484 9. INHIBITION IN CELLS AND TISSUES 



amounts entering the cycle by these two routes (Freedman et al., 1958). It 

 was found that in fasted animals the primary route is the former condensa- 

 tion, with fats being used for energy, whereas in animals given glucose there 

 was an appreciable amount of pyruvate oxidatively decarboxylated. In 

 contrast to liver, the Murphy- Sturm sarcoma oxidatively decarboxylated 

 pyruvate even in the fasted animal. Thus the branching point must 

 somehow differ in these two tissues and this difference could serve as the 

 basis for differential response to inhibitors acting on enzymes in this re- 

 gion. These experiments, incidentally, illustrate well the fact that the nu- 

 tritional state of the animal is sometimes of the utmost importance in 

 their susceptibility to inhibitors, and examples of this w^ill be cited in the 

 chapters dealing with the inhibitors on which it has been studied. 



Finally we must consider the relationship of the response to inhibitors 

 to the height of the functional activity of the tissue. It is commonly stated 

 that those tissues with the greatest activity are more susceptible to inhi- 

 bition than quiescent tissues. This is not necessarily true in general, since 

 a very active function in one tissue may depend on an entirely different 

 metabolic basis than a less active function in another tissue. However, if 

 one restricts attention to a single function, the statement may have some 

 validity. It is quite obvious that an inhibitor depressing processes con- 

 nected with cell growth or division will more readily affect those cells that 

 are growing rapidly and can have very little or no effect on nongrowing 

 cells. It is on this principle that some metabolic inhibitors have been used 

 to suppress selectively growing tumor cells or rapidly proliferating micro- 

 organisms in the body. It has been noted previously that the functional 

 dependency on the levels of ATP can be the origin of different responses 

 to inhibitors; an activity requirhig a high iVTP level will be depressed be- 

 fore one capable of proceeding with low concentrations of ATP, when for- 

 mation of ATP is interfered with. It has also been observed that increasing 

 activity would appear to imply in some cases a progressively greater frac- 

 tion of a type of metabolism different from that of the resting cell, so that 

 an inhibitor specifically blocking this •■activity" type of metabolism would 

 presumably be able to depress more easily cells with high activity. Another 

 factor which has not been considered as yet is the possibility that an in- 

 hibitor enters an active cell more raj^idly than a resting cell. This could 

 easily be the case with ionic inhibitors since in many cells activity involves 

 a depolarization of the plasma membrane with resultant breaking down of 

 the electrostatic barrier to penetration. So that one might predict on the 

 basis of the above reasoning that the administration of an inhibitor to an 

 animal would primarily cause changes in function in the most active tis- 

 sues, such as the heart or brain with respect to conduction and contraction, 

 or the kidney with respect to active transport processes, or the hematopoi- 

 etic system or testes with respect to cell proliferation, and in general 



