Reversal of the Adverse Chronic Effects of the Unsaturated Derivative of Valproic Acid—2-n-Propyl-4-Pentenoic Acid—on Ketogenesis and Liver Coenzyme A Metabolism by a Single Injection of Pantothenate, Carnitine, and Acetylcysteine in Developing Mice

Like treatment with the parent compound valproic acid (VPA), acute and/or chronic treatment with the unsaturated derivative, 2-n-propyl-4-pentenoic acid (4-en-VPA), decreased ketogenesis and lowered free CoA, acetyl CoA, and free carnitine levels in the livers of normal developing mice. Concomitantly, there were manifold increases in the content of medium-chain acyl CoA esters (4-en-VPA CoA and 4-en-VPA CoA metabolites). Acute cotreatment of 4-en-VPA-treated animals with pantothenate, carnitine, and acetylcysteine caused significant amelioration of these metabolic aberrations. In animals chronically treated with 4-en-VPA, a single injection of pantothenate, carnitine, and acetylcysteine returned the 4-en-VPA-depressed levels of β-hydroxybutyrate in plasma and free CoA and acetyl CoA in liver to normal. These findings support the hypothesis that VPA-and 4-en-VPA-induced hepatic dysfunction is produced by CoA sequestration rather than by irreversible inhibition by alkylation of the enzymes of fatty acid β-oxidation by reactive intermediates. The findings also support the important but little-known role of carnitine in CoA metabolism—carnitine relieves the inhibition of pantothenate kinase, the rate-controlling first enzyme in the pathway of CoA synthesis by its product, free CoA, and by CoA esters.