368 4. ALLOXAN 



reported by Wieland and Bergel (1924), Labes and Freisburger (1930), 

 and Lieben and Edel (1932). Inhibitions of several enzymes had been found 

 by various workers, including Purr and Weil (1934), Hopkins et al. (1938), 

 Bernheim (1938), and Lehmann (1939). Lusini (1894) and Koehme (1894) 

 had shown that alloxan is rapidly and completely metabolized in the body, 

 and others had provided evidence that it disappears rapidly from neutral 

 or alkaline solutions. Alloxan was thus known in 1943 to be a very unstable 

 substance capable of oxidizing SH groups and exerting effects on various 

 enzymes and metabolic systems, but there was no clue to the mechanism 

 involved in the /5-cell necrosis. One must be careful to distinguish between 

 the direct effects of alloxan in animals and the secondary effects resulting 

 from the alterations of the /3-cells and insulin release. There have been 

 many studies on animals made diabetic by the administration of alloxan, 

 but such work is not within our province inasmuch as these secondary ef- 

 fects are related only to insulin deficiency and are typical of the diabetic 

 state rather than the immediate actions of alloxan. The following reviews 

 on the diabetogenic action of alloxan are recommended: Duff (1945), 

 Goldner (1945), Lukens (1948), Houssay (1950), Lazarow(1954 a), and Falk- 

 mer (1961). 



CHEMICAL PROPERTIES 



The structure and reactions of alloxan in aqueous solution are poorly 

 known because relatively little work has been done on its chemistry since 

 the modern concepts of chemical structure and reactivity were formulated, 

 and also because it is a complex, unstable, and reactive substance. Even 

 its reactions with thiols have not been adequately investigated and for this 

 reason it is difficult to understand the effects on enzymes and particularly 

 how it can selectively damage the pancreatic /5-cells. Although alloxan is 

 a tetraoxypyrimidine, its properties differ in several respects from the 

 usual pyrimidines, due probably to the presence in alloxan of the — CO — 

 CO — CO — grouping, this supposedly containing a highly reactive central 

 CO group. 



Acid-Base Properties 



The dioxypyrimidines, such as uracil and thymine, are very weak acids 

 {pK^^ = 9.5) but alloxan is definitely stronger and probably exists at 

 physiological pH mainly in the anionic form. The p/C^ of alloxan was given 

 as 7.20 by Richardson and Cannan (1929) and as 6.63 by Labes and Freis- 

 burger (1930). The acidity is due to the lability of the H atoms resulting 

 from enolization and to the increased possibilities for resonance following 

 ionization. The ionization is usually represented as: 



