In vitro effects of eight-carbon fatty acids on oxidations in rat liver mitochondria

Sodium valproate, a commonly used anticonvulsant agent, is a simple branched-chain fatty acid which interferes with beta-oxidation and ammonia metabolism in most patients, with hepatotoxic consequences in some cases. Rat liver mitochondria incubated with valproate displayed time-dependent inhibitions of state 3 oxidation rates with all the substrates tested, but most markedly with glutamate, pyruvate, alpha-ketoglutarate and acylcarnitines (Ki = 125 microM with glutamate and palmitoylcarnitine, and 24 microM with pyruvate). The inhibition of glutamate appeared to be specifically directed against the glutamate dehydrogenase pathway of this oxidation. Valproate was less effective when added to uncoupled mitochondria, suggesting the formation of an inhibitory species by an ATP-dependent mechanism. Mitochondria from clofibrate-treated rats were less sensitive to valproate inhibition. Neither fasting nor the presence of 1 mM L-carnitine affected the inhibition of beta-oxidation. The branched-chain isomer, 2-ethylhexanoic acid, had similar effects to valproate, but the straight-chain octanoic acid was totally different in its spectrum of actions on mitochondria. The data support the theory that valproate may inhibit by sequestration of CoA as valproyl-CoA, but also suggest that there are other mechanisms responsible for some of the inhibitions. Furthermore, it argued that while mitochondrial respiration is decreased, valproate is not an inhibitor of oxidative phosphorylation per se.