752 6. ARSENICALS 



altered (based on staining), and the cells finally agglutinate and lyse 

 (Chatton and Tellier, 1934). There is little else to help us understand the 

 mechanisms by which the arsenicals act on these protozoa. 



Mechanism of Trypanocidal Action 



There is little more to be discussed in regard to the mechanisms of tox- 

 icity, since it seems to be generally accepted that the trypanosomes are 

 inactivated and killed because of a block in keto acid oxidation, but there 

 is no proof of this. Inhibition of respiration and accumulation of pyruvate 

 in trypanosomes have been demonstrated at low arsenical concentrations; 

 e. g., respiration is depressed 50% by atoxyl oxide, tryparsamide oxide, 

 oxophenarsine, and other arsenoxides in the concentration range 0.005- 

 0.05 mM (Fulton and Christophers, 1938; Harvey, 1949), but still these 

 concentrations are 10-100 times higher than those for trypanocidal action. 

 There is no doubt that trypanosomes possess respiratory systems very 

 sensitive to the arsenicals, and even arsenite inhibits well at 0.02 mM 

 (Desowitz, 1956), other SH reagents being much less potent. There should 

 be more study of the metabolism of organisms removed from arsenical- 

 treated animals, since one could relate any changes observed to the state 

 of the trypanosomes. This was done by Cantrell (1951, 1953), as we have 

 discussed before, and his results are quite at variance with all work done 

 in vitro. The glucose utilization is not altered, while actually somewhat 

 less pyruvate is present, a reuslt very difficult to explain by any known 

 action of the arsenicals. In fact, from the known nature of trypanosomal 

 metabolism, it is rather unexpected that the arsenicals depress so readily. 

 The blood forms of most trypanosomes do not oxidize pyruvate, have no 

 pyruvate oxidase activity in extracts, and do not even utilize succinate 

 efficiently. In some {Trypanosoma vivax and Trypanosoma rhodesiense) 

 the respiration is not inhibited by cyanide and there is no detectable cyto- 

 chrome system. The R. Q. is often around 0.1-0.2 for the oxidation of 

 glucose and most trypanosomes aerobically convert glucose to various or- 

 ganic acids, such as pyruvate, succinate, acetate, formate, and others. 

 Trypanosoma equiperdum, upon which so much experimental work with 

 the arsenicals has been done, almost quantitatively converts glucose to 

 pyruvate under aerobic conditions, the cycle being absent. Spirochaetes 

 also are known to grow better under anaerobic or semianaerobic conditions, 

 and oxygen is in a way toxic to them. The problem then comes up as to 

 the system with which the arsenicals react. If lipoate is the target substance, 

 what is its function in these protozoa? Or are other dithiol components 

 the sites of attack ? Such matters seem to have been mainly ignored in dis- 

 cussing the mechanisms of the trypanocidal action, and there is really 

 no evidence at all as to how the arsenicals act on these organisms. 



Protection and reversal by thiols have been claimed to support the 



