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TOXICOLOGY

Toxicity of Valproic Acid in Mice with Decreased Plasma and Tissue Carnitine Stores

Clinical Pharmacology and Toxicology and Department of Research, University Hospital Basel, Basel, Switzerland (A.C.K., L.To., S.K.); Institute of Anatomy and Embryology (K.B.) and Institute of Pathology (L.Te.), University of Basel, Basel, Switzerland; and Institute of Clinical Pharmacology, University of Bern, Bern, Switzerland (H.S., J.R.)

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.

Address correspondence to: Dr. Stephan Krähenbühl, Clinical Pharmacology and Toxicology, University Hospital, CH-4031 Basel, Switzerland. E-mail: kraehenbuehl{at}uhbs.ch

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