598 6. ARSENICALS 



balance in the dog is also not proof of a direct action on metabolism. Meyer 

 (1881) found that the blood CO2 is reduced in rabbits poisoned by arsenite 

 and obtained evidence that some acid, probably lactic acid, appears in the 

 blood, indicating a disturbance in carbohydrate metabolism, while Araki 

 (1893) showed that lactate appears in the urine under such conditions. The 

 conversion of arsenite to arsenate in some tissues was observed by Spitzer 

 (1898) and he investigated tissue respiration with the idea that arsenite 

 might serve as an oxygen acceptor (i. e., as an oxidizable substrate), 

 but found only depression instead of stimulation. 



It is often difficult to understand why a particular observation, intrinsi- 

 cally of little significance or very similar to the results of others, is occa- 

 sionally responsible for stimulating further important work. In the present 

 field it was the demonstration by Onaka (1911) at Heidelberg that arsenite 

 in low concentration (0.023 mM) inhibits the respiration of goose erythro- 

 cytes. Such results must come at the right time and place to be influential. 

 It was at this time and place that Warburg was working on the inhibitory 

 effects of cyanide and carbon monoxide; thus Warburg became interested 

 in arsenite as a respiratory inhibitor, although for some years under the mis- 

 taken impression that it acts like cyanide on the iron-containing enzymes 

 involved in oxygen activation, an error shared by several others during 

 this period. Battelli and Stern (1911) at the same time made the observation 

 that, although arsenite acts on respiration about as well as cyanide, it 

 depresses succinate oxidation by muscle minces much less readily, around 

 5 mM being required for definite inhibition, results which should have 

 given a clue to the basic difference in the sites of action of these inhibitors. 

 Much later, Dresel (1926) was still assuming that arsenite behaves like 

 cyanide and carbon monoxide in depressing respiration, and thought 

 it would be a more useful inhibitor for this purpose because it is not volatile. 

 Szent-Gyorgyi (1930) eventually showed that arsenite has virtually no 

 effect, even at concentrations as high as 10 mM, on cytochrome oxidase 

 using p-phenylenediamine as the substrate. A new approach to the action 

 of the arsenicals was needed and this was provided by the study of Voegtlin 

 et al. (1923), in which it was shown that various thiols can antagonize the 

 effects of oxophenarsine on trypanosomal motility. In conjunction with 

 the recently proposed general role of glutathione and SH groups in cellular 

 metabolism, this led immediately to the concept that the arsenicals might 

 react with thiols in the cells and interrupt oxidative processes. Further 

 work by Voegtlin and his colleagues, and by others, has established this 

 mechanism of inhibition, and there has been a steady increase in confidence 

 that this is indeed the primary site of attack. 



The next important advance was made by Krebs (1933 a, b) in showing 

 that arsenite causes the marked accumulation of pyruvate and other 

 keto acids during the metabolism of amino acids in kidney preparations. 



