392 4. ALLOXAN 



wondered if alloxan might be a circulating hormone controlling insulin 

 secretion. When the diabetogenic action was soon established, it was sug- 

 gested by several workers that hyperalloxanemia might be a contributory 

 factor in the genesis of diabetes. The presence of alloxan in tissues would 

 not be surprising inasmuch as it could arise from the metabolism of the 

 pyrimidines and purines, and, indeed, is chemically obtained from urate. 

 Alloxan is formed from urate in leucocytes in the presence of hydrogen per- 

 oxide due to the action of myeloperoxidase (Soberon and Cohen, 1963). 

 Much work has been done in attempting to determine the levels of alloxan 

 in the blood under various conditions, but the results are discordant, pos- 

 sibly due to the unsatisfactory analytical methods often used. One would 

 certainly never expect to find high concentrations in any tissue because 

 of the instability of alloxan; we shall see that injected alloxan is mainly 

 destroyed in a few minutes. Abderhalden (1946) claimed that the frequent 

 concurrence of gout and diabetes might be interpreted to mean that ab- 

 normal purine metabolism could give rise to sufficient alloxan to be diabeto- 

 genic. Numerous studies in the rat, rabbit, dog, horse, and man have 

 shown that the normal alloxan content of blood is probably between 0.015 

 and 0.2 mg% (Archibald, 1945; Schioler, 1948; Huisman et al., 1950; 

 Loubatieres and Bouyard, 1951 a; Sobotka and Luisada-Opper, 1954), 

 this corresponding to 0.001-0.014 milf alloxan. Some, for example Karrer 

 et al. (1945), could detect no alloxan in the blood or urine of diabetics. 

 There may be some question as to the validity of the analyses since the 

 specificities of the methods are often doubtful, and possibly the normal 

 values given above do not refer to alloxan. In any event, the alloxan con- 

 centration in normal blood is very low. 



With respect to the etiology of diabetes, the real problem is whether 

 alloxan occurs at elevated levels in the blood or islets under abnormal con- 

 ditions. Lang (1866) reported a patient who voided a yellow urine which 

 turned reddish blue on standing, and interpreted this as due to alloxan 

 or a precursor (possibly dialurate) forming murexide. As far as I know, 

 no further cases of this type have been recorded and it may be that alloxan 

 was not involved. Tipson and Ruben (1945) stated that abnormal over- 

 production of alloxan or failure to destroy it might lead to abnormally 

 high levels and claimed to have detected alloxan in the livers of various 

 species, using the barium test in deproteinized extracts (Ruben and Tip- 

 son, 1945). These results are not convincing. The question of the con- 

 version of urate to alloxan in animals has never been satisfactorily an- 

 swered, but Grunert and Phillips (1951) could find no alloxan formed from 

 urate in liver homogenates, and Lee and Stetten (1952) detected no labeled 

 alloxan following administration of urate- 1,3-Ni^. Soberon and Cohen 

 (1957) claimed, however, that incubation of rat neutrophils with urate-2-C^^ 

 leads to around 10% conversion to alloxan. Seligson et al. (1951) reasoned 



