182 1. lODOACETATE AND lODOACETAMIDE 



Effects of lodoacetate on Cell Membranes and Permeability 



Before discussing the effects of iodoacetate on active transport processes, 

 we shall examine the rather meager evidence that actions directly on the 

 membrane can be exerted. The permeability of erythrocytes to glycerol and 

 various monosaccharides appears not to be affected by even high concen- 

 trations of iodoacetate (Wilbrandt, 1937, 1938; Hunter, 1947; Danielli, 1954) 

 the integrity of the membrane here not being dependent on glycolysis.* 

 However, the results with ions are quite different. lodoacetate causes a 

 loss of K+ from eyrthrocytes and is lytic (Ponder, 1949; Flynn and Maizels, 

 1949). It is quite certain that part of the K+ loss is due to structural changes 

 in the membrane. Green and Parpart (1953) believed that the primary ac- 

 tion of iodoacetate is on the membrane to facilitate loss of K+, and Love 

 et al. (1955) reported that iodoacetate produces both an inhibition of K+ 

 influx and an increase in efflux. lodoacetate at 0.125 mM has no effect on 

 erythrocyte K+ but if 5 mM ferricyanide, which has no effect alone, is also 

 present there is a marked loss of K+, and it was concluded that the effects 

 of iodoacetate on permeability are unrelated to glycolysis (Passow and 

 Gruner, 1963). lodoacetate at 0.1 mM slightly decreases both K+ influx and 

 efflux in the rat uterus but the former more, so there is a net depression 

 of uptake (Daniel, 1963). The inhibition of glucose transport in the intestine 

 was claimed to occur at concentrations of iodoacetate without effect on 

 glycolysis, and the action was attributed to an effect on the membrane or 

 on ATPase (Rummel et al., 1958). The extrusion of Na+ from muscles previ- 

 ously treated to gain Na+ is inhibited by iodoacetate and the Na"^ influx 

 actually rises (Frazier and Keynes, 1959). An analysis of the results led to 

 the conclusion that there is an increased permeability to Na+, that the effect 

 is not entirely on glycolysis, and that iodoacetate may react with SH groups 

 in the membrane. These few reports do not invalidate the concept that the 

 primary effect of iodoacetate usually is to inhibit active transport, but in- 

 dicate clearly that other factors may be involved, and that in the future 

 such studies should include, where possible, data on permeability and evi- 

 dence for or against membrane structural changes and lysis. 



Methods for Localizing the Site of Action of Inhibitors Reducing Accumulation 



If accumulation of a substance is inhibited, there are three general sites 

 for the inhibition: (1) the active transport, (2) the membrane permeability, 

 and (3) the metabolic utilization of the substance, if this occurs. The last 

 mechanism is not very common and is fairly easily recognized, so we shall 



* It seems strange that the transport of ghicose is unaffected by iodoacetate in 

 view of the results with ions and the fact that it is not a simple diffusion. Perhaps 

 more quantitative and reHable metliods would demonstrate definite changes. 



