The anticonvulsive drug, valproic acid (VPA), inhibits the biosynthesis of carnitine,
and may contribute in this way to carnitine deficiency associated with VPA therapy.
The conversion of [3H]-butyrobetaine into [3H]-carnitine was determined 60 min following
a single intraperitoneal (i.p.) dose of 1.2 mmol/kg VPA in rats. The fraction of radioactivity
found in [3H]-carnitine in the liver decreased from 63.2 +/- 1.50% to 39.2 +/- 1.11%
(mean +/- SEM). Total carnitine in the liver also decreased, whereas the precursor
butyrobetaine increased from 5.01 +/- 0.71 nmol/g to 8.22 +/- 0.82 nmol/g (mean +/-
SEM). VPA also exhibited a dramatic effect on the conversion of an unlabeled loading
amount of butyrobetaine. The increment in total carnitine caused by butyrobetaine
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 through butyrobetaine hydroxylase (EC 220.127.116.11.).
The drug in vitro, however, did not inhibit the enzyme directly. Searching for the
mechanism of action, we found that VPA decreased the level of alpha-ketoglutarate
(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 level of 1-glutamate showed a rather
dramatic decrease in the liver. Moreover, alpha-KG proved to have a protective role
against VPA in the [3H]-butyrobetaine conversion experiment.