RESISTANCE TO THE ARSENICALS 



763 



it was stated that the differences in the SH contents are not statistically 

 significant. It may be noted that the number of SH groups per cell corre- 

 sponds quite closely to the number of arsenical molecules bound per cell in 



the normal strain, but we shall see that much less arsenical is bound in the 

 resistant forms. Akiba and Ishii (1952) found that a resistant strain of E. 

 coli had 40-50% fewer SH groups than normals, but this could not account 

 for the degree of resistance. Indeed, it is difficult by any modification of 

 thiols to explain resistance factors of 100-1000. Arsenite-resistant blue 

 ticks contain about twice as many SH groups as normal ticks, but it is 

 not known if this is directly related to the resistance (Thompson and John- 

 ston, 1958). 



If the arsenicals are trypanocidal through interference with metabolism, 

 we might expect to find the metabolism of resistant trypanosomes to be 

 altered. It has been known for some time that certain metabolic systems 

 of tolerant organisms cannot be readily depressed by arsenicals in the intact 

 cell. Thus the suppression of glucose utilization in trypanosomes by oxo- 

 phenarsine runs quite parallel to the sensitivity of the organism to the 

 arsenical (Schueler et al., 1947). Harvey (1949) showed that it requires 

 about 10 times as much oxophenarsine to inhibit the respiration of resistant 

 trypanosomes compared to normal ones, although inhibitions by other 

 substances are the same in both. Such work does not necessarily indicate 

 differences in the enzymes or metabolic systems, since the arsenical may 

 not gain access to these systems because of permeability changes in the 

 resistant forms. In general, the over-all metabolism of normals and resis- 

 tants has been found to be the same. Some differences were claimed by 

 Williamson (1953), using methylene blue reduction with a variety of sub- 

 strates. The strain was made resistant to Melarsen and was also resistant 

 to the pentavalent arsenicals and the diamidines. No differences were seen 

 with glucose, ethanol, or formate, and only slight differences with malate, 

 but with the other six substrates there were marked differences (see ac- 

 companying tabulation). This appears to indicate that either (1) the meta- 

 bolism of these cells was altered, or (2) the permeabilities to these substrates 



