486 9. INHIBITION IN CELLS AND TISSUES 



might be interpreted as indicating a spectrum of different cholinesterases 

 instead of variable mixtures of two enzymes. There is no reason to suppose 

 that this phenomenon is restricted to human sera and it is probable that 

 similar genetic variations occur with regard to other enzymes and other 

 species. The over-all effects of inhibitors on animals may thus vary from 

 one individual to another because the susceptible enzyme occurs in different 

 forms and these forms in different proportions. When two or more enzymes 

 catalyze the same reaction and inhibition of each is different, the over-all 

 inhibition is: 



i'l^i + i2V2 + ... + inVn ,„ ^-, 



t = (9-27) 



where Vf^ is the total uninhibited rate. 



Some readers may believe that an undue amount of emphasis has been 

 placed in this chapter on the complexities of interpretation when inhibitors 

 are used in living systems. It is certainly not the intention to discourage but 

 only to point out some of the reasons for not adopting the naive approach 

 that has often been evident. One cannot with impunity ignore the almost 

 limitless complexity of functioning, metabolizing, and self-perpetuating 

 cells and it is only reasonable to expect that disturbances in the normal 

 state will be beset by an equal degree of complexity in their interpretation. 

 The situation is by no means hopeless but it is only by the realization of the 

 difficulties that theoretical and technical advances can be made, so that 

 the ultimate answers will become penultimate. "Only the most fortunate 

 combination of circumstances will allow one to relate quantitatively the 

 action of an enzyme in an extract and its activity in the intact cell" (Da- 

 venport, 1956). One of the aims of the investigator is to ensure the occur- 

 rence of this "fortunate combination of circumstances." "An outstanding 

 biochemist once remarked that only uninhibited investigators use inhibitors 

 in complex biological systems" (Racker, 1956); it would, perhaps, be more 

 correct to say that only uninhibited investigators draw dogmatic conclu- 

 sions from such experiments. 



