250 1. lODOACETATE AND lODOACETAMIDE 



tate is partially blocked by ergotoxine. One might temporarily suggest the 

 changes shown in Fig. 1-26, pending further experimental evidence, as 

 showing the major effects of low and high doses of iodoacetate. At low doses, 

 tissue utilization of glucose is not appreciably depressed directly and may 

 be increased somewhat due to release of insulin whereas, at lethal dosage 

 levels, tissue utilization of glucose is mainly suppressed and sympathetic 

 stimulation is superimposed. Other factors can well be imagined; e.g., the 

 fall in blood pressure usually seen after iodoacetate may also contribute to 

 sympathetic and adrenal activation. 



It must not be assumed that all the effects of toxic doses of iodoacetate 

 are attributable entirely to a selective block of the EM pathway. There is 

 evidence that other pathways must be affected. For example, blood keto 

 acids (pyruvate and a-ketoglutarate) rise to about the same degree as blood 

 glucose after high doses of iodoacetate (El Hawary, 1955; Handler, 1945), 

 and acetone bodies (acetone and acetoacetate) may be elevated also. 



Chronic Toxicity and Tissue Damage 



The marked effects of iodoacetate on the retina prompt us to inquire wheth- 

 er other tissues may be especially sensitive to this inhibitor, due to either 

 a predominant glycolytic activity or a functional dependence on glycolysis, 

 or a particular function (such as cell proliferation) which involves SH groups 

 other than those of 3-PGDH. Karli (1952) in his study of retinal degenera- 

 tion examined animals several days after the administration of iodoacetate 

 to determine if the retinal damage is indeed selective, and discovered 

 marked degenerative changes in the testes. The formation of spermatozoa 

 was completely inhibited and the cells concerned with spermatogenesis were 

 damaged; the epididymal canal contained spermatids and spermatocytes 

 in various stages of degeneration. Certainly testis as a whole does not have 

 an unusually high glycolytic activity, but here one is concerned with only 

 a certain type of cell which may have quite different metabolic character- 

 istics than the bulk of the cells. Many types of proliferating cells seem to 

 depend on the glycolytic pathway, but in addition have a reasonably high 

 energy requirement (see page 260). It has been demonstrated that inverte- 

 brate spermatogenesis m vitro is very sensitive to iodoacetate, 50% inhi- 

 bition being given by 0.04 mM (Schneiderman et al., 1953). Injections daily 

 of 5 mg bromoacetate in rats lead to marked atrophy of the seminal vesicles 

 in a few days (Schiller, 1935). A cessation of the estrus cycle in female rats 

 occurs. Hematopoietic depression might also be anticipated, and Laszt and 

 Verzar (1936) observed a 28% reduction in erythrocyte count and a com- 

 parable fall in hemoglobin in young rats fed 1-2 mg iodoacetate per day. 

 The skin has a relatively high proliferation rate, and it was noted that a 

 dermatitis appeared between 8 and 14 days, with subsequent loss of hair. 



