REVERSAL IN CELLS AND WHOLE ANIMALS 643 



Diffusion of the Inhibitor from the Cells 



Inhibitors that are stable and are not metabohzed must eventually dif- 

 fuse out of the cells if the EI complex is to dissociate and enzyme activity 

 is to be restored. Such occurs most simply when inhibited tissue slices are 

 placed in an inhibitor-free solution, or when an inhibited organ is perfused 

 with an inhibitor-free medium. Diffusion from the tissues also occurs in 

 whole animals as the inhibitor is excreted through the kidneys or the lungs. 

 Just at the rate of entrance of an inhibitor into a cell may modify the rate 

 of inhibition, so the rate of leaving the cell may affect the recovery from 

 the inhibition. The processes involved may be represented as: 



(13-74) 



This is kinetically the same as the case in which the inhibitor undergoes 

 monomolecular destruction (reactions 13-59) and the same principles and 

 equations apply here. In other words, the rate of reversal may be limited 

 by either i)rocess or may depend on both. 



Examples of the Reversal of Cellular Inhibition 



Only a very cursory examination of cellular inhibition reversal will be 

 given. Although the degrees of reversibility have often been reported in the 

 studies of such inhibitions, very little quantitative work that could be 

 submitted to kinetic analysis is available. It will suffice to mention certain 

 examples that illustrate the different types of reversal. 



The rate of reversal of inhibition is probably determined mainly by the 

 efflux of the inhibitor from the cells or tissues when most inhibitors are 

 administered to whole animals. This is not primarily because of a low per- 

 meability to the inhibitors but to the low concentration gradient across the 

 plasma membranes. The concentration of the inhibitor falls in the serum 

 as the inhibitor is excreted or metabolized and the release of inhibitor from 

 the tissues is consequently dependent on these secondary factors. The fall 

 of inhibitor concentration in the tissues, as in the case of acetazolamide 

 (Table 8-2), is then controlled mainly by the rate of fall of the serum level 

 and is often not related to the dissociation of the EI complex. It has been 

 postulated by Peters (1952) that the prolonged inhibition exerted by fluoro- 

 acetate is at least partly related to the inability of the fluorocitrate form- 

 ed to leave the mitochondria rapidly. The true inhibitor is then in a sense 

 trapped where it is formed. 



