Amelioration of Adverse Effects of Valproic Acid on Ketogenesis and Liver Coenzyme A Metabolism by Cotreatment with Pantothenate and Carnitine in Developing Mice: Possible Clinical Significance

Abstract

ABSTRACT. Very young children with organic brain damage, intractable seizures, and developmental retardation are at particular risk of developing fatal hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mechanism of valproate-associated hepatic failure in these children is unclear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into poorly metabolized valproyl CoA and valproyl CoA metabolites. The other theory proposes that the unsaturated valproate derivative 2-n-propyl-4-pentenoic acid and/or metabolically activated intermediates are toxic and directly cause irreversible inhibition of enzymes of B-oxidation. The present study shows for the first time that in developing mice, when pantothenic acid and carnitine are administered with valproate, at least some of the effects of valproate are mitigated. Perhaps most importantly, the /3-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatment with carnitine alone was without effect. Findings support the CoA depletion mechanism of valproate inhibition of Boxidation and other CoA-and acetyl CoA-requiring enzymic reactions and stress the role of carnitine in the regulation of CoA synthesis at the site of action of pantothenate kinase. (Pediatr Res 31: 419-423, 1992) The new anticonvulsant drug, valproic acid (2-n-propylpentanoic acid, 2-n-propylvaleric acid), is particularly effective in the treatment of the types of seizures peculiar to infants and young children: infantile myoclonic spasms, febrile seizures, and petit ma1 (absence) (reviewed in Ref. 1). Yet this is the age group that is most susceptible to the hepatotoxic effects of the drug, particularly if the children have organic brain damage and are also receiving other anticonvulsant drugs (2). In a study of possible mechanisms of this complication, we found that valproate reduced the physiologic ketonemia of suckling mice (3, 4) and fasting epileptic children (5). In the livers of normal developing mice, valproate produced extraordinary decreases in the levels of free CoA, acetyl CoA, and free carnitine (4). Concomitantly, the concentration of medium-chain acyl CoA esters [including valproyl CoA and its metabolites (6)] increased some 6-to 7-fold (4). As in our normal developing mice, valproate also reduced plasma P-hydroxybutyrate levels and liver CoA and acetyl CoA levels in fasted adult rats (7, 8). In isolated adult rat hepatocytes, valproate inhibited oxidation of fatty acids and pyruvate, fatty acid synthesis, gluconeogenesis, ketogenesis, and ureagenesis (6, 7,9-11). In view of the 100 or so synthetic and catabolic enzyme reactions requiring CoA or acetyl CoA as substrates, cofactors, or activators, the above diverse ill effects of valproate on liver metabolism can largely be explained by sequestration of free CoA into nonmetabolized or poorly metabolized valproyl CoA and valpro...

Beneficial Interaction of Thymoquinone and Sodium Valproate in Experimental Models of Epilepsy: Reduction in Hepatotoxicity of Valproate

“…There is sufficient information in the literature that SVP is metabolized to unsaturated toxic products in the body [33,34,35]. These studies have shown that metabolites formed by omega oxidation pathway, 2-n-propyl-4-pentenoic acid and other delta dehydrogenation products may cause hepatotoxicity.…”

Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia

“…In acute acetaminophen toxicity, CoASH levels decrease simultaneously with decreasing HMGCS2 enzymatic activity (51,52). Potentially fatal valproic acid therapy-induced hepatic dysfunction, which is associated with impaired β-oxidation of fatty acids and ketogenesis due to sequestration of CoASH into poorly metabolized valproyl CoA, can be prevented by administration of CoASH precursors (53,54). In rodents, hepatic CoASH concentrations decrease in response to an HFD (55), while the concentration of pantothenic acid actually increases (56), suggesting that hepatic CoASH homeostasis is dysregulated in obesity.…”

Vitamin B5 and N-Acetylcysteine in Nonalcoholic Steatohepatitis: A Preclinical Study in a Dietary Mouse Model

“…Concomitant administration of L-carnitine and pantothenate was reported to overcome the feedback inhibition of PANK (13, 49). This success might reflect the fact that L-carnitine can accept acyl groups from acyl-CoA, thereby importing acyl groups into mitochondria to facilitate fatty acid β-oxidation and liberating CoA (50).…”