EFFECTS OBSERVED IN THE WHOLE ANIMAL 



723 



to a change in the reactivity with the cellular components, or to a change 

 in the ability to penetrate into the cells. We have no adequate evidence 

 relative to the former, but there is positive evidence that penetrability is a 

 major factor. Let us first consider what little is known about the influence 

 of structure on the reactivity with enzymes. Barron and Singer (1945) 

 found that phenylarsenoxide and several derivatives comparably inhibit 

 succinate oxidase (see accompanying tabulation). Certainly one can detect 



Inhibition of succinate 



Relative activity toward: 



no correlations here and the wide variations in activity cannot be readily 

 explained by these data. However, succinate oxidase can be considered 

 as a model system only, since other enzymes in the cells are more sensitive 

 and important. The authors also found that phenylarsenoxide and the 

 p-COOH derivative are equally inhibitory to malate dehydrogenase. Roth- 

 schild et al. (1954) reported that choline oxidase is inhibited to the same 

 degree by the phenylarsenoxides in the table above, but such a high con- 

 centration (1 mM) was used that accurate comparisons cannot be made. 

 The 29-COOH and ^o-NH^ derivative exert identical inhibitions on amine 

 oxidase (Singer and Barron, 1945). Other data on less important enzymes 

 are equally unrewarding. There seems to be no evidence for marked differ- 

 ences in enzyme inhibitory action, but ideally studies should be made on 

 the keto acid oxidases. 



Turning to the explanation of variations in toxicity based on permea- 

 bility, we are on more solid ground. First, we shall see that penetration 

 of an arsenical into protozoans is a very important factor in determining 

 the susceptibility. Second, Hogan and Eagle (1944) showed that the amount 

 of arsenical taken up by erythrocytes is proportional to the toxicity of 

 the arsenical (Fig. 6-6). A similar relationship was demonstrated for liver 

 and kidney following injection of equivalent doses of various arsenoxides, 

 the more toxic the compound the greater the amount found in the tissue 

 (see accompanying tabulation). Finally, the amount of arsenical taken up 

 by trypanosomes is also proportional to the trypanocidal activity (Fig. 6-8) 

 (Eagle and Magnuson, 1944). Although these results might be interpreted 

 as due to different degrees of binding, in view of the lack of evidence for 



