660 6. ARSENICALS 



obtained with rat liver submitochondrial preparations oxidizing succinate. 

 If the proper concentration of arsenite-BAL is used, there is often a def- 

 inite stimulation of O2 uptake, indicating a loss of respiratory control 

 such as is caused by 2,4-dinitrophenol (Fluharty and Sanadi, 1961). BAL 

 can be replaced by two other dithiols, dihydrolipoate and dihydrolipo- 

 amide, but all monothiols tested are ineffective with arsenite. Similar 

 results have been obtained on myosin ATPase, arsenite-BAL stimulating 

 2- to 3-fold, whereas neither arsenite nor BAL alone has an effect, and 

 here monothiols are ineffective (Fluharty and Sanadi, 1962 a). 



The effects of butarsen present a different picture. This arsenical uncou- 

 ples oxidative phosphorylation in liver mitochondria above 0.02 mM, 

 but is more effective in the presence of a monothiol, while BAL reverses 

 its action (Fluharty and Sanadi, 1963). In other words, butarsen alone acts 

 rather hke arsenite-BAL. Butarsen also activates the mitochondrial ATPase, 

 and this is favored by some monothiols and reversed by BAL. Butarsen is 

 able to stimulate O2 uptake which has been depressed by oligomycin, and 

 oligomycin inhibits the ATPase activity brought out by butarsen; thus the 

 site of action of butarsen has been postulated to be between the electron 

 transport chain and the oligomycin-sensitive phosphorylation coupling step. 



Before considering various theories for the mechanism involved, it 

 will be well to summarize some of the other enzymic and metabolic systems 

 in which thiols have been shown to augment the action of the arsenicals. 

 Some of these have been mentioned (page 645). It may be recalled that 

 Peters and Stocken (1947) found oxophenarsine-BAL to be more toxic 

 than oxophenarsine alone to Colpidium and rats. Various aldehyde dehy- 

 drogenases are inhibited more potently by arsenite-mercaptoethanol than 

 by arsenite alone; indeed, the NADP-dependent yeast enzyme and the 

 beef liver dehydrogenase are essentially unaffected by arsenite alone (Ja- 

 koby, 1958). Several other dehydrogenases do not behave in this manner. 

 If the mercaptoethanol is replaced by BAL, any inhibition exerted by the 

 arsenite is reversed. The incorporation of acetate into fatty acids by an 

 enzyme preparation from rat liver is moderately inhibited by arsenite, but 

 almost abolished when either mercaptoethanol or BAL is added (see accom- 

 panying tabulation) (Brady et al., 1960). The acetyl-CoA carboxylase 



