ELECTRON TRANSPORT 661 



and acyl-CoA-malonyl-CoA transcarboxylase from wheat germ respond 

 similarly (Hatch and Stumpf, 1961). The former enzyme is inhibited 

 7% by 0.5 mM arsenite, 93% by 0.5 mM arsenite-BAL, and 7% when 

 the BAL is in 4-fold excess over the arsenite. Butarsen, on the other hand, 

 inhibits quite potently alone, and its action is only reduced by either 

 glutathione or BAL. The synthesis of palmitate from acetyl-CoA and 

 malonyl-CoA in pigeon liver extracts is unaffected by 0.025 mM arsenite, 

 but inhibited 63% when mercaptoethanol is present (Bressler and Wakil, 

 1962). The inhibition of milk xanthine oxidase by arsenite is increased 

 moderately by mercaptoethanol (Peters and Sanadi, 1961). Thus this phe- 

 nomenon is not general but occurs sufficiently often to be of interest in 

 interpreting how arsenicals act. 



It has been assumed that a vicinal dithiol group is involved in oxi- 

 dation-reduction and coupled phosphorylation, oxidation of these groups 

 being accompanied hy the formation of high-energy phosphate (Fluharty 

 and Sanadi, 1960). It is then postulated that these groups are not easily 

 accessible to arsenite, perhaps because of the hydrophobic nature of this 

 region, and that the combination of the arsenite with BAL allows pene- 

 tration to the dithiol site (Fluharty and Sanadi, 1961). The arsenite-BAL 

 complex cannot very well be active by itself because excess BAL reverses 

 the effect; furthermore, the arsenite-BAL probably does not react with 

 a monothiol group since other SH enzymes are not inhibited. Thus a disso- 

 ciation of the arsenite-BAL complex following penetration to the site is 

 pictured, the enzyme dithiol group having roughly the same affinity as 

 BAL for the arsenite (Fluharty and Sanadi, 1962 a). Butarsen is believed 

 to be directly uncoupling because it can penetrate fairly well to the dithiol 

 group, due to its greater lipid solubility, although monothiols may further 

 increase its activity to some extent (Fluharty and Sanadi, 1963). The 

 uncoupling by arsenite-BAL is not due to structural changes resulting 

 from mitochondrial swelling, since kinetic and reversibility studies indicate 

 the swelling to be secondary (Fluharty and Sanadi, 1962 b). The depression 

 of the uncoupling action by Mg++ and NAD is not understood (Fluharty 

 and Sanadi, 1961), but possibly these cofactors simply react at or near 

 the vulnerable dithiol group. Although it is difficult to propose a reasonable 

 alternative to this theory, there are facts which are not easily explained. 

 Why are the monothiols completely ineffective in potentiating the action 

 of arsenite ? One might expect mercaptoethanol to facilitate penetration to 

 some extent. Is arsenite really so lipid-insoluble as to need help for penetra- 

 tion, since it should exist mainly as arsenious acid? And, in addition, the 

 arsenite molecule would be much smaller than the arsenite-BAL complex. 

 Why do the monothiols often favor the activity of butarsen, while dithiols 

 abolish its activity? The butarsen-BAL complex would be smaller and more 

 lipid-soluble than the complexes with monothiols. There is a need for study 



