CHAPTER 12 



RATES OF INHIBITION 



The various formulations of inhibition presented in the previous chap- 

 ters generally represent or describe systems after equilibrium has been 

 reached with respect to the inhibitor. In other words, it has been assumed 

 that the reaction of an inhibitor with an enzyme has proceeded until the 

 maximum inhibition under the conditions has been achieved. The most 

 important constant characterizing such equilibrium states is the inhibitor 

 dissociation constant, K^, which expresses the affinity of the enzyme for 

 the inhibitor. However, from the value of X^ it is impossible to deduce the 

 rate at which the inhibition will occur. Some inhibitors react so rapidly 

 with enzymes that equilibrium is reached in times too brief to measure 

 with the usual techniques, while other inhibitors may act very slowly 

 and a steady inhibition will be reached only after several hours, or actually 

 never reached because of secondary factors that reduce or extend the in- 

 hibition. The time course of the development of inhibition is often as im- 

 portant a characteristic as the final state reached in studies on either iso- 

 lated enzymes or living organisms. 



The rates at which inhibitors act may be of significance in a variety 

 of ways when complex metabolic systems are investigated. If an inhibitor 

 acts on two or more enzymes but the rate of reaction with one of these en- 

 zymes is much faster than with the others, some degree of specificity in 

 the inhibition may be observed over a period of time. It is also possible 

 that the effects on a tissue will be different when an enzyme is inhibited 

 rapidly or slowly. In the latter case, for example, the tissue has greater op- 

 portunity to adapt to the inhibition as it progresses. When the response 

 of some cell function is being measured, the rate at which this occurs in 

 the presence of an inhibitor depends not only on the events that transpire 

 between the site of inhibition and the functional process but also on the 

 rate of enzyme inhibition. If one is concerned with the kinetics of functional 

 disturbance, data on the rates of the primary inhibition should be obtained 

 if possible, instead of assuming, as has been done in some cases, that the 

 primary inhibition is practically instantaneous and the delay in depression 

 of function is entirely due to factors frequently designated as "biological 

 lag." With regard to studies on isolated enzymes, it is only by quantitative 



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