Studies on the beneficial effect of levocarnitine chloride (LC-80) on organic acidemias, especially propionic acidemia and methylmalonic acidemia

The beneficial effect of LC-80 in the therapy for organic acidemias, especially propionic acidemia and methylmalonic acidemia, was compared with those of its optical isomers, d-carnitine chloride (d-isomer) and dl-carnitine chloride (dl-isomer) in rat liver mitochondria. LC-80 at concentrations of 5 and 10 mM did not inhibit the mitochondrial function, while the d-isomer at a concentration of 5 mM significantly reduced the respiratory control ratio (RCR) of mitochondria. In addition, the dl-isomer at concentrations of 10 and 20 mM also significantly reduced RCR in a concentration-dependent manner. Thus, it seems likely that the d-isomer inhibits the mitochondrial function. On the other hand, the inhibition of mitochondrial function induced by a preincubation with propionate (4.76 mM) was significantly reversed by LC-80 (5 and 10 mM) in a concentration-dependent manner, while the d-isomer (5 mM) had no effect on the inhibitory effect of propionate. Moreover, although the dl-isomer (10 and 20 mM) significantly reversed the inhibitory effect of propionate as compared with the d-isomer, its effect was significantly weaker as compared with the effect of LC-80. The substrate specificity of rat liver mitochondrial carnitine acetyltransferase (CAT) was more potent with propionyl CoA than with acetyl CoA. Kinetic studies indicate that the d-isomer is a competitive inhibitor of CAT. These results suggest that LC-80 is useful in the clinical treatment of organic acidemias, whereas the d-isomer has a harmful effect in clinical application.