EFFECTS OF TEMPERATURE: CELLULAR SYSTEMS 775 



than are the enzymes themselves. It will suffice here to enumerate some of 

 these factors as a basis for evaluating and interpreting the experimental 

 results. 



Sometimes the rate of inhibition may be limited or controlled by the 

 diffusion of the inhibitor to the enzymic site of its action, and the eventual 

 degree of inhibition may be determined by the distribution of the inhi- 

 bitor between the extracellular and intracellular phases. When penetration 

 of the inhibitor into the cell is slow, relative to the other processes involved 

 in the inhibition, the temperature dependence of the inhibition may reflect 

 changes in the permeability of the plasma membrane and have little to do 

 with the kinetics of the enzyme inhibition. Although simple diffusion rates 

 in water are not altered greatly by changes in the temperature {Q^q is 

 usually around 1.2 for molecules the size of most inhibitors), the rates of 

 membrane penetration are frequently quite sensitive to temperature (^^q 

 often between 2 and 4). It w^ould be predicted that the lower the permea- 

 bility to a substance, the greater would be the temperature effect, inas- 

 much as the energy barrier for penetration (akin to the activation energy 

 in a chemical reaction) would he higher than for a rapidly penetrating sub- 

 stance. In addition, the energy barrier may change with the temperature 

 due to structural, modifications in the membrane. The temperature charac- 

 teristics (// values, see page 792) for cell membrane penetration by electro- 

 lytes or nonelectrolytes lie usually in the range between 15 and 25 kcal/ 

 mole (Davson and Danielli, 1952; Bowyer, 1957; Glynn, 1957) and are 

 quite comparable to the values obtained for enzyme rates, cellular meta- 

 bolism, and tissue function. Thus, if a high ^^q or temperature character- 

 istic is found for the rate at which an inhibition develops, one may not 

 conclude from this alone that the process is not limited by a membrane 

 penetration step. It is quite possible that in the case of an inhibitor that 

 enters the cell with some difficulty, a depression of the temperature would 

 soon cause the rate of penetration to be limiting; thus, the temperature 

 characteristics of the inhibition would change as the temperature is lowered. 

 The equilibrium distribution of an inhibitor between the medium and the 

 cell interior is probably not very sensitive to temperature changes, unless 

 the process of uptake is active (metabolically dependent). Thus, the rates 

 at which inhibitions develop in cells will alter more with temperature than 

 will the final equilibrium inhibition levels. 



Cellular metabolism is an expression of multienzyme systems and mani- 

 fold enzymic pathways. What has been said in the previous section on multi- 

 enzyme systems applies directly to cell processes. The rate that is measured 

 (e.g., the uptake of oxygen, the formation of lactate, the synthesis of pro- 

 tein, or the disappearance of a substrate) is often a composite of several 

 rates relating to different pathways, with each pathway having its own 

 characteristic response to temperature and inhibition. Much more com- 

 plex situations can occur. Controlling or homeostatic processes, effective 



