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


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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 β-oxidation. The present study shows for the first time that in developing mice, when pantothenic acid and carntine are administered with valproate, at


least some of the effects of valproate are mitigated. Perhaps most importantly, the β-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 β-oxidation 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. SIMILAR CONTENT BEING VIEWED BY OTHERS SUPPRESSION OF EXAGGERATED


NMDAR ACTIVITY BY MEMANTINE TREATMENT AMELIORATES NEUROLOGICAL AND BEHAVIORAL DEFICITS IN AMINOPEPTIDASE P1-DEFICIENT MICE Article Open access 03 August 2022 KETOGENIC DIET-PRODUCED


Β-HYDROXYBUTYRIC ACID ACCUMULATES BRAIN GABA AND INCREASES GABA/GLUTAMATE RATIO TO INHIBIT EPILEPSY Article Open access 13 February 2024 MICE PRENATALLY EXPOSED TO VALPROIC ACID DO NOT SHOW


AUTISM-RELATED DISORDERS WHEN FED WITH POLYUNSATURATED FATTY ACID-ENRICHED DIETS Article Open access 11 July 2023 ARTICLE PDF AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of


Pediatrics, St. Louis, 63110, Missouri Jean Holowach Thurston & Richard E Hauhart * Neurology and Neurological Surgery [Neurology), St. Louis, 63110, Missouri Jean Holowach Thurston


Authors * Jean Holowach Thurston View author publications You can also search for this author inPubMed Google Scholar * Richard E Hauhart View author publications You can also search for


this author inPubMed Google Scholar RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Thurston, J., Hauhart, R. 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. _Pediatr Res_ 31, 419 (1992).


https://doi.org/10.1203/00006450-199204000-00023 Download citation * Received: 25 September 1991 * Accepted: 10 December 1991 * Issue Date: 01 April 1992 * DOI:


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