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
Jh. Thurston et Re. Hauhart, 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, Pediatric research, 31(4), 1992, pp. 419-423
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.