The oxidation of hexanoic acid and derivatives by liver tissue in vitro.

Experiments with labeled octanoic acid have shown that liver slices cleave the fatty acid to 2-carbon fragments which condense to form acetoacetate (l-3). The earlier findings (1, 2) of an equal distribution of the isotope between the carboxyl and carbonyl groups of acetoacetate after utilization of carboxyl-labeled octanoate indicate a random recondensation of 2-carbon fragments, while later findings do not support random recondensation and suggest two types of 2-carbon fragments (4, 5). In the case of the 6-carbon hexanoic acid, the analytical work of Jowett and Quastel (6) and Leloir and Mufioz (7) indicates the formation of only 1 mole of acetoacetate from hexanoate rather than the 1.5 moles as required by a recondensation mechanism. The in z&o isotope experiments of Morehouse and Deuel (8) also do not favor recondensation in acetoacetate formation from hexanoate. The recent work of Crandall and coworkers (4, 5), however, supports the same recondensation mechanism for octanoate and hexanoate. None of these studies reveals the detailed course of fatty acid oxidation or the nature of the oxidized intermediates formed prior to cleavage of the carbon chain. Several isolated reports (9-23) have dealt with the metabolism of a variety of possible fatty acid oxidation intermediates, but these have not been specifically devised to reveal the rate and extent of acetoacetate formation from the derivatives as compared to the parent fatty acid. Previous studies in this laboratory (10) demonstrated the formation of 1 mole of acetoacetate from 1 mole of /3,&diketohexanoate by liver homogenates and a purified liver enzyme. This possible intermediate and a number of other unsaturated, hydroxy, and keto derivatives of hexanoate have been utilized in the present study. Acetoacetate was stable in the washed liver particle system employed, and this system was therefore