698 6. ARSENICALS 



PENETRATION OF ARSENICALS INTO CELLS 



Inasmuch as the entrance of arsenicals into cells and tissues is an im- 

 portant factor in determining the degree of effect produced, particularly 

 in certain microorganisms, it will be well to take up at this time what 

 little is known about the permeability of cells to the arsenicals. As with 

 any substances which are bound to proteins, it is often difficult by the 

 usual analyses to determine whether the arsenical has really entered the 

 cells or is adsorbed or chemically reacted with extracellular material or 

 the plasma membrane. 



Arsenite 



Several observations of an indirect nature purport to prove that the 

 effects of arsenite are limited by membrane penetration. Dresel (1926) 

 found that suspensions of avian erythrocytes and hemolysates respire at 

 comparable rates, but that 0.05 mM arsenite inhibits the latter 40% 

 and the former only 9%. Since the respiration was measured over 1-hr 

 periods, it is difficult for me to believe that the differences can be attributed 

 to permeability barriers. As discussed previously (page 602), un-ionized 

 arsenious acid should be the dominant form in solutions at physiological 

 pH and that it would fail to penetrate into these cells during a 1-hr period 

 is very unlikely. Bergstermann and Mangier (1948) also reported that iso- 

 lated succinate dehydrogenase is inhibited more than the enzyme in muscle 

 brei, and thought that permeability factors would explain this. 



There are several reasons why enzymes or metabolic processes would 

 exhibit different sensitivities to inhibitors in intact cells or extracts (see 

 Chapter 1-9). (1) The nature of the metabolism may be quite different in 

 the two situations due to changes in the substrates used, altered concen- 

 trations of cofactors and coenzymes, different ionic environments, and 

 many other factors. This is especially true when some very general process 

 like respiration is involved. (2) Structural alterations and sometimes disrup- 

 tion of organized enzyme complexes may make the sensitive components 

 more or less accessible to the inhibitor. (3) The binding of the inhibitor 

 to nonenzyme material may be either increased or decreased in noncellu- 

 lar preparations, depending, for one thing, on the type of extract or degree 

 of purification of an enzyme. Bergstermann and Mangier (1948) indeed 

 pointed out that this might also explain their failure to find inhibition in 

 a muscle brei. (4) Enzymes are often protected against the arsenicals by 

 their substrates and within the cell the localized substrate concentration 

 may be high, particularly in the case of enzymes operating in sequence. A 

 number of other factors might be imagined. It is not necessary that extracts 

 be more sensitive than cellular preparations. Ramachandran and Gottlieb 

 (1963) found the glucose respiration of Caldariomyces cells to be inhibited 



