654 6. ARSENICALS 



especially notable for the cholinesterases of plasma or erythrocytes (Mounter 

 and Whittaker, 1953). Lewisite, phenylarsenoxide, and diphenylchloroarsine 

 are all rather weak inhibitors, while arsenite inhibits well below 1 mM. 

 Human erythrocytic cholinesterase inhibited by arsenite can be completely 

 reactivated by prolonged dialysis and this was taken as evidence that the 

 reaction is not with SH groups (Markwardt, 1953 a), although it is by no 

 means a valid conclusion. It is odd that oxophenarsine, which is only about 

 1/100 as potent an inhibitor as arsenite, inactivates irreversibly. The fact 

 that the inhibition increases with pH, in contrast to what one would predict 

 for reaction with SH groups, along with other evidence, led Mounter and 

 Whittaker (1953) to conclude that cholinesterase contains an SH group 

 which is abnormal in that it is strongly modified by surrounding groups, 

 or that arsenite inhibits by electrostatically binding to the esteratic site 

 because of the dipole nature of the As=0 bond. It seems unhkely that 

 this second explanation could account for the slow reversibility of the 

 inhibition or even for the rather potent inhibitions observed, since one would 

 not expect the binding to be very strong. The mechanism of inhibition of 

 cholinesterase is thus not evident at the present time. 



Comparison of Arsenicals 



Pentavalent arsenicals generally produce much less inhibition than the 

 corresponding trivalent compounds, as one would expect from the fact that 

 the pentavalent arsenicals do not react with SH groups. It may well be 

 that some of the inhibition observed with the pentavalent arsenicals arises 

 from trivalent impurities or reduction in the enzyme preparation. This 

 situation is clearest when one compares arsenite and arsenate, since arsenate 

 is reduced less readily than the organic arsenicals. We have already com- 

 pared the actions of the arsenoso and arsinoso compounds as related to 

 the concept of monothiol and dithiol enzymes. There is little one can say 

 relative to the various phenylarsenoxides, since substitution of groups on 

 the ring sometimes increases and sometimes decreases the inhibitory potency 

 and there seem to be no obvious rules; indeed, most of the substituted 

 phenylarsenoxides are of comparable potency. One rather disturbing com- 

 parison is between phenylarsenoxide and its dithioglycolate acting on 

 urease, since the latter is at least 5 times more potent (Gordon and Quastel, 

 1948). It is not difficult to envision a transfer of the arsenical from the thio- 

 glycolate to a more avid enzyme SH group, but how can one account for 

 the greater potency of the mercaptide, unless one assumes an entirely 

 different mechanism of inhibition? 



Striking differences are often observed between the actions of arsenite 

 and of the organic arsenoxides, in general the latter being much more potent 

 inhibitors, as may be seen by comparing the data in Table 6-3 for succinate 

 oxidase (Barron and Singer, 1945), a-glycerophosphate dehydrogenase 



