662 6. ARSENICALS 



of other arsenicals and their complexes. With regard to the other enzymes 

 and metabolic systems in which thiols augment arsenical action, less can be 

 said about mechanism. It is difficult to understand why BAL should facili- 

 tate penetration of arsenite to a dithiol group on myosin ATPase, particu- 

 larly since ATP, a highly ionic substance, penetrates well enough. 



TRICARBOXYLATE CYCLE 



The generally potent and fairly selective inhibition of the or-keto acid 

 oxidases by the arsenoso compounds should lead to definite disturbances 

 in the operation of the cycle in particulate preparations and tissues. Oxida- 

 tion of pyruvate, lactate, or acetate has been found to be strongly depressed 

 by these arsenicals in most microorganisms and tissues (Table 6-4), as 

 would be expected if these substances are metabolized through the cycle. 

 The values in the table are often not accurate because correction was not 

 made for the effects on the endogenous respiration; also the concentrations 

 used are far too high in many cases. Nevertheless, the effectiveness of the 

 arsenicals in blocking the oxidation of these substrates is evident. Other 

 results on subcellular preparations oxidizing pyruvate may be found in 

 Table 6-3. Just as certain pyruvate oxidases from microorganisms are 

 relatively resistant to the arsenicals, the oxidation of pyruvate by some 

 bacteria and yeasts is suppressed by arsenicals weakly or not at all. It is 

 unlikely that the small inhibition by 5 mM arsenite in Rhoclotorula can be 

 explained on the basis of inadequate penetration (Litchfield and Ordal, 

 1958). Rao and Gunsalus (1955) found that the oxidation of pyruvate by 

 Acetobacter aceti is insensitive to 1 mM arsenite and suggested that lipoate 

 may not be involved. 



In connection with the effects of arsenicals on pyruvate utilization, it is 

 appropriate that we now consider the susceptibilities of other pathways 

 of pyruvate metabolism not involving the cycle. Hellerman et al. (1962) 

 showed that 0.004-0.008 mM butarsen inhibits the formation of citrate 

 from pyruvate in rat Walker carcinoma mitochondria, but has little effect 

 on the disappearance of pyruvate. The production of C^^Og from labeled 

 pyruvate is also unaffected by butarsen, which is in contrast to the results 

 obtained with heart mitochondria. Possibly another pathway for pyruvate 

 utilization not involving lipoate is involved. The anaerobic dismutation 

 of pyruvate to acetate and lactate is generally not as well inhibited as the 

 oxidation (Barron and Singer, 1945). Arsenite abolishes pyruvate oxidation 

 by Lactobacillus brevis, and the accumulation of lactate and acetoin indi- 

 cates that dismutation is relatively unaffected and further that the reaction, 



2 Pyruvate -> a-acetolactate -> acetoin 



