766 6. ARSENICALS 



has really very little to do with the mechanism of the resistance, especially 

 in microorganisms. To call such phenomena "Dauermodifikations'' or 

 "permanent modifications" or "lingering modifications" does not help to 

 explain the mechanism. 



It is more important for us to determine why the resistant forms can 

 withstand such relatively high concentrations of the arsenicals. The possible 

 explanations might be classified under the following headings: 



[A) Decreased penetration of the arsenicals into the cells 



{B) Decreased affinity of the cells or their receptors for the arsenicals 



(C) Increased destruction of the arsenicals 



{D) Alteration of the metabolic pathways so that vulnerable com- 

 ponents are no longer necessary 



We have mentioned that no change in trypanosomal SH groups has been 

 found which would account for the high degrees of resistance; if such did 

 occur, it would certainly result in a modification of metabolism inasmuch 

 as these SH groups should be functional in enzyme reactions. If there were 

 a decrease in the receptor sites, it would probably be secondary to a pri- 

 mary change in the metabolism. It is difficult to conceive of an increased 

 inactivation of the arsenical being responsible for the tolerance and there 

 is no good evidence that such occurs; in fact, it has generally been observed 

 that organisms resistant to high concentrations of arsenite are not capable 

 of metabolizing it. Neuschlosz (1920) thought that an increased ability 

 to oxidize arsenite might explain resistance in paramecia, and Turner 

 (1954) considered this with regard to bacteria growing in cattle dips, but 

 found some of the tolerant forms not to oxidize arsenite. The last possibility 

 has been discussed and we have concluded that there are insufficient data; 

 in certain instances metabolism may be altered but whether this is primary 

 or secondary we do not know. Let us then consider the evidence for the 

 first explanation based on altered permeability. 



Early work had indicated that trypanosomes made resistant to dyes do 

 not take up the dye from solution, and it was soon found that certain strains 

 resistant to the arsenicals, and showing cross-resistance to dyes, also do 

 not become stained when exposed to the dyes. Jollos (1921) in his experi- 

 ments with arsenite-resistant paramecia analyzed filtrates from the media 

 in which the paramecia had been exposed to arsenite, and found that the 

 resistant ones take up less arsenite. Yorke et al. (1931 b) examined trypar- 

 samide-resistant trypanosomes and showed that they do not take up 

 appreciable amounts of tryparsamide oxide, whereas normals completely 

 remove it from the medium; they postulated that resistance is basically 

 due to the inability of the arsenical to penetrate into the resistant forms. 

 These results were confirmed by Hawking (1937), who also showed that 



