768 6. ARSENICALS 



ganism is not resistant, depresses staining in the resistants. The difficulty 

 is, however, that we are confronted by the same problem as previously: 

 Is it binding or penetration which is altered? The above results could be 

 explained in either way. 



The following is perhaps the most likely explanation from the available 

 data. There are two quite different stages or processes in the trypanocidal 

 action of an arsenical: (1) the penetration of the arsenical into the cell, 

 and (2) the reaction of the arsenical with SH groups within the cell. Each 

 process is controlled by different factors. The penetration is not primarily 

 dependent on the phenylarsenoxide nucleus but on the substituent groups 

 (i. e., their size, distribution, and charge), while the intracellular reactions 

 are dependent on the arsenoxide group and only secondarily on the substi- 

 tuents (there is no evidence of major differences between the phenylarsen- 

 oxides with regard to enzyme inhibition). The fact that acrifla vine-resistant 

 and atoxyl-resistant strains are similar also indicates that the resistance 

 is not specifically related to the arsenoxide portion of the molecule. When 

 trypanosomes become resistant to a particular type of arsenical, a change 

 occurs in the membrane whereby the transmembrane passage of that arsen- 

 ical and all those penetrating in the same manner is impeded, whereas those 

 arsenicals penetrating by different routes are unaffected by the changes 

 which have taken place and enter as readily as previously; the response to 

 the unsubstituted neutral phenylarsenoxide would thus be unaffected. 

 Resistance in these organisms would then be primarily a matter of membrane 

 changes and alterations in permeability. What these changes are one does 

 not know but it may well be modification of charged groups within the 

 membrane, particularly as changes in dye penetration occur simultaneously. 

 WiUiamson and Rollo (1959) pointed out that cross-resistance behavior 

 cannot be explained entirely on an ionic basis, and that the results suggest 

 stereospecific structural changes associated with the initial arsenical uptake. 

 It is also possible that the mechanisms of penetration involve systems which 

 are normally operative in the uptake of metabolites, so that the metabolism 

 might be altered secondarily. It must be emphasized that the bulk of this 

 work has been done with trypanosomes, and we do not know if similar 

 changes occur in other microorganisms or in those cases of resistance in 

 the higher animals. The information obtained from the studies of resistance 

 has provided very interesting concepts of arsenical penetration, but has 

 not added a great deal to our knowledge of the biochemical mechanisms 

 by which the arsenicals act within the cells. It has also made evident that, 

 in comparing the relative potencies of a series of arsenicals, the differences 

 cannot be safely interpreted in terms of differential effects on enzyme 

 systems but rather may be related to differential penetration only, and 

 the practical problem of finding a safe arsenical has been mainly one of 

 finding molecules which will penetrate host cells relatively less readily 

 than the parasite cells. 



