456 9. INHIBITION IN CELLS AND TISSUES 



is thus possible for inhibitors of oxidation, such as cyanide, to stimulate 

 the utilization of glucose, and for other inhibitors, acting at different loci, 

 to modify the rates of reactions secondarily. 



There are many other mechanisms which may be postulated and it will 

 suffice to mention a few of these. The inhibition of an enzyme that destroys 

 some important metabolic substance may increase the steady-state level of 

 this substance and accelerate reactions with which it is concerned. Inhibi- 

 tion of ATPase, for example, can secondarily influence many reactions de- 

 pendent on ATP. The inhibitor may also increase permeability in some 

 manner and thus stimulate reactions whose rates are limited by access of 

 substrate to the enzyme, or it may either directly or indirectly damage the 

 cell so that the structural disorganization will allow reactions to be released 

 from their normal control, which may be simply a spatial separation of 

 reactants. Any change in functional activity induced by an inhibitor can 

 in turn alter metabolism; the temporary stimulation often observed in 

 nerve and muscle following the application of an inhibitor could be related 

 to the partial depolarization of the membrane, with consequent flow of 

 ions and activation of pump mechanisms. Some attention has been given 

 to the protection of the enzyme against denaturation, due to combination 

 with the inhibitor and stabilization of the active structure (Spiegelman 

 and Reiner, 1945; Reiner, 1959, p. 171), but it seems unlikely that dena- 

 turation within the cell would be of significance in determining metabolic 

 rate, and it must also be very uncommon for a substance to combine with 

 an enzyme in such a way that it stabilizes its structure and simultaneously 

 does not interfere with its catalytic activity. Lastly, the possibility that 

 the inhibitor is simply an activator or substrate for enzymes other than 

 those inhibited must be kept in mind. The designation of a substance as 

 an enzyme inhibitor must not prevent us from considering the substance 

 as capable of a great variety of actions on a system so complex as the 

 living cell. 



INTRACELLULAR EQUILIBRIA AND SECONDARY EFFECTS 



OF INHIBITORS 



A multitude of enzymically catalyzed reactions proceed simultaneously 

 within the organized structure of the protoplasm of the living cell. Many 

 of these reactions are interrelated: some form substances used by other 

 reactions, some provide energy required by endergonic processes, some are 

 involved in the synthesis of material necessary for the catalysis of other 

 reactions, while others may be important in the disposal or modification 

 of the products of metabolism. Protoplasm must take up the material and 

 generate the energy to synthesize its own substance, including the enzymes 

 and coenzymes which are necessary for these very reactions; it is a system 



