ENZYME INHIBITION AND CHANGES IN CELL FUNCTION 463 



in intracellular pH or ionic composition, brought about by the inhibition, 

 might affect the activity of the cell. 



Nonenzymic Effects of Inhibitors on Cell Function 



An inhibitor that has been found to be quite specific metabolically, 

 acting only on a particular enzyme or group of enzymes, may still possess 

 the ability to react in some manner with the components of the functional 

 systems in the cell or to modify function in other nonenzymic ways. Many 

 tissues have an electric potential across the cell membrane; the functional 

 activity and metabolism will depend upon and vary with the fluctuations 

 in this potential. This would apply particularly to muscle and nerve but the 

 membrane processes may also be important in kidney, marine invertebrate 

 eggs, plant cells, and various microorganisms. These membrane potentials 

 may be modified by inhibitors either by action on enzymes (both within 

 the cell and at the surface of the cell) or nonenzymically. Many inhibitors 

 are ions and can change the potential directly, especially if used in rela- 

 tively high concentrations (usually above 10 mM, although the permea- 

 bility to the ion is of importance). The ion that accompanies the inhibitor 

 ion must also be considered. The Na^ with inhibitors such as malonate of 

 fluoride may have a measurable effect on membrane potentials in concen- 

 trations above 10 mil/; such effects of Na"*" have been demonstrated on rat 

 atrial potentials. The potassium salts of inhibitors should be avoided in 

 work with intact cells for this reason, since K^ usually has a marked effect 

 on the resting potential. 



All inhibitors that react with groups on proteins must be assumed to 

 attack not only the enzymes but also the various proteins of the cell. These 

 proteins may be in the plasma membrane and their modification induce 

 jiermeability changes that will secondarily affect metabolic systems. It is 

 likely that many of the effects observed with heavy metal ions and organic 

 metal compounds are due to such actions; e.g., the rapid cytolysis sometimes 

 seen is probably unrelated to any enzyme action and is indicative of the 

 effects on membrane structure. The inhibition of metabolism in yeast by 

 uranium salts would appear to be the result of a decrease in the permea- 

 bility to various substrates and there is no evidence that this is an effect 

 on enzymes (Barron et al., 1948a). Inhibitors that are lipid-soluble or pos- 

 sess polycyclic structures could interfere with the interactions of cell mem- 

 brane components; the bipyridines and phenanthrolines may act in this 

 way, in addition to their chelation of metal ions. 



It is usually difficult and often impossible to distinguish between the 

 enzymic and nonenzymic actions of inhibitors. It is doubtful if any type 

 of kinetic analysis would be useful. In some cases a variation of the in- 

 hibitor structure may be informative. For instance in the example of the 

 metal chelating agents, given above, the testing of bipyridines or phenan- 



