732 6. ARSENICALS 



being a depletion of high-energy substances generated in the cycle and 

 secondary alterations in various metabolic pathways associated with the 

 cycle. We shall now examine this theory to determine if it fits the facts. 

 The fundamental evidence for this theory may be summarized as follows: 

 (1) arsenicals depress oxidative processes in tissues both in vitro and in 

 vivo; (2) the keto acid oxidases are very sensitive to the arsenicals; (3) ac- 

 cumulation of keto acids occurs in the tissues and blood of poisoned animals; 

 and (4) the symptoms of arsenical poisoning are, at least partially, similar 

 to those of thiamine deficiency, this also interfering with the oxidation of 

 the keto acids. It is worthwhile to examine this last point in greater detail. 

 Sexton and Gowdey (1947) presented a long table listing the changes in 

 arsenical poisoning and thiamine deficiency, pointing out numerous simi- 

 larities, although such similarities had been suggested much earlier. Their 

 interest had been stimulated by the rapid recovery of a patient with arsen- 

 ical encephalopathy and neuritis after administration of thiamine, and they 

 showed that thiamine given to patients receiving oxophenarsine, and who 

 exhibited high blood pyruvate levels, caused a fall in these levels, and that 

 blood levels of pyruvate could be maintained at normal values by the si- 

 multaneous administration of thiamine and oxophenarsine to dogs. It is 

 difficult to understand, if the lipoate is inactivated by the arsenicals, how 

 the giving of thiamine could reverse this inhibition, and such has not been 

 demonstrated on isolated systems or enzyme preparations. In comparing 

 the symptoms of thiamine deficiency with arsenical poisoning, one must 

 distinguish between acute and chronic effects, the acute toxicity perhaps 

 not being pertinent in this regard. The classical symptoms of thiamine 

 deficiency are: anorexia, weakness, loss of weight, peripheral neuritis, 

 edema, gastrointestinal disturbances, and cardiac failure. Certainly this 

 picture fairly closely parallels chronic arsenical poisoning, with the possible 

 exception of the cardiac effects, which have not been studied adequately. 

 However, the arsenicals can produce effects not seen in thiamine defi- 

 ciency. The lack of an exact parallelism is not surprising because the bio- 

 chemical lesion in the two cases is not identical. First, it is not certain that 

 thiamine deficiency expresses itself solely as a depression of keto acid oxi- 

 dation, or that arsenicals exert a perfectly specific effect on these enzyme 

 systems. Second, the matter of penetration and distribution of the arseni- 

 cals is important; the relative effects on the various tissues would not neces- 

 sarily be the same in the two situations inasmuch as some tissues might 

 be relatively impermeable to the arsenicals and yet suffer readily from thia- 

 mine deficiency. Conversely, arsenicals may be concentrated in certain tis- 

 sues, as the kidney, which might suffer more damage than in thiamine 

 deficiency. There are, however, certain discrepancies to be explained; for 

 example, the marked effects of the arsenicals on hematopoietic tissues, 

 which is not paralleled exactly by thiamine deficiency, as well as the liver 



