ARSENICALS 597 



this chapter, since it is not an SH reagent and interferes with phospho- 

 rylations instead, but the pentavalent organic arsenicals will be included 

 because they produce their effects after reduction. A phenomenon observed 

 as early as 1896 is that certain organisms become increasingly resistant 

 to the arsenicals during continuous exposure. Because of the practical 

 aspects of this in chemotherapy, it has been intensively studied and has 

 provided much information relevant to the basic actions of the arsenicals. 

 Any complete theory of arsenical action must include some explanation 

 of resistance. 



The toxic effects of arsenite on a variety of microorganisms, plants, 

 and invertebrates have been studied since 1850, and the concept was 

 evolved that it is a so-called protoplasmic poison, exerting a nonspecific 

 protein-coagulating action, a theory no longer valid. The idea that arsenicals 

 produce their effects by interfering in some manner with metabolism is 

 also very old and a good deal of work was done in the nineteenth century 

 to demonstrate this, but the results led to no definite conclusion. The 

 difficulty was mainly in finding the right enzymes or metabolic systems 

 to be tested, and the many negative results discouraged some workers 

 into believing that a metabolic explanation for the mechanism is not valid. 

 The earliest metabolic work which has come to my attention is that of 

 Basilius Savitsch (1854), working at Dorpat under Buchheim's direction. 

 He reported that yeast fermentation is depressed by arsenite, although 

 the action is rather weak and slow to develop. Johannsohn (1874) continued 

 this work at Dorpat and found fermentation to be reduced 16% by 5.5 mM 

 arsenite over a period of 24 hr; an inhibition of 26% by 9.2 mM arsenite 

 was also observed. The growth of yeast is definitely inhibited at these con- 

 centrations. On the other hand, Schulz (1888) obtained a fairly potent inhi- 

 bition of yeast fermentation, 0.25 mM arsenite depressing in around 30%, 

 and 0.7 mM around 65%. The reason for this discrepancy in potency 

 is not immediately apparent. These observations on yeast did not seem 

 to influence significantly the concepts of arsenical action, and similar 

 experiments to answer similar problems were being done many years later. 



Pharmacological studies in the meantime were being made by Sklarek 

 (1866), who recorded a primary central action leading to reflex depression 

 and motor paralysis, and by Ringer and Murrell (1878), who confirmed 

 the central action but also observed the more rapid occurrence of rigor 

 mortis in poisoned muscles and hence a direct effect on skeletal muscle. 

 Several reports pointed to some metabolic interference in whole animals, 

 but much argument ensued as to whether these effects, are primary or 

 secondary. For example, Cunze (1866) concluded that the decrease in body 

 temperature caused in rabbits by arsenite indicates a metabolic depression, 

 but Von Boeck (1871) correctly surmised that such evidence is not satisfac- 

 tory. On the other hand. Von Boeck's demonstration of an effect on nitrogen 



