EFFECTS OF ENZYME OR METABOLIC RATE 861 



level of function, an inhibitor will depress the function when it has lowered 

 the metabolism to or beyond this required rate. Therefore, if two tissues 

 require the same metabolic activity, but one has a higher metabolic rate 

 than the other, it will be more difficult to depress the function in the for- 

 mer. In a way, it is the margin of safety between metabolic sujDply and 

 demand that is critical. If a tissue is stimulated to greater activity and its 

 metabolism does not increase proportionally, it will be more easily in- 

 hibited. The ability of some tissues to adapt to inhibition in various ways 

 can modify the results very significantly. 



Florijn and Smits (19J:9) explained the relatively selective action of ure- 

 thane and arsenite on tumor tissue by making two assumptions: (1) tumor 

 tissue has a high respiratory rate due to the high energy requirement, 

 whereas normal tissues operate much below the maximal metabolic ca- 

 pacity, and (2) a certain concentration of an inhibitor always blocks the 

 same fraction of the inhibitor-sensitive system. Tumor respiration will 

 thus be depressed more readily than normal tissue respiration; in the lat- 

 ter the residual portion of the inhibitor-sensitive systems can be suffic- 

 iently increased to maintain the original respiratory level. In other words, 

 normal tissues can compensate to inhibition by their reserve capacity 

 whereas tumor tissue cannot. 



In order to test this hypothesis, studies were done on the inhibition of 

 tissue 'respiration and yeast fermentation by urethane and arsenite (Florijn 

 et al., 1950). The respiration of rat liver and kidney minces was varied by 

 changing the oxygen tension and adding 2,4-dinitrophenol. The fermenta- 

 tion rate of yeast increases with time in the presence of ammonium sulfate 

 and the inhibition can be tested during varying intervals. The inhibitions 

 observed at these different metabolic rates are shown in Fig. 15-28 and it 

 is seen that the effects of the inhibitors generally increase with increasing 

 rates. It was felt that these results give support to the proposed mechanism 

 for the selective action of the two inhibitors on tumor tissue. It may be 

 noted that in essentially every case, even though the inhibition is greater 

 at higher metabolic rates, that the remaining respiration or fermentation 

 is greater than at low metabolic rates. These interesting results are very 

 difficult to interpret with assurance because it is not known in what way 

 an increase in oxygen tension will alter the patterns of oxidative or fer- 

 mentative metabolism. If it is assumed that the arsenite acts principally 

 on the keto acid dehydrogenases, the question as to what increased oxygen 

 tension does to the rates of the processes forming and utilizing pyruvate 

 and «-ketoglutarate is posed. Since pyruvate oxidation in mitochondrial 

 suspensions is generally accelerated by augmenting the oxygen tension, it 

 might be supposed that in pure oxygen the tricarboxylic acid cycle and 

 the oxidation of pyruvate make up a greater fraction of the total respiration 

 than in air, and thus that an inhibitor, such as arsenite, that blocked py- 

 ruvate oxidation would be more effective. However, this explanation 



