180 1. lODOACETATE AND lODOACETAMIUE 



A simple calculation will illustrate this. If we assume different initial val- 

 ues of KjP and that the inhibitor reduces K by 50%, the depressions of 

 ACc will vary as shown in the accompanying tabulation. The effect of the 



inhibitor on . IC^, will be greater the lower the KjP ratio. This is on a per 

 cent basis; the absolute loss of the substance from the cells will be greater 

 in the midrange of KIP. If one starts out with depleted cells, the inhibition 

 of the accumulation rate is given by: 



AC. -AC ^ 



^-^^H (1-6) 



AC, - AC 



where ?\. is the inhibition of active transport. If P is very small relative to 

 K, the inhibition of the accumulation rate will be essentially the same as 

 the inhibition of active transport, but if P is larger the inhibition of the 

 accumulation rate will be reduced. These simple examples are presented 

 to demonstrate that the inhibition experimentally observed, either on AC^ 

 or Vf., is not necessarily the same as on the active transport process, and 

 that changes in the permeability can bring about the same effects as changes 

 in transport. In the system assumed here it is also clear that an inhibitor 

 could reduce AC^ to a lower but stable value; with iodoacetate this is not 

 so likely since the inhibition increases progressively with time and the gra- 

 dient will likewise steadily fall. 



A further factor must be considered if the substance transported can be 

 metabolized in the cells, in which case at equilibrium we have: 



^«e = ^"e + ^'^e (1''^) 



where v„,^ is the rate of metabolic disappearance at equilibrium. An inhi- 

 bitor not only can act on transport or diffusion, but also can modify the 

 rate of utilization and thereby affect accumulation as measured by the in- 

 tracellular concentration of the substance. This factor cannot be neglected 

 in studies with glucose or amino acids, since iodoacetate can affect the 

 utilization of both. Thus rat diaphragm takes up «-aminoisobutyrate and 

 leucine aerobically, and iodoacetate at 0.5 mM increases the tissue/medium 

 ratio from 1.09 to 2.68 (Peckham and Knobil, 1962). Even anaerobically 



