Valproate hydroxylation by human fetal tissues and embryotoxicity of metabolites

The oxidative biotransformation of sodium valproate was studied in liver, lung, brain, and adrenal homogenates from human conceptuses with gestational ages ranging from 50 to 77 days. Analyses of metabolites by GC/MS indicated the formation of 3-hydroxy-, 4-hydroxy-, and 5-hydroxyvalproic acid, with hydroxylation occurring preferentially at the 4- position. The adrenal homogenate was consistently the most active fetal tissue studied, with rates of hydroxylation similar to those in rat and macaque liver homogenates. Reaction rates in the fetal adrenal homogenate were approximately four times those in fetal liver and approximately 10 times the rates of the same reactions measured in fetal brain and lung. Although valproic acid itself (0.8 mmol/L) was highly embryotoxic to cultured whole rat embryos, none of the hydroxylated metabolites produced by human fetal tissues exhibited significant embryotoxicity at equimolar concentrations. This suggests that hydroxylation of valproic acid in human fetal tissues is a process of detoxification, and implies that valproic acid is a direct-acting teratogen.