64 P-AMINOBENZOIC ACID 



role of the time element in the detoxication of pentavalent arsenicals. 

 Injection of PABA up to 3 hours before the administration of the arsenical 

 affords protection for nearly all animals. On the other hand, when the 

 animals receive the vitamin subsequent to the administration of the ar- 

 senical, the detoxicating effect is less pronounced and continues to decrease 

 with increasing time interval. Sandground suggests^ that this time in- 

 terval coincides with the time required for the in vivo reduction of the 

 pentavalent arsenicals (or for the oxidation of the arsenobenzenes) to 

 the corresponding arsenoxides, the toxicity of wiiich is not reduced by 

 PABA.^' ^^ In support of this theory the author points to the relatively 



}i RAs = AsR -^ RAsO <-^5L RASO3H2 



slow development of host toxicity and of parasiticidal activity of the pen- 

 tavalent compounds, as compared with the rapid appearance of both these 

 effects in the case of the arsenoxides. The fact that PABA does not de- 

 crease the trypanocidal effect of the pentavalent arsenicals is interpreted 

 by Sandground as indicating that the vitamin does not interfere in the 

 reduction of the arsonic acid to the arsenoxide. 



The reviewers find some difficulty in subscribing to this view. If the 

 toxicity of arsonic acids can be ascribed to their conversion to the arsenoxide 

 (detoxication of which is not effected by PABA) and if PABA offers no 

 appreciable obstruction to the conversion, it would seem unlikely that 

 PABA could materially reduce the toxicity of the pentavalent arsenical. 



In further studies Sandground^^ showed that the three isomeric amino- 

 benzoic acids, the hydroxy and nitro analogs of PABA, phenylacetic acid, 

 phenylpropionic acid, and benzoic acid, itself, all confer some degree of 

 protection. This observation led him to consider unlikely the direct com- 

 bination of arsenical and detoxicant to produce a non-toxic complex as a 

 mechanism of action. Similarly, the possibility of competition for a specific 

 enzyme site was excluded in view of the protective activity of compounds 

 so unrelated structurally to the arsonic acids as phenylglycine or benzyl 

 succinate. The only structural arrangement which appears to be a pre- 

 requisite for activity is a carbocyclic system of five or six members, as- 

 sociated with a free carboxyl group. Esterification or amidation of the acid 

 group reduces activity. 



The apparent lack of specificity of PABA in this connection is supported 

 by the data of Martin, ^^ who found that the administration of thyroxine 

 along with the vitamin nullifies to a great extent its detoxicating property. 

 The theory was advanced that PABA functions by virtue of its ability to 



i» L. Peters, Proc. Soc. Exptl. Biol. Med. 53, 147 (1943). 



" J. H. Sandground, /. Pharmacol. Exptl. Therap. 80, 393 (1944). 



12 G. J. Martin, Am. J. Pharm. 118, 394 (1946). 



