Glutathione alloxan

In addition in the pancreas cells of alloxan-treated rats we observed the decreasing in the activity of key antioxidative enzymes namely SOD and glutathione peroxidase (Figure 13). 

Hermenegildo C, Raya A, Roma J, Romero FJ. Decreased glutathione peroxidase activity in sciatic nerve of alloxan-induced diabetic mice and its correlation with blood glucose levels. Neurochem Res 1993 18 893-896. 

Alloxan apparently also acts by interacting with SH groups and lowering the blood glutathione, since its action is prevented by SH-containing compounds such as glutathione, cysteine, BAL (2,3-dimercaptopropanol) or thioglycolic acid administered immediately before or within a few minutes after injection of alloxan [82, 86, 87]. However, the actual mechanism by which alloxan acts is still rather poorly understood. 

The effect of alloxan diabetes on congenital malformations of the foetus has been examined in mice made diabetic prior to conception. Alloxan can induce agnathia, cranioschisis, chaniorrhachischisis, cleft palate, microglossia and fused ribs in a number of animals tested [88]. Development of chick embryos at the early stage is also inhibited by alloxan [89]. Addition of glutathione completely protects the embryos [89]. 

Alloxan, Glutathione, Ascorbic Acid, and Experimental Diabetes.. 69... 

The last of Hopkins many contributions to biochemistry was the demonstration that an enzyme—succinic dehydrogenase—was dependent for its activity on free SH groups in its structure (Hopkins et al., 1938). He used alloxan to oxidize the SH and inactivate the enzyme, and showed that glutathione (GSH) provided partial protection for the enzyme by reducing the alloxan. Then, from Glasgow, came the unexpected discovery that injected alloxan caused intense hypoglycemia in rabbits, followed by necrosis of the beta cells in the islets of Langerhans of the pancreas (Shaw Dunn et al., 1943). 

Whatever the true mode of action of alloxan in producing diabetes, it seems likely that it is due to its properties as an oxidant. Other oxidants might have much the same effect, as is suggested by the report (Patterson, 1949) that dehydroascorbic acid (DHA), in doses of 0.7 g./kg. body weight on three successive days, produced diabetes in rats. This could be prevented by the prior administration of cysteine, glutathione, or BAL (Patterson and Lazarow, 1950). Many other aspects of alloxan diabetes have been reviewed in an earlier volume of this series (Bailey, 1949). 

In the absence of reducing agents (e.g. reduced glutathione, GSH) alloxan may act as a scavenger for O2 " (Bromme etal. 1999). In the presence of electron donors, however, alloxan acts as a prooxidant. The production of O2 was shown by lucigenin enhanced chemiluminescence as well as by the formation of formazan from nitroblue tetrazoUum. Both reactions were inhibited by superoxide dismu-tase and partially be catalase. Melatonin inhibited alloxan-mediated chemiluminescence. 

A. Lazarow In view of the fact that we have such an eminent selection of organic chemists here, I wonder whether they would be willing to suggest a possible structure for the 305 reaction product of alloxan and glutathione. 

T. Wleland Can you rule out with certainty that alloxan doesn t react with the amino group of glutathione ... 

G. Wald Do you get different products in the reaction between alloxan and glutathione as compared with alloxan and cysteinylglycine ... 

A. Lazarow I d like to present some data that may have a bearing on the relation of binding of glutathione to glyceraldehj de phosphate dehydrogenase. When crystalline egg albumin is treated with alloxan there is a plateau at 305 m/i but no real peak. When, however, the crystalline egg albumin is denatured with Duponol there is a tenfold increase in extinction and a maximum becomes evident at 305. I wonder, therefore, whether glutathione may also be bound to a number of proteins, possibly by a peptide linkage. 

A. Lazarow Although glutamjdcysteine reacts with alloxan to give an extinction at 305 m/u amounting to 16% of that obtained with glutathione, there is no peak at 305 m/x as was obtained with denatured crystalline egg albumin. 

J. A. Stekol Dr. Lazarow, my impression of your idea is that a decrease in the glutathione content of tissues by alloxan administration has something to do, perhaps, with the induction of diabetes. Am I correct ... 

In interpreting these facts we have suggested that alloxan may kill the beta cell because it reacts with glutathione or with some essential sulfhydryl enzyme within the beta cell and on the basis of theoretical considerations we have postulated that the selectivity of alloxan may be due to a low glutathione concentration writhin the beta cell, occurring as a consequence of its specialization for insulin synthesis (44). Alloxan does react with a number of sulfhydryl enzymes and we have recent evidence to show that alloxan also reacts with coenzyme A. 

However, at the present time there is no direct evidence as to the mechanism by which alloxan kills beta cells. In view of the facts, it is reasonable to expect that the glutathione present within the beta cell would, by reacting with alloxan, protect critical enzymes within these cells against the diabetogenic effects of alloxan. 

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