EFFECTS OF 2-DEOXY-D-GLUCOSE 399 



Effects of 2-DG on Various Metabolic Pathways 



Infusion of acetate-C^^OO" into rabbits and determination of the respired 

 C^^Og were done prior to and after 2-DG injections; no alteration of acetate 

 oxidation was observed (Wick d al., 1957). The total COg produced decreas- 

 ed, partly due to the hypothermia brought about by 2-DG. This was taken 

 as evidence that any block by 2-DG is previous to the tricarboxylate cycle. 

 An effect of 2-DG on citrate levels in ascites carcinoma cells in the presence 

 of pyruvate was reported by Letnansky and Seelich (1960). The citrate 

 begins to rise 2 min after addition of 18.3 mM 2-DG and eventually reaches 

 levels definitely higher than in untreated suspensions. The utilization of 

 pyruvate is also depressed around 50%. These observations might be in- 

 terpreted as originating from some action on the cycle, but more recently 

 (Seelich and Letnansky, 1961) it was shown that methylene blue reduces 

 the high citrate levels and promotes pyruvate utilization in the presence of 

 2-DG. It was postulated that this is caused by oxidation of NADPH to 

 NADP, which is necessary for isocitrate oxidation. The rise in citrate may 

 be due to a deficiency of NADP, possibly because lactate is not formed in 

 the presence of 2-DG and NADPH is not oxidized, and also due to a drop in 

 ATP. The results can thus be satisfactorily explained on the basis of the 

 mechanisms previously discussed without assuming any direct action on 

 the cycle. 



Lipogenesis in human fetal liver from glucose is depressed by 2-DG, 

 incorporation of l-C^* being lowered 33% and of 6-Ci* 18% at 6.1 mM 

 (Villee and Loring, 1961). This can, of course, be attributed to an inhi- 

 bition of glycolysis. Plasma fatty acids in man rise as much as 330% 

 following intravenous infusion of 2-DG at 60 mg/kg, and this might be 

 interpreted as a depression of fatty acid synthesis so that the normal equi- 

 librium is disturbed and fatty acids are mobilized from the tissues (Laszlo 

 et al., 1961). On the other hand, there is evidence that 2-DG augments 

 epinephrine release, so that this could be partly responsible. 



The appearance of labeled amino acids from labeled glucose in brain 

 slices is also depressed by 2-DG (Tower, 1958). 2-DG not only prevents the 

 accumulation of glutamate but causes a profound fall in the intracellular 

 level, glutamine decreasing less markedly. It is believed that glutamate 

 accumulation is important in K+ uptake by brain and it was found, as 

 expected, that this is inhibited around 60% by 10 mM 2-DG. The role of 

 such changes in the central actions of 2-DG in the whole animal is not as 

 yet understood. The incorporation of L-valine-C^* into protein in ascites 

 cells is almost abolished by 10 mM 2-DG; since this may be reversed by 

 glucose, it is likely that the inhibition is related to glycolytic suppression 

 (Riggs and Walker, 1963). The DNA content of a rat carcinoma is reduced 

 by feeding 2-5% 2-DG in the diet and possibly this is related to the observed 

 inhibition in growth (Sokoloff et al., 1956). 



