INHIBITION OF CARNITINE BIOSYNTHESIS BY VALPROIC ACID IN RATS - THE BIOCHEMICAL-MECHANISM OF INHIBITION

The anticonvulsive drug, valproic acid (VPA), inhibits the biosynthesi s of carnitine, and may contribute in this way to carnitine deficiency associated with VPA therapy. The conversion of [H-3]- butyrobetaine i nto [H-3]-carnitine was determined 60 min following a single intraperi toneal (i.p.) dose of 1.2 mmol/kg VPA in rats. The fraction of radioac tivity found in [H-3] carnitine in the liver decreased from 63.2 +/- 1 .50% to 39.2 +/- 1.11% (mean +/- SEM). Total carnitine in the liver al so decreased, whereas the precursor butyrobetaine increased from 5.01 +/- 0.71 nmol/g to 8.22 +/- 0.82 nmol/g (mean +/- SEM). VPA also exhib ited a dramatic effect on the conversion of an unlabeled loading amoun t of butyrobetaine. The increment in total carnitine caused by butyrob etaine in liver was reduced from 161 +/- 15.4 nmol/g to 53.2 +/- 5.11 nmol/g (mean +/- SEM). These data prove that VPA reduces the flux thro ugh butyrobetaine hydroxylase (EC 1.14.11.1.). The drug in vitro, howe ver, did not inhibit the enzyme directly. Searching for the mechanism of action, we found that VPA decreased the level of alpha-ketoglutarat e (alpha-KG; a cofactor of butyrobetaine hydroxylase) from 73.5 +/- 2. 90 nmol/g to 52.9 +/- 2.2 nmol/g (mean +/- SEM) in the liver. The leve l of l-glutamate showed a rather dramatic decrease in the liver. Moreo ver, alpha-KG proved to have a protective role against VPA in the [H-3 ] butyrobetaine conversion experiment. Copyright (C) 1996 Elsevier Sci ence Inc.