GENERAL DEVELOPMENT OF A LOCALIZATION PROGRAM 531 



involved in respiration, the possibility of a direct functional effect is usually 

 ignored, but when no adequate inhibition has been found on any respira- 

 tory pathway or transport of substrate into the cell, one is left with at 

 least two iDOSsibilities — an action through functional depression or an ac- 

 tion on some metabolic system not yet tested. This can be resolved only 

 by finding an inhibition on some system and hence every effort must be 

 expended in testing all possible systems that may be contributing significant- 

 ly to respiration. Occasionally some investigation of the tissue's particu- 

 lar patterns of respiratory metabolism must be made to determine the major 

 contributing pathways. In rare instances it is possible to "isolate" the func- 

 tional system and test it directly. Examination of glycerinated muscle 

 fibers may demonstrate an action on the contractile elements unassociated 

 with oxidative reactions. A good example of this problem arose in the 

 study of the effects of drugs and inhibitors on the respiration of electrically 

 stimulated brain slices (Mcllwain, 1959). The respiratory depression pro- 

 duced by inhibitors such as cyanide, iodoacetate, malonate, or fluoride 

 (Heald, 1953) could arise either from a general inhibition of respiratory 

 pathways or from a more specific effect on ionic distributions and movements 

 across the cell membranes so that the tissue becomes incapable of respond- 

 ing to the electrical impulses. A functional depression with a secondary 

 effect on metabolism can occur more readily in intact tissues than in slices 

 because conduction of activating impulses could conceivably be blocked 

 more easily than the over-all metabolism of the tissues. 



A depression of cellular growth can result from a great variety of inhi- 

 bitory mechanisms inasmuch as in growing cells a major portion of the me- 

 tabolism and most of the metabolic pathways are involved in the formation 

 of new cell material. Some of the most likely mechanisms may be listed. 



I. Inhibition of the energy-generating systems responsible for the major 

 fraction of the respiration (as discussed above). 



II. Inhibition of the synthesis of some coenzyme or growth factor. 



III. Inhibition of some step in protein or nucleic acid synthesis. 



IV. Incorporation as an abnormal analog into a synthetic pathway result- 

 ing in a metabolic block if one of the abnormal substances formed cannot 

 undergo further metabolism or is unable to function as its normal analog. 



V. Inhibition of the uptake of precursors for synthetic processes (such 

 as amino acids for the formation of protein). 



VI. Direct disturbance of the mitotic sequence (such as inhibition of 

 spindle formation or of the protoplasmic movements associated with 

 cleavage). 



