388 4. ALLOXAN 



mer (1961) also reported a fall in islet glutathione in the sculpin, the islets 

 here being susceptible to isolation and analysis. It would thus seem definite 

 that alloxan can react with the SH groups of y5-cells. 



Substances Antagonizing the Diabetogenic Action of Alloxan 



There are many substances which delay, decrease, or abolish the action 

 of alloxan on the /5-cells when they are administered previously, or occa- 

 sionally with the alloxan. Our interest in such protective substances is in 

 the information they may shed on the mechanisms by which alloxan acts. 

 Some protectors are listed in Table 4-1; others not listed include dimer- 

 caprol, propanol, isopropanol, o-phenylenediamine, bisulfite, thioglycolate, 

 yeast pentose nucleotides, methionine, norepinephrine, phenylephrine, 

 3,4-diaminotoluene, and l,2-dimethyl-4-amino-5-(ribitylamino)benzene. In 

 many cases it is a matter of the simple inactivation of the alloxan before 

 it gets to the islets (e. g., glutathione, cysteine, borate, ascorbate, 1,2- 

 dienolglucose, and metal ions). Nitrite and p-aminopropiophenone both 

 elevate blood glutathione and favor the formation of methemoglobin, so 

 that the effect is secondary but similar. In not one of these cases do we 

 learn much of interest, except that thiols must be administered not longer 

 than 5 min before the alloxan if protection is to be observed (Lazarow, 

 1946), and this shows that the thiols are not reactivating alloxan-inhibited 

 systems and that the important effects of alloxan on the /?-cells occur within 

 5 min, a conclusion substantiated from other evidence. Epinephrine and 

 other pressor amines apparently act by producing pancreatic vasoconstric- 

 tion so that the injected alloxan cannot reach the islets, since phentolamine 

 (Regitine) prevents both vasoconstrictive and antidiabetogenic activities 

 (Meade and Klitgaard, 1960). Deoxycorticosterone presumably acts through 

 alteration of blood electrolytes, since Na+ deficiency has been shown to 

 increase the sensitivity to alloxan due to a lowered blood level of glutathione 

 (Grunert and Phillips, 1949). The protections by nicotinamide, barbiturate, 

 and glucose are more interesting. 



It had been shown that alloxan can compete with NAD for certain 

 yeast apoenzymes (see page 400), so Lazarow et al. (1950) attempted to 

 combat the diabetogenic action of alloxan by injecting NAD, but without 

 success, due probably to the failure to penetrate into the cells. However, 

 nicotinamide injected up to 1 hr before the alloxan protects quite well 

 at a dose of 915 mg/kg (7.5 millimoles/kg). Lazarow and his group presented 

 four possible mechanisms for the protection: (1) nicotinamide is methylated 

 to iV-methylnicotinamide, which reacts with aldehydes and might react 

 with alloxan, (2) the conversion of nicotinamide to iV-methylnicotinamide 

 removes the methyl group from methionine, leaving homocysteine, which 

 might inactivate alloxan, (3) nicotinamide is also converted in part to 

 NAD(H) and this might protect the enzymes from alloxan, or even the 



