The toxicity of fluoroacetate and the tricarboxylic acid cycle

Abstract

1. 1. The hypothesis that fluoroacetate is a competitive inhibitor for acetate in tissue metabolism ( Bartlett and Barron) has been examined and found incapable of explaining some of the enzymatic effects of the poison. 2. 2. Using a homogenate from guinea pig kidney, free from residual oxidizable substrates, and reinforced with Mg ++ and adenine nucleotides, it was found that this readily oxidizes fumarate and citrate. In presence of fluoroacetate, citrate accumulates during the oxidation of fumarate, without an accompanying accumulation of acetate. 3. 3. With the same homogenate, fumarate and pyruvate together give 20–50% increased oxygen uptake as compared with fumarate alone, and there is even formation of citrate in absence of poison. Fluoroacetate produces inhibition without accumulation of acetate, but this is less than with fumarate alone. 4. 4. Fluoroacetate has no action upon the pyruvate dehydrogenase component of the brain pyruvate oxidase system. It also has no effect upon the activity of the enzymes aconitase, oxalosuccinate decarboxylase, fumarase and oxaloacetate decarboxylase, as tested by a pigeon liver preparation. 5. 5. The fact that no single enzymatic reaction has been found to be inhibited by fluoroacetate 6. and yet that the reactions of the tricarboxylic cycle are stopped with accumulation of citrate requires a hypothesis in addition to that proposed by Barron and Bartlett. 7. 6. It is suggested that, in the kidney preparation, fluoroacetate is not the inhibitor but that it is transformed into another substance which is inhibitory. 8. 7. The accumulation of citrate can be observed with concentrations of 0.05 mM (15 μg Nafluoroacetate per bottle) which approximates to the amounts causing toxic effects in vivo. 9. 8. It was confirmed that malonate inhibits the enzymatic decarboxylation of oxaloacetate. 10. 9. Some experiments upon kidney brei are described.