REVERSAL OF VALPROIC ACID-ASSOCIATED IMPAIRMENT OF CARNITINE UPTAKE IN CULTURED HUMAN SKIN FIBROBLASTS

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 camitine is through inhibition of plasmalemmal camitine 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 mu mol/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 camitine concentrations of 50 mu mol/L (normal physiological concentration), 20 mu mol/L (as seen in secondary carnitine deficiency disorders), or 5 mu mol/L (as seen in the homozygous plasma membrane carnitine transporter defect) and the camitine uptake was determined. The inhibitory effect of valproic acid on camitine uptake was completely reversed, for all 3 carnitine concentration conditions, following greater than or equal to 5 days of growth in valproic acid-free medium. (C) 1994 Academic Press, Inc.