502 10. EFFECTS OF MORE THAN ONE INHIBITOR 



TWO INHIBITORS ACTING ON CELLULAR AND TISSUE 



METABOLISM 



There are many possible ways in whicli the actions of two inhibitors may 

 be related when the system acted upon is as complex as the cell. The pur- 

 pose of the present section is to outline some of these interrelationships. 

 It is evident that the previously discussed simultaneous actions on enzymes 

 or multienzyme systems may occur within cells but we shall now be 

 concerned with situations usually observed only in living organisms. 



Effect of One Inhibitor on the Metabolism or Distribution of Another 



Inhibitor 



The products from the metabolic alteration of inhibitors may be either 

 active or inactive. The depression of this transformation by a second inhi- 

 bitor could result in a reduction of inhibition if an active inhibitor is being 

 formed (lethal synthesis) or an accentuation or prolongation of the inhi- 

 bition if the original inhibitor is being inactivated. Not many of the com- 

 mon enzyme inhibitors are rapidly metabolized and their rate of disappear- 

 ance is seldom a factor in determining the degree of their action in isolated 

 cell or tissue preparations. However, in the intact animal the eventual fate 

 of the inhibitor often depends upon some enzymic degradation. Not many 

 instances of lethal synthesis have been demonstrated as yet but the prin- 

 ciple can be easily illustrated. When fluoroacetate is administered, there is 

 an accumulation of citrate in the tissues due to the block produced on acon- 

 itase by the fluorocitrate formed from the fluoroacetate. Potter (1951) 

 showed that malonate could reduce the amount of citrate formed in the 

 presence of fluoroacetate, presumably by reducing the amount of oxal- 

 acetate available for condensation with the fluoroacetate through an inhi- 

 bition on the succinic dehydrogenase. Thus if citrate accumulation were 

 being used as a criterion for fluoroacetate inhibition, malonate would antag- 

 onize this by depressing the metabolism of the fluoroacetate. It is interest- 

 ing that in the heart this antagonism was not observed, indicating another 

 pathway for the formation of oxalacetate, an example of the metabolic 

 information that may be obtained with the use of two inhibitors. The re- 

 sults in thymus tissue are shown in Fig. 10-5. The final result in a partic- 

 ular case depends usually on the times of addition of the inhibitors rel- 

 ative to each other, their rates of action, and what is being measured. For 

 example, if malonate was given before the fluoroacetate, a block in citrate 

 formation occurred for a couple of hours but if the two inhibitors were giv- 

 en together, some citrate accumulated before the malonate had an oppor- 

 tunity to exert its full effect. It might be expected that arsenite would 

 also antagonize the citrate accumulation by blocking the entry of fluoro- 



