462 9. INHIBITION IN CELLS AND TISSUES 



to determine how these inhibitory responses will be modified by changes 

 in the availability of substrate, the depletion of oxygen supply, or the 

 process of active growth. 



RELATIONS BETWEEN ENZYME INHIBITION AND CHANGES 

 IN CELL FUNCTION 



Frequently it is desired to determine in what manner an inhibitor can 

 influence a particular functional activity of a cell or organ — such as cell 

 division, movement, impulse conduction, secretion, or active transport — 

 and thereby learn something about the enzymic processes upon which this 

 function is dependent. The tricky problem of correlating the observed 

 functional changes with the metabolic inhibition thus arises. All of these 

 cellular activities require energy, either directly expended on function or 

 indirectly for the synthesis of the functional components. The use of in- 

 hibitors that presumably will specifically depress certain enzymes in the 

 metabolism involved in energy formation and utilization will usually 

 produce some measurable modification of the function. But there are many 

 other mechanisms by which function can be altered by inhibitors and an 

 effect need not be interpreted as due to the interference with the energy 

 supply. It has been pointed out that for several reasons it is not always 

 possible to assume that within the cell the inhibitor is duplicating the in- 

 hibition observed on isolated systems. There are many instances where a 

 fair degree of inhibition is exerted on the cellular metabolism without 

 marked effects on function and there are also cases where function can be 

 essentially abolished without detectable disturbance in metabolism. Such 

 complexities often make accurate correlation very difficult. Of all the as- 

 pects of the problem, however, the most important is the specificity of the 

 inhibitor, the degree to which we can be certain that a particular enzyme 

 or metabolic pathway is being blocked without significant action of other 

 systems. Specificity will be discussed in detail in Chapter 17 and only the 

 most pertinent points will be mentioned here. 



The depression of function by an inhibitor is generally interpreted in 

 terms of a reduction in the energy supply for the process but it should be 

 borne in mind that there are other mechanisms that may be operative. 

 Let us assume that cardiac or skeletal muscle contraction has been found 

 to be altered by p-chloromercuribenzoate. Some possible mechanisms for 

 this action would be: an effect directly on the contractile elements, a mo- 

 dification of the membrane leading to changes in ionic permeability and 

 electrical behavior, a depression of the coupling between excitation and 

 contraction, an interference with the formation or destruction of acetyl- 

 choline, or an inhibition of the transfer or high-energy phosphate as well 

 as a suppression of its generation. In some cases, a direct or indirect change 



