Some effects of synthetic fluoro compounds on the metabolism of acetate and citrate.

The work described here was started to extend knowledge of the relative effects of fluoro compounds with special reference to fluoroacetate and fluorocitrate; it was hoped that it would have particular application to effects upon the liver and to the biochemical mechanism of convulsions induced by fluorocitrate. Bartlett & Barron (1947) showed originally that acetate accumulates after fluoroacetate poisoning; but this effect is probably indirect, as Buffa & Peters (1949) found that the poisoning induced a citrate accumulation, and Peters, Wakelin, Buffa & Thomas (1953) demonstrated that this was due to the synthesis from the fluoroacetate offluorocitrate, which blocked the tricarboxylic acid cycle at the aconitase stage. The specificity ofthis inhibition was clearly demonstrated on highly purified aconitase preparations by Morrison & Peters (1954). This work left questions still to be answered. For instance, the livers of male rats showed no increase in citric acid concentrations as a result of fluoroacetate poisoning, according to Buffa & Peters (1949), Potter & Busch (1950) and Fawaz & Fawaz (1953); but Ord & Stocken (1953) recently reported an apparent conversion of fluoroacetate into fluorocitrate by rat liver. There was also the problem why Hastings, Peters & Wakelin (1953) found no indication that convulsions induced by fluorocitrate were connected with any ionic imbalance. [14C]Acetate was used in vivo to study inhibition ofacetate metabolism as a whole. Previous work by Gould, Sinex, Rosenberg, Solomon & Hastings (1949) had shown that [carboxy-'4C]acetate upon injection into rats was about 85% converted into labelled carbon dioxide in 4 hr., and Lifson & Swanson (1953) have indicated that influoroacetatepoisoned mice the rate of conversion of [13C]acetate into radioactive carbon dioxide was decreased by approximately 45 %. These results were confirmed by us and extended to fluorocitrate and fluoropyruvate. The latter compound proved particularly