SPECIFICITY OF INHIBITION 871 



a good many of the conclusions reached from work of this nature will have 

 to be re-evaluated in the light of more extensive knowledge of enzyme 

 susceptibility. In the future volumes covering the individual inhibitors, 

 every effort will be made to present complete surveys of all the enzymes 

 tested so that the specificities through the concentration ranges may be 

 estimated. 



Specificity in Competitive Inhibitions 



If one or more of the enzymes is inhibited competitively, the treatment 

 must be modified by the introduction of the {1 + [(S)/^^]} term in the 

 denominator of the expression for the inhibition. Since the magnitude of 

 this term will usually vary from enzyme to enzyme, the degree of specificity 

 now depends on K, and (S) as well as on Kj and (I). In those multienzyme 

 systems in which the concentrations of the intermediates may vary follow- 

 ing inhibition, the final specificity will depend on the degrees to which the 

 concentrations of competing substrates can rise. In other words, from the 

 relative values of the K/s it might be predicted that adequate specificity 

 would be achieved, but if the concentration of the substrate acted upon by 

 the enzyme being studied can rise sufficiently to reduce the inhibition, 

 the actual specificity may be quite low. 



Specificity in Intracellular Inhibitions 



The possibility of achieving a specific inhibition in cells or tissues is 

 much less than in cell extracts or enzyme preparations, due not only to 

 the greater number of opportunities for inhibition but also to our lack of 

 knowledge as to intracellular conditions and the behavior of inhibitors 

 within cells. We have seen that the inhibitor concentration is an important 

 factor in the determination of the si^ecificity. The intracellular concentra- 

 tion of an inhibitor is usually not known so that it is difficult to evaluate 

 the specificity even when the in vitro actions of the inhibitor on many en- 

 zymes are known. Since the inhibitor concentration in the cells may be 

 either higher or lower than outside, the intracellular specificity may be 

 greater or less than determined on isolated enzymes. 



The specificity can be altered by any factors that affect the individual 

 inhibitions, so that pH, temperature, ionic strength, and similar variables 

 can introduce further complications. Unless the in vitro inhibitions are 

 determined at intracellular pH, the specificities in the cell may be signifi- 

 cantly different than predicted. Indeed, it has been emphasized that the 

 susceptibilities of enzj^mes to inhibitors may be quite different depending 

 on whether the enzyme has been isolated and is in an artificial medium or 

 is in its natural environment within the cell. One further factor is in some 

 cases very important: the specificity may vary with the time after intro- 

 duction of the inhibitor. In the first place, some enzymes are inhibited 



