6.8 mM. Again, dialuric acid and BuOOH were less potent inhibitors while ninhydrin and NEM were more potent inhibitors of aconitase in intact liver cells. In intact liver cells, glucose and 3-O-methylglucose, but not mannoheptulose and citrate provided protection against alloxan inhibition. The results show that aconitase is not an enzyme particularly sensitive towards alloxan inhibition and thus apparently not a primary site for mediation of alloxan toxicity as it is the glucokinase. This makes a primary site of alloxan action in the mitochondria extremely unlikely. On the other hand the results demonstrate that both the intact mitochondrial and plasma membrane as uptake barriers provide protection against alloxan toxicity. In addition the results clearly show, that 3-O-methylglucose provides protection against alloxan action only at the level of the plasma membrane through inhibition of alloxan uptake into the cell, while the site of protection of mannoheptulose is only the sugar binding site of the glucokinase. In contrast, glucose is shown here to be the only sugar with a dual protective effect both through inhibition of alloxan uptake through the plasma membrane like 3-O-methylglucose and through protection of the glucokinase sugar binding site against alloxan inhibition of the enzyme like mannoheptulose. In the light of these results the unique protective potency of glucose as compared to that of other sugars is not surprising.

3-O-Methylglucose↗
PubMed1991

Differential actions of central alloxan upon opioid and nonopioid antinociception in rats: a further examination.

Previous work demonstrated that central pretreatment with alloxan significantly reduced antinociception induced by morphine and 2-deoxy-D-glucose (2DG), an opioid-mediated stressor, but not induced by continuous cold-water swims (CCWS), a nonopioid-mediated stressor. The alloxan-induced deficits in 2DG antinociception were ameliorated by coadministration of D-glucose (3 M, 3M-DG). The present study evaluated this relationship further by: a) examining whether central alloxan reduced morphine antinociception following either simultaneous 3M-DG and alloxan coadministration, alloxan followed 10 days later by 3M-DG and 3M-DG alone, and b) determining whether central alloxan pretreatment altered nonopioid antinociception induced by the muscarinic cholinergic agonist, pilocarpine. Morphine (2.5-5 mg/kg, SC) antinociception on the tail-flick and jump tests was significantly reduced by central alloxan. In contrast, simultaneous coadministration of 3M-DG and alloxan failed to alter morphine antinociception. This ameliorative effect of 3M-DG was not due to its ability to affect morphine antinociception, and was time-dependent in that delays in 3M-DG administration failed to affect the alloxan-induced deficit. Central alloxan pretreatment failed to alter pilocarpine antinociception on the tail-flick test, and increased pilocarpine antinociception on the jump test. That central alloxan reduced opioid (e.g., morphine and 2DG), but not nonopioid (e.g., CCWS, pilocarpine) forms of antinociception suggests a specific mode of action, possibly through disruptions of glucoprivic control mechanisms which is in keeping with the suggestion that opioid systems are sensitive to changes in central glucose function.

Alloxan↗
PubMed1978

Alloxan stimulation and inhibition of insulin release from isolated rat islets of Langerhans.

The rate of alloxan-induced insulin release was measured from rat islets maintained in a simple perifusion system. Insulin release during the five-minute exposure to alloxan reached its maximum rate after two to three minutes of the exposure and then rapidly declined. This insulin release was dependent upon extracellular calcium and was associated with an increased 45Ca uptake by isolated islets. Once exposed to alloxan, however, the islets did not release insulin when stimulated again with D-glucose or alloxan. These effects of alloxan on insulin release (stimulation and subsequent inhibition) and the increased 45Ca uptake were prevented by the presence of 3-0-methyl-D-glucose during the alloxan exposure. These findings indicate a close correlation between alloxan-induced insulin release and the subsequent inhibition of further insulin release. D-glucose, when present during the entire five-minute exposure to alloxan, protected competitively against alloxan inhibition of insulin release. In addition, D-glucose, when present immediately after brief (one to three minutes) alloxan exposures, reversed some of the subsequent inhibition of insulin release. These findings suggest that alloxan and D-glucose were competing for a common site on the beta-cell. The possibility of this site being a receptor responsible for the initiation of insulin release is discussed.

Alloxan↗