RT Journal Article
SR Electronic
T1 Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 568
OP 575
DO 10.1124/jpet.107.131185
VO 324
IS 2
A1 Andrea Caroline Knapp
A1 Liliane Todesco
A1 Konstantin Beier
A1 Luigi Terracciano
A1 Hans Sägesser
A1 Jürg Reichen
A1 Stephan Krähenbühl
YR 2008
UL http://jpet.aspetjournals.org/content/324/2/568.abstract
AB The aim of this study was to investigate whether a decrease in carnitine body stores is a risk factor for valproic acid (VPA)-associated hepatotoxicity and to explore the effects of VPA on carnitine homeostasis in mice with decreased carnitine body stores. Therefore, heterozygous juvenile visceral steatosis (jvs)+/– mice, an animal model with decreased carnitine stores caused by impaired renal reabsorption of carnitine, and the corresponding wild-type mice were treated with subtoxic oral doses of VPA (0.1 g/g b.wt./day) for 2 weeks. In jvs+/– mice, but not in wild-type mice, treatment with VPA was associated with the increased plasma activity of aspartate aminotransferase and alkaline phosphatase. Furthermore, jvs+/– mice revealed reduced palmitate metabolism assessed in vivo and microvesicular steatosis of the liver. The creatine kinase activity was not affected by treatment with VPA. In liver mitochondria isolated from mice that were treated with VPA, oxidative metabolism of l-glutamate, succinate, and palmitate, as well as β-oxidation of palmitate, were decreased compared to vehicle-treated wild-type mice or jvs+/– mice. In comparison to vehicle-treated wild-type mice, vehicle-treated jvs+/– mice had decreased carnitine plasma and tissue levels. Treatment with VPA was associated with an additional decrease in carnitine plasma (wild-type mice and jvs+/– mice) and tissue levels (jvs+/– mice) and a shift of the carnitine pools toward short-chain acylcarnitines. We conclude that jvs+/– mice reveal a more accentuated hepatic toxicity by VPA than the corresponding wild-type mice. Therefore, decreased carnitine body stores can be regarded as a risk factor for hepatotoxicity associated with VPA. The American Society for Pharmacology and Experimental Therapeutics