274 1. lODOACETATE AND lODOACETAMIDE 



that iodoacetamide uncouples mitochondrial oxidative phosphorylation, 

 while iodcacetate does not; he postulated some permeability barrier although 

 this does not now seem very likely. The blocking action of iodoacetate on 

 the cardiostimulatory action of epinephrine (Table 1-42) and the absence 

 of an effect of iodoacetamide at 50 times the concentration are also difficult 

 to explain. One must have more comparative studies of the actions on 

 isolated glycolytic enzymes and especially 3-PGDH before some of the un- 

 predicted results can be reasonably interpreted. Some of the differences may 

 arise from the group charge introduced by iodoacetate and the absence of 

 this with iodoacetamide, but it does not seem possible to explain all the 

 data on this basis. 



The effects of iodoacetate and iodoacetamide on cardiac mitochondrial 

 oxidations (Table 1-14) and atrial characteristics (Table 1-35) have been 

 discussed. In contrast to most of the results on isolated enzymes, many 

 mitochondrial oxidations are somewhat more effectively inhibited by iodo- 

 acetate, but few consistent correlations can be made. The effects on the 

 atria are often quite different, both quantitatively and qualitatively, but 

 certainly iodoacetamide is not markedly more potent, although the pH 

 was 7.4, i.e., there is no evidence that penetration is a factor, which might 

 be interpreted as indicating that much of the action is on the cell membranes. 



Iodoacetate and the Other Haloacetates 



The important differences between the haloacetates may be summarized 

 as follows: (1) bromoacetic and chloroacetic acids are somewhat stronger 

 acids than iodoacetic acid, and hence would not be expected to penetrate 

 better, and (2) bromoacetate reacts a little slower than iodoacetate with 

 SH groups, whereas chloroacetate reacts very slowly. Fluoroacetate is 

 omitted from discussion here because it is completely unlike iodoacetate. 

 One would thus predict bromoacetate to act much like iodoacetate, al- 

 though somewhat less potently, and chloroacetate to have little activity 

 as an alkylating agent or glycolytic inhibitor. These predictions are borne 

 out in all the work reported. Bromoacetate exhibits similar toxic effects on 

 animals compared to iodoacetate (Steinauer, 1874; Dalgaard-Mikkelson et 

 al, 1955), also inhibits many SH enzymes (Table 1-43), inhibits the EM 

 pathway readily, and produces muscle rigor. The effects of chloroacetate 

 on animals are quite different and probably related to other sites of action 

 (Fuhrman et al., 1955). Some selected relative potencies for these three 

 haloacetates are given in Table 1-44. Although bromoacetate is an effective 

 alkylating agent, there seems to be no evidence that it possesses advantages 

 over iodoacetate for this purpose. 



Bromo-, chloro-, and iodo-substituted aliphatic acids of longer chain 

 length than acetic acid are relatively weak or completely ineffective alkyl- 

 ating agents, not reacting with SH groups (Schroeder et al, 1933 b) or 



