CHAPTER 13 



REVERSAL OF INHIBITION 



The rates at which inhibited enzymes may be reactivated are frequently 

 quite important in experimental studies of inhibition and particularly so 

 when the inhibitors are administered to whole animals. This is evident 

 when one considers the i^roblems arising in the clinical use of the irrevers- 

 ible enzyme inhibitors, such as the phosphofluoridates (e.g., diisopropyl- 

 fluorophosphate or DFP) that inhibit cholinesterases, or certain of the 

 hydrazine derivatives (e.g. iproniazid) that inactivate monoamine oxidase. 

 The degree of reversibility of the inhibition in the tissues of patients de- 

 termines the frequency with which the inhibitor must be administered to 

 achieve and maintain a desired level of effect, the duration of the action 

 when the administration of the inhibitor is stopped, and often the effective- 

 ness of the inhibitor when it is used for a specific purpose. However, even 

 in work with isolated enzymes or cellular preparations, the readiness with 

 which the inhibition is reversed is important. The kinetics of the inhibi- 

 tion, for one thing, depend on whether the inhibition is rapidly reversible 

 or not, as discussed in previous chapters. Most kinetics are formulated on 

 the principle that reversibility occurs and that mass-action equilibria are 

 achieved. When reversal is slow, it may be impossible to reach a state of 

 true equilibrium if the enzyme is unstable and processes of inactivation 

 proceed concurrently with the development or reversal of the inhibition. 

 In any quantitative study of inhibition, it is advisable to determine the re- 

 versibility of the inhibition or of the effects measured. In some cases the 

 loss of enzyme activity may be associated with some type of inactivation 

 of the enzyme, as distinguished from simple inhibition due to the binding 

 of the inhibitor to the enzyme surface, and the most straightforward way 

 to test this is to determine the degree to which the activity can be restored 

 by the removal of the inhibitor. Very few studies have been made of the 

 kinetics of inhibition reversal and of the factors that may influence it, and 

 one may look in vain in most of the treatises on enzymes for any discussion 

 of this phenomenon. 



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