METABOLISM OF THE ARSENICALS 785 



further shown that the distribution is not uniform among the tissue pro- 

 teins, but the protein fractions were separated only on the basis of solu- 

 bility so that accurate characterization is impossible. It was felt that most 

 of the arsenic is bound to protein SH groups. 



METABOLISM OF THE ARSENICALS 



The metabolism of the arsenicals will be considered in three categories: 

 the breakdown of the more complex arsenicals to active forms, the oxidation- 

 reduction reactions, and the reactions whereby the active arsenicals are 

 chemically altered. 



Splitting of Complex Arsenicals 



It is now well known that the arsphenamines are not themselves active 

 but must be split and oxidized to the corresponding arsenoxides. Results 

 such as those of Voegtlin and Smith (1920), who showed that arsphena- 

 mines act slowly, are less potent than the arsenoxides, and cleave in solu- 

 tion, and of Rosenthal (1932 a), who showed that arsphenamine after 

 injection into rats can be recovered to the extent of 10-12% in the liver as 

 oxophenarsine, which could account for the therapeutic activity, paved 

 the way for the demonstration by Tatum and Cooper (1934) that oxo- 

 phenarsine has a better therapeutic index than the arsphenamines and 

 is more clinically effective. Eagle (1939 a) eventually reported that the 

 arphenamines remain inactive under anaerobic conditions but in the pre- 

 sence of oxygen are oxidized to arsenoxides, even in the absence of tissue. 

 The tetraarsenoacetate: 



OOC—CH2—As=As—As=As—CH2— coo- 

 has also been shown to be trypanocidal, but only after splitting to aceto- 

 arsenoxide and possibly arsenite (Barbour et at., 1925). 



Oxidation-Reduction Reactions 



We have mentioned the early work indicating that the pentavalents 

 must be reduced before parasiticidal activity is exhibited. We shall now 

 discuss in more detail these changes as they occur in the tissues. There is 

 probably sufficient evidence that under the appropriate conditions arsenite 

 can be oxidized to arsenate, and arsenate reduced to arsenite, in tissues 

 or tissue preparations (Binz, 1897). Reduction of pentavalent arsenicals 

 can occur nonenzymically, and thiols such as glutathione (Gordon and 

 Quastel, 1948) may contribute along with other reductants; oxidation 

 of the trivalent forms can also occur nonenzymically, as with Fe+++ in 



