EFFECTS ON METABOLISM 401 



2-3 times this concentration might be achieved in the cat or rabbit, for 

 example. It is very difficult to estimate the peak alloxan concentration 

 at the ^-cells following injections, since it depends to a great extent on the 

 rate of injection, and also on the site of the injection and the rate of des- 

 truction. It may well be that peak concentrations higher than that given 

 by Lazarow occur, although much lower levels are equally possible, par- 

 ticularly after subcutaneous or intraperitoneal injections. Inspection of 

 Table 4-2 shows that few enzymes are markedly inhibited in this range. 

 Some, like choline acetylase, pyrophosphatase, and urease, which are quite 

 potently inhibited, could scarcely be implicated in the diabetogenic action. 

 Certain ATPases and kinases are sensitive and might be involved. 3-Phos- 

 phogyceraldehyde dehydrogenase appears to be quite sensitive but the 

 data are insufficient to evaluate this. The high susceptibility of the liver 

 acetylating enzyme indicates a possible action on transacetylations involv- 

 ing coenzyme A, but it is difficult to understand how such an inhibition 

 could result in such rapid cytological changes in the /5-cells. Certain cycle 

 enzymes are the most sensitive to alloxan of the enzymes studied (You- 

 nathan, 1962). Some inhibition of the oxidation of pyruvate-fumarate 

 mixtures in rat kidney mitochondria is evident at 0.003 mM alloxan, and 

 0.03 mM seems to inhibit completely. The same is true for the oxidation 

 of pyruvate and malate. The same enzymes in liver mitochondria are much 

 less sensitive to alloxan, so we must take into account these tissue dif- 

 ferences and, unfortunately, we do not know how /?-cell mitochondria 

 would respond. The site of inhibition was believed to be at the level of 

 NAD, although the only evidence is the partial protection exerted by NAD, 

 and this could be explained in other ways. We also know nothing about 

 the permanency of such cycle inhibitions in the /?-cells. If the inhibitions 

 described by Younathan are irreversible, the concentrations of alloxan 

 estimated to occur from diabetogenic doses would certainly interfere mark- 

 edly with the operation of the cycle and would presumably induce damage 

 of the cells. If enzyme inhibition is indeed responsible for the changes in 

 the /5-cells, it may well be that no single enzyme can be implicated and that 

 several systems are inactivated simultaneously. These matters will be 

 discussed more fully in a later section (page 412). 



EFFECTS ON METABOLISM 



Alloxan may be thought of as structurally related to part of the ribo- 

 flavin molecule, and for this reason its effect on respiration was studied 

 by Bernheim (1938). The oxygen uptake of guinea pig liver suspensions 

 in increased and the R. Q. is simultaneously decreased from 0.83 to 0.69 

 by alloxan at 0.17 mM, this concentration exerting maximal effects. There 

 is an 8- to 10-fold stimulation of ethanol oxidation, with increased for- 



