Reversal of Valproic Acid-Associated Impairment of Carnitine Uptake in Cultured Human Skin Fibroblasts

Abstract

Much attention has focussed on the role of valproic acid induced secondary carnitine deficiency in predisposing children to life-threatening hepatotoxicity and a Reye-like syndrome. One mechanism by which valproic acid therapy induces serum and tissue depletion of carnitine is through inhibition of plasmalemmal carnitine uptake. In cultured control human skin fibroblasts, this effect is directly proportional to the duration of exposure and concentration of valproic acid; the maximal effect of valproic acid exposure time is achieved by 14 days, beyond which there appears to be no additional significant effect (1). To determine whether this effect is reversible, we preincubated control fibroblasts with varying concentrations (0-1700 μmol/L) of valproic acid for 14 days, washed the fibroblasts free of valproic acid, and then continued the fibroblast growth in valproic acid-free medium for periods of 4 hours to 14 days. The fibroblasts were subsequently incubated with fixed carnitine concentrations of 50 μmol/L (normal physiological concentration), 20 μmol/L (as seen in secondary carnitine deficiency disorders), or 5 μmol/L (as seen in the homozygous plasma membrane carnitine transporter defect) and the carnitine uptake was determined. The inhibitory effect of valproic acid on carnitine uptake was completely reversed, for all 3 carnitine concentration conditions, following ≥5 days of growth in valproic acid-free medium.