EFFECTS OF 2-DEOXY-D-GLUCOSE 397 



glucose and 2-DG reduce the ATP level immediately and the ADP level 

 very soon (Ibsen et al., 1962). The most commonly accepted explanation 

 of the Crabtree effect is a depletion of ADP, since the rate of mitochondrial 

 oxidation in ascites cells depends on the level of ADP. (8) 2-DG causes the 

 loss of enzymes from the ascites cells (measured with lactate dehydrogen- 

 ase) whereas glucose does not (Hofmann et al., 1962). Indeed, glucose 

 seems to antagonize this action of 2-DG. Whether this observation has any 

 bearing on the Crabtree effect is not known. (9) Both glucose and 2-DG 

 still exert respiratory inhibition in the presence of sufficient iodoacetate 

 to block almost completely the glycolytic pathway (Ibsen et al., 1958; 

 Wenner and Cereijo-Santalo, 1962). It seems that although the Crabtree 

 effect is not abolished by iodoacetate, it may be diminished. If the initial 

 phosphorylation of hexoses is responsible for the Crabtree effect, iodoacetate 

 would not be expected to inhibit it, except as it might reduce ATP for the 

 kinase reactions. (10) Glucosone inhibits the Crabtree effect produced by 

 both glucose and 2-DG (Yushok, 1964), but this is probably the result of 

 the inhibition of hexokinase by glucosone. Summarizing these results, it 

 would appear that glucose and 2-DG inhibit respiration by basically the 

 same mechanism and that this is related to their phosphorylation. It is 

 difficult to understand the diminished Crabtree effect in the presence of 

 glucose and 2-DG together, observed by Wenner and Cereijo-Santalo (1962), 

 but this should be investigated further, inasmuch as Ram et al. (1963) 

 stated that the respiratory inhibition by glucose is not enhanced by 2-DG, 

 apparently no antagonism being noted. 



Glucose and 2-DG not only depress the oxidation of pyruvate in ascites 

 cells but even more strongly the oxidation and C^'^Oa formation from label- 

 ed palmitate (Sauermann, 1964). Inhibition of palmitate oxidation occurs 

 to the extent of around 80% at the relatively low concentration of 1.8 

 mM 2-DG. The inhibitions are approximately 29% for acetate, 58% for 

 pyruvate, and 92% for palmitate at 18 mM 2-DG. There would thus appear 

 to be some effect on fatty acid oxidation which is exerted prior to the uti- 

 lization of acetyl-CoA. This action is not related to the inhibition of glyco- 

 lysis for several reasons, including the demonstration that it occurs in the 

 presence of iodoacetate. Some effect on fatty acid oxidation might be 

 expected from a lowering of the ATP level, but it was felt that this is not 

 the entire explanation because of the relatively small effect on acetate 

 oxidation. It is not necessary, however, that a fall in ATP should affect 

 acetate and palmitate oxidations equally. One awaits with interest the 

 elucidation of this interesting effect. 



The Crabtree effect has been discussed in some detail because it illus- 

 trates one way in which 2-DG can alter carbohydrate metabolism through 

 the alteration of levels of P, and the adenine nucleotides. It is quite possi- 

 ble that part of the effect of 2-DG on tissues is the result of a lowering 



