Heterozygotes for plasmalemmal carnitine transporter defect are at increased risk for valproic acid-associated impairment of carnitine uptake in cultured human skin fibroblasts.

One of the mechanisms by which chronic valproic acid (VPA) therapy induces serum and tissue depletion of carnitine in normal controls is through inhibition of plasmalemmal carnitine uptake (Tein et al 1993). To determine the effect of VPA on proven heterozygotes for the plasmalemmal carnitine transporter defect, we studied this system in cultured human skin fibroblasts with reduced Vmax for the carnitine transporter using L-[3H]carnitine. There was en exponential dose-dependent decrease in carnitine uptake with increasing VPA concentrations and the relative inhibitory effect was the same for all three carnitine concentrations for a given cell line. Importantly, the lower the maximal velocity of carnitine uptake of the heterozygote, the lower the number of carnitine transporters and the lower the carnitine uptake per given concentration of VPA. The degree of inhibition was also directly proportional to the time of VPA preincubation up to a specific maximal saturation time. The maximal effect of VPA exposure time was reached by 10 days in the control cell line and by 3 days in the two heterozygote lines, probably reflecting earlier saturation. We conclude that patients who are heterozygous for the plasmalemmal carnitine transporter defect are at increased risk for VPA-associated serum and tissue depletion of carnitine through inhibition of plasmalemmal carnitine uptake.