172 1. lODOACETATE AND lODOACETAMIDE 



port system of several.* Wilbrandt has termed primary inhibitors those 

 which act directly on transport systems and secondary inhibitors those de- 

 pressing metabolic energy formation. 



One should perhaps avoid the assumption that there is a general energy 

 production intracellularly, the ATP formed being used by all the functional 

 processes, e.g., that in muscle the ATP generated in the EM pathway and 

 the cycle is used indiscriminately for maintenance of the membrane po- 

 tential and for contraction. There is some evidence that compartraentaliza- 

 tion of ATP occurs occasionally and that the ATP used in a particular proc- 

 ess may be generated in the region of that process. It is possible that the 

 EM pathway and the cycle provide energy in a definite pattern, and that 

 exergonic sequences occur in the membrane and are especially involved in 

 active transport. 



Factors Involved in the Intracellular Accumulation of Substances 



Although it is not necessary that active transport lead to a higher con- 

 centration of a substance within the cell than in the medium, this is the 

 usual result and often one criterion for active transport. The effects of an 

 inhibitor on the accumulation of a substance are frequently determined 

 and the results interpreted in terms of modification of active transport, 

 lodoacetate generally reduces the accumulation, whether transmembrane 

 or transcellular, and often induces a loss of the substance from the cell, as 

 is evident from the summary presented in Table 1-31. Thus iodoacetate 

 not only depresses the accumulation of K+ in K+-depleted cells but causes 

 a loss of K+ from normal or semidepleted cells. The interpretation of such 

 data is more complex than in simple transport systems. There are two op- 

 posing processes: the active transport of the substance in one direction, 

 and the passive diffusion of the substance in the other direction, the latter 

 being determined by the permeability of the membrane for the substance. 

 The higher the permeability, the greater the rate of diffusion and the more 

 active the transport mechanism must be to lead to accumulation or main- 

 tain a high intracellular level of the substance. If an inhibitor is found to 

 reduce accumulation or lead to loss of a substance from the cell, it could 

 be acting by two general mechanisms: depression of the active transport 

 or acceleration of the rate of loss. The latter will be brought about by an 

 increase in membrane permeability and such an action is more likely for 

 those inhibitors reacting with protein groups. 



* The division of possible sites of action into exergonic and endergonic does not 

 imply that only the former may be enzymic. Enzymes are undoubtedly often involved 

 in the transport system in the membrane; one example is ATPase. Effects on the 

 transport system can be through several different mechanisms and are not to be in- 

 terpreted only as structural changes. 



