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 beta-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 beta-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.
Thurston
J H
JH
Department of Pediatrics, Washington University School of Medicine, St. Louis Children's Hospital, Missouri 63110.
Hauhart
R E
RE
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D002331:Carnitine / Q000494:pharmacology; D003065:Coenzyme A / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000037:antagonists & inhibitors / Q000633:toxicity*; D007657:Ketone Bodies / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D010205:Pantothenic Acid / Q000494:pharmacology
D005229:Fatty Acids, Monounsaturated; D007657:Ketone Bodies; D010205:Pantothenic Acid; C045022:2-propyl-4-pentenoic acid; D002331:Carnitine; D003065:Coenzyme A; D000111:Acetylcysteine