The effect of succinate and amytal on the reduction of acetoacetate in animal tissues

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Abstract
(1) In many animal tissues succinate accelerated the aerobic rate of reduction of acetoacetate as previously demonstrated for sheep heart. This effect was especially pronounced in liver. (2) Acetoacetate served as a major substrate of respiration in the diaphragm of various species and also in epididymal fat, testis and brain of the rat. (3) The determination of intermediate metabolites formed in respiring sheep heart and rat liver on addition of succinate and acetoacetate indicates that succinate was oxidized in preference to all other substrates. (4) Under conditions where 2,4-dinitrophenol stimulated respiration the rate of reduction of acetoacetate was diminished. (5) Amytal greatly increased the aerobic rate of reduction of acetoacetate in rat liver and sheep heart. (6) In liver homogenates the inhibition of respiration by amytal did not exceed 75%. The remaining 25% represent the capacity of the amytal-insensitive or "extramitochondrial" pathway of electron transport. (7) Anaerobically fumarate, glutamate, a-oxoglutarate, pyruvate and citrate accelerated the rate of reduction of acetoacetate in rat-liver homogenates. With these substrates the aerobic rates of reduction were lower than the anaerobic rates. Succinate was the only substrate in rat liver that increased the rate aerobically but not anaerobically. (8) Citrate reacted anaerobically with acetoacetate according to the scheme: 2 Acetoacetate + citrate [forward arrow] 2 B [beta]-hydroxybutyrate + 2 carbon dioxide + succinate. (9) Maximum rates for the reduction of acetoacetate were found on addition of mixtures of substrates such as citrate plus fumarate. The rates measured permit the assumption (Devlin and Bedell, 1960) that in the respiration of rat liver a substantial part of the electrons reaching oxygen passes through the acetoacetate-[beta]-hydroxybutyrate system. (10) Creatine phosphate had no effect on the rates of acetoacetate reduction but abolished the inhibition of respiration by 2,4-dinitrophenol. (11) The observations on the formation of [beta]-hydroxybutyrate from acetoacetate summarized in paragraphs 1,4, 5, 7 and 10 are in agreement with Scheme L according to which the reduction takes place whenever reaction (1) is more rapid than reaction (2).