TRICARBOXYLATE CYCLE 667 



of Aldridge and Cremer (1955) on rat liver mitochondria (see accompanying 

 tabulation), in which the concentrations required to inhibit 50% were 



determined. In all of this work one must realize that more than the direct 

 effect on the enzyme acting on the substrate is measured; e. g., the inhibi- 

 tion of malate oxidation is probably not due to an action on the malate 

 dehydrogenase. 



The effects of arsenite on the utilization of citrate are variable and 

 depend on the prex)aration and the experimental conditions. The oxidation 

 of citrate is sometimes moderately inhibited, as in avocado or Schizophyl- 

 Inm (see above), but is often rather resistant. Krebs and Johnson (1937) 

 reported that the oxidation of citrate by pigeon muscle mince is not affected 

 by 3 mM arsenite, although the oxidation is made incomplete, presumably 

 by blocking at the or-ketoglutarate oxidase, and similar results have been 

 obtained in yeast (Hirsch, 1952), mycobacteria (Yamamura et ah, 1954), 

 rat kidney (E. H. Kaplan et al., 1954), and rat liver (Sherman and Corley, 

 1952). On the other hand, citrate oxidation is completely inhibited by 

 5 mM arsenite in epiphyseal cartilage (Whitehead and Weidmann, 1959), 

 and lewisite oxide at 0.0033 mM inhibits isocitrate oxidation 92% in rat 

 liver mitochondria (Chappell, 1964 a). Chappell believes that this latter 

 inhibition is not direct but is due to the block of malate formation and a 

 deficiency of NADP, the regeneration of which is mediated through malate 

 dehydrogenase and a transhydrogenase. The oxidation of isocitrate in 

 rat brain mitochondria is not affected by 10 mM arsenite when NADP 

 is added (Murthy and Rappoport, 1963). These results demonstrate the 

 complex interrelationships which must be taken into account in interpreting 

 the effects of the arsenicals on the cycle. Anaerobic citrate dissimilation by 

 Aerobacter is readily inhibited by arsenite around 3 mM (Brewer and Werk- 

 man, 1939; Dagley and Dawes, 1953). The formation of citrate is, of course, 

 quite strongly inhibited in all the organisms and tissues studied. 



