Claude Liebecq

The toxicity of fluoroacetate and the tricarboxylic acid cycle

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.

Oxoglutarate translocator of rat-heart mitochondria: regulation by aspartate

The oxoglutarate translocator participates in the transfer of reducing equivalents from the cytosol to the mitochondrial respiratory chain via the malateaspartate shuttle, by a cyclic process exchanging external malate for internal 2oxoglutarate [ 11. The catalytic components of the shuttle (the cytosofic and matricial glutamate-oxaloacetate transaminases and malate dehydrogenases, and the oxoglutarate and glutamate-aspartate translocators) act in sequence: one of the products is a substrate of the following step. Do allosteric effecters regulate the operation of the shuttle? This paper describes regulatory effects of aspartate on the oxoglutarate-translocator step of the shuttle working in the opposite direction (efflux of reducing equivalents from the mitochondrial matrix).

Effet du fluoroacétate et des rayons X sur la teneur en acide citrique du foie de la souris

In contrast to rats, male mice injected with sodium fluoroacetate accumulate citrate in their livers, whereas females do not. Whole-body irradiation reduces the level of accumulated citrate in the liver as well as in other tissues of the mouse.

La pseudohémoglobine et le catabolisme des composés hémiques

(1) Coupled oxidation by atmospheric oxygen of systems containing hæmoglobin and various reducing agents results in the successive formation of “oxyhæm”, “oxohæm”, and “pseudohæm” from the prosthetic group of hæmoglobin. (2) Of the “verdoglobins”, sulfhæmoglobin is analogous to “oxohæm” whereas choleglobin and pseudohæmoglobin are “pseudohæms” and apparently identical. (3) It is at present impossible to decide whether the green intermediate in the physiological formation of bilirubin is sulfhæmoglobin or pseudohæmoglobin. (4) Part of the bilirubin formed in the body is probably derived from catalase, hæmatin, myoglobin and the cytochromes.