AEROBIC METABOLISM OF CARBOHYDRATE 131 



The determination and interpretation of C-l/C-6 ratios are complicated 

 by many factors. The operation of the pentose-P pathway may be limited 

 by the rate of reoxidation of NADPH. In many cells there is apparently 

 a deficiency of NADPH oxidases and similar systems. In ascites cells the 

 principal hydrogen acceptor for NADPH is pyruvate (Wenner, 1959). Thus 

 pyruvate will overcome the effects of iodoacetate (see accompanying tab- 

 ulation). When iodoacetate prevents the formation of pyruvate, NADPH 



Pyruvate Iodoacetate ^ , ,^ „ t> ^• 

 / T,^^ , nir^ C-i/L-b Katio 



(miJf) {ynM) 



cannot be oxidized readily, and the pentose-P pathway slows. Thus iodo- 

 acetate can indirectly depress the pentose-P pathway. McLean (1962) found 

 that phenazine methosulfate can counteract the inhibition of C^^Oa formed 

 from glucose- 1-C^* by iodoacetate in rat mammary gland, and postulated 

 that the phenazine methosulfate acts as an alternative electron acceptor, 

 thereby restoring the activity of the pentose-P pathway. She also obtained 

 evidence that the pentose-P pathway and fatty acid synthesis are tightly 

 geared, and that iodoacetate depresses the pentose-P pathway, not by act- 

 ing on it directly but by interfering with the enzymes of the malonyl-CoA 

 pathway. Such interrelationships may at least partly explain the rather 

 marked inhibitions of the pentose-P pathway activity by iodoacetate. If 

 a large fraction of the pyruvate formed from the EM pathway is not oxi- 

 dized through the cycle but goes into various syntheses, the C^^Og from glu- 

 cose-6-C^* may be quite low (the 6-C^* ends up as the methyl group on 

 pyruvate so that it can be released as C^^Og only after recycling). If iodo- 

 acetate affects in any way the distribution of pyruvate, it will alter the 

 C-l/C-6 ratio; e.g., if iodoacetate increases the relative amount of pyruvate 

 going into the cycle, the formation of C^^Oa from glucose-6-C^'* will be inhib- 

 ited less than the EM pathway. These considerations make the interpreta- 

 tion of such experiments very difficult. An increase in the formation of 

 C^^Og from glucose-6-C^^ by iodoacetate would not be expected, yet occurs 

 in the mammary gland and other tissues; is this due to the fact that fatty 

 acid synthesis is markedly inhibited and more pyruvate is diverted into 

 the cycle? An increase in C^^Og from glucose- 1-C^'* by iodoacetate can also 

 occur (as in Walker rat carcinoma) and is perhaps related to the accumu- 

 lation of glucose-6-P. Ferricyanide, which acts earlier in the EM pathway 



