VARIATION OF INTRACELLULAR INHIBITION WITH pH 713 



Solving for (B^)(, and (B^) in the uninhibited system, it is found that: 



Thus the expressions indicating the change in (B,) upon inhibition are in 

 these cases modified in a simple manner, even when all the components 

 of the system ionize. 



The same procedure as outlined here can be applied to the various types 

 of multienzyme systems and their inhibitions to obtain expressions for the 

 concentrations of the intermediates and to predict the behavior of the 

 rates of formation of the products. 



VARIATION OF INTRACELLULAR INHIBITION WITH pH 



The various ionic forms of an ionizing inhibitor — I, HI, H^I, etc. — 

 usually penetrate cell membranes at greatly different rates. It is generally 

 assumed that the uncharged form penetrates the most rapidly and the 

 highest charged form the least rapidly (this is discussed in more detail on 

 page 721). It would appear that in some cases, for practical purposes, cer- 

 tain forms of the inhibitor may not penetrate at all. Inhibitors in this 

 respect do not differ from other weak acids or bases and useful information 

 bearing on the entrance of inhibitors into cells may be obtained from results 

 on these noninhibiting substances. The fundamental problem in the theo- 

 retical approach to intracellular inhibition is the calculation of the con- 

 centration of the active form of the inhibitor within the cell. 



The effects of changes in pH on cellular inhibition produced by non- 

 ionizing inhibitors must depend on variations in the membrane permeability 

 to the inhibitor or to alterations in the metabolism brought about by shifts 

 in the intracellular pH. It would be predicted — and there is some experi- 

 mental evidence to support this — that neither the permeability nor the 

 internal pH vary markedly if the external pH does not deviate too far from 

 the normal physiological pH of the medium. Thus little effect of pH on inhi- 

 bition would be expected over this restricted range. However, different 

 types of cells undoubtedly behave in various ways when the external pH is 

 changed and also the response of the internal pH will vary with the nature 

 of the buffers in the medium. The pH effects in such systems cannot be 

 treated theoretically and we shall restrict our discussion mainly to ionizable 

 inhibitors. 



Distribution of Ionizable Inhibitors between the Medium and the Cells 



The final concentrations of the ionic forms of an inhibitor within a 

 cell will depend on the external pH, the internal pH, the form or forms of 

 the inhibitor that can penetrate the membrane, and the buffer capacity of 



