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

Very young children with organic brain damage, intractable seizures, a nd developmental retardation are at particular risk of developing fata l hepatic dysfunction coincident with valproate therapy, especially if the children are also receiving other anticonvulsant drugs. The mecha nism of valproate-associated hepatic failure in these children is uncl ear. There are two major theories of etiology. The first concerns the manyfold consequences of depletion of CoA due to sequestration into po orly 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 beta-oxidati on. 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 beta-hydroxybutyrate concentration in plasma and the free CoA and acetyl CoA levels in liver do not fall so low. Cotreatme nt with carnitine alone was without effect. Findings support the CoA d epletion mechanism of valproate inhibition of beta-oxidation and other CoA- and acetyl CoA-requiring enzymic reactions and stress the role o f carnitine in the regulation of CoA synthesis at the site of action o f pantothenate kinase.