EFFECTS OBSERVED IN THE WHOLE ANIMAL 731 



from these toxic doses of arsenite. It is interesting that arsenite simulta- 

 neously can triple liver citrate. Citrate levels in other tissues are increased 

 more moderately (Berry et al., 1954 b). What is the source of the citrate 



and why would it accumulate? Hallman (1940) has shown that arsenite 

 is a potent inhibitor of citrate formation from a variety of substrates in 

 kidney and testis, and a block of the cycle at the keto acid oxidases would 

 lead one to expect a reduction in citrate. The answer to these and related 

 problems must await more extensive investigation with wider dosage 

 ranges, chronological correlations, and more detailed analyses. 



Mechanisms of Arsenical Toxicity 



The possible mechanisms by which the arsenicals produce their effects 

 on tissues and on whole animals will be discussed briefly to sumarize our 

 knowledge. The concept of arsenoreceptors in the cells as proposed by 

 Ehrlich (1909) is valid and emphasizes the selectivity of action; it has 

 been necessary to determine exactly what these receptors are. That these 

 receptors involve SH groups was postulated by Ehrlich and put on a firm 

 basis by Voegtlin et al. (1923), but the nature of these SH groups was not 

 understood, so that Voegthn et al. (1925) could state, "In fact, our data seem 

 to indicate that the sulfhydryl group of glutathione actually represents 

 the "arseno-receptor" of mammalian protoplasm." However, as Brown 

 and Kolmer (1929) soon showed, intensive arsenical therapy does not sig- 

 nificantly reduce tissue glutathione (although they stated that the toxic 

 effects may be related to glutathione depletion). Voegtlin admitted that 

 other SH groups, perhaps fixed in the cells, could also be involved. The 

 evolution of the concept of the selective action of the arsenicals on lipoate 

 and keto acid oxidation has been described. The present generally accepted 

 theory of the mechanism might be put somewhat as follows: arsenicals 

 block specifically the oxidation of the a-keto acids, particularly pyruvate, 

 by inactivation of the lipoate component of such systems, and thus interfere 

 with the main oxidative pathways of the tricarboxylate cycle, the result 



