658 6. ARSENICALS 



on the experimental conditions. Ochoa (1940, 1941) found that the P:0 

 ratio for the oxidation of succinate by pigeon brain dispersions drops 

 from 2.02 to 0.94 upon addition of 0.8 mM arsenite, but this was inter- 

 preted as due to the strong inhibition of the oxidation of pyruvate formed 

 from the succinate, restricting the system to a lower efficiency of phospho- 

 rylation, rather than a direct uncoupling action. Lehninger (1949) claimed 

 that phosphorylation accompanying the oxidation of NADH by a partic- 

 ulate rat liver preparation is inhibited almost completely by 9 mM arsenite 

 without change in the O2 uptake, indicating a marked uncoupling activity, 

 and Hunter and Ford (1955) reported a fall in the P:0 ratio from 2.9 to 

 caused by 2 mM arsenite in rat liver mitochondria oxidizing /?-hydroxy- 

 butyrate, but the Og uptake was inhibited 96% so that no conclusions can 

 be drawn from this. More recently, Fluharty and Sanadi (1960, 1961) 

 found moderate reductions in the P:0 rations for the oxidation of succinate 

 and /?-hydroxybutyrate by rat liver mitochondria produced by 1-2 mM 

 arsenite, but it is doubtful if these results can be taken to indicate direct 

 uncoupling. Others have observed no significant changes in the P:0 ratio. 

 Crane and Lipmann (1953) reported that O2 uptake and phosphorylation 

 are depressed equally by 0.1 mM arsenite when succinate is being oxidized 

 by rat liver homogenate, and Aldridge (1957) could detect no change in 

 the P:0 ratio from concentrations of phenylarsenoxide which depress 

 76% the oxidation of pyruvate by rat liver mitochondria. Fletcher and 

 Sanadi (1962) found very little or no reduction in the P:0 ratios brought 

 about by 0.1 mM arsenite in heart mitochondria oxidizing pyruvate, 

 /5-hydroxybutyrate, and glutamate. Evidence from cellular preparations 

 generally supjjorts a lack of uncoupling activity for the arsenicals. For 

 example, Stickland (1956 a) remarked that 1 mM arsenite actually stim- 

 ulates somewhat the uptake of phosphate by yeast while having little effect 

 on the respiration, although such results are difficult to interpret. It is 

 probably fair to say that the asenicals are generally not direct uncouplers 

 and seldom exert this effect under ordinary conditions. This is confirmed 

 by the lack of effect on ATP:P=^2 exchange catalyzed by mitochondria, 

 arsenite concentrations of 1-10 mM having variable but minimal actions 

 (Plaut, 1957; Avi-Dor and Gonda, 1959; Sagisaka and Shimura, 1962 b). 

 However, Fluharty and Sanadi (1960, 1961) have found that this exchange 

 in rat liver mitochondria is depressed 50% by 0.05 mM arsenite. The reasons 

 for the discrepancies are not apparent, but Swanson (1955, 1956 a, b) 

 emphasized the importance of tonicity, various ions, and other experimental 

 factors in determining the response of ATPiP^s exchange to arsenite. Of 

 course, in certain intances these exchange reactions are probably not 

 related to oxidative phosphorylation. Enzymes catalyzing phosphate 

 transfers, such as the kinases, are only moderately sensitive to the arsenicals 

 (Table 6-3), and actions on them probably do not contribute much to the 

 effects of the arsenicals on metabolism or function. 



