Das Alloxan als Oxydationsmittel für Thiolgruppen, als Kapillargift und als Krampfgift

Labes, Richard; Freisburger, Hans

doi:10.1007/bf01859325

Cited by 35 publications

(4 citation statements)

References 7 publications

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“…Dithiothreitol inactivates the thiol reagent alloxan (Labes & Freisburger, 1930;Lazarow, 1949) (Figure 1), and thereby yields dialurate, through reduction of alloxan at the 5-CO group, its most reactive keto group (Patterson et al, 1949;Brown, 1962;Webb, 1966). The ability of alloxantin to inhibit glucokinase can be explained by its rapid break down into alloxan and dialurate (Abderhalden, 1949;Brown, 1962), so that its inhibitory effect is actually due to the action of alloxan.…”

Section: Discussionmentioning

confidence: 99%

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Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition

Lenzen

Brand

Panten

1988

British J Pharmacology

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1 In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B-cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined. 2 With a half-maximal inhibitory concentration of 5 /M, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective. 3 Ninhydrin also inhibited glucokinase with a half-maximal inhibitory concentration of 5 gM. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective. 4 Only glucose derivatives with a sufficiently bulky substituent in position C-2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and Nacetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition. 5 DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C-2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase. 6 The present results support our contention, that the pancreatic B-cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan.

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Section: Discussionmentioning

confidence: 99%

“…Thus alloxan, uramil and ninhydrin inhibit pancreatic B-cell (Lenzen et al, 1987a) and liver (Hara et al, 1986;Meglasson et al, 1986;Lenzen et al, 1987a) glucokinase as a result of their sulphhydryl reactivity (Labes & Freisburger, 1930). Alloxan has a quinoid structure (Webb, 1966).…”

Section: Discussionmentioning

confidence: 99%

Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition

Lenzen

Brand

Panten

1988

British J Pharmacology

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“…In light of the observation made in 1930 by Labes and Freisburger that tissue SH groups are readily oxidised by alloxan [32], Lazarow concluded from his studies in 1946 that alloxan might produce diabetes without being systemically toxic by interaction with sulfhydryl enzymes, which are essential only for the function of the pancreatic B cell [23,[34][35][36][37]. Because both monothiols and dithiols were able to protect animals against the diabetogenic action of alloxan [34][35][36], but only dithiols could reverse the action of alloxan [37], it was hypothesized that the mechanism of such an enzyme inhibition might be the formation of an S-S bridge between essential SHgroups [37].…”

Section: Alloxan Diabetesmentioning

confidence: 99%

“…In 1943 alloxan was already known to be a very unstable substance [1,5,6] capable of oxidising SH groups [31][32][33] and to be rapidly and completely metabolised in the body [6]. In light of the observation made in 1930 by Labes and Freisburger that tissue SH groups are readily oxidised by alloxan [32], Lazarow concluded from his studies in 1946 that alloxan might produce diabetes without being systemically toxic by interaction with sulfhydryl enzymes, which are essential only for the function of the pancreatic B cell [23,[34][35][36][37].…”

Section: Alloxan Diabetesmentioning

confidence: 99%