Effects of Anticonvulsants on human P450c17 (17α-hydroxylase/17,20 lyase) and 3ß-hydroxysteroid dehydrogenase type 2

Purpose: Women with epilepsy apparently have a higher incidence of polycystic ovary syndrome (PCOS) than do women without epilepsy. Whether the underlying disease or the antiepileptic drug (AED) treatment is responsible for this increased risk is unknown, although clinical reports implicate valproic acid (VPA) as a potential cause. The steroidogenic enzymes 3 beta HSDII (3-hydroxysteroid dehydrogenase) and P450c17 (17 alpha-hydroxylase/17,20 lyase) are essential for C19 steroid biosynthesis, which is enhanced during adrenarche and in PCOS. Methods: To determine whether the AEDs VPA, carbamazepine (CBZ), topiramate (TPM), or lamotrigine (LYG) directly affect the activities of human 3 beta HSDII and P450c17, we added them to yeast expressing human P450c17 or 3 beta HSDII and assayed enzymatic activities in the microsomal fraction. Results: Concentrations of VPA <= 10 mM had no effect on activities of P450c17; however, VPA inhibited 3 beta HSDII activity starting at 0.3 mM (reference serum unbound concentration, 0.035-0.1 mM) with an IC50 of 10.1 mM. CBZ, TPM, and LTG did not influence 3 beta HSDII or P450c17 activities at typical reference serum unbound concentrations, but did inhibit 3 beta HSDII and P450c 17 at concentrations > 10-fold higher. Conclusions: None of the tested AEDs influenced 3 beta HSDII or P450c17 activities at concentrations normally used in AED therapy. However, VPA started to inhibit 3 beta HSDII activity at concentrations 3 times above the typical reference serum unbound concentration. Because inhibition of 3 beta HSDII activity will shift steroidogenesis toward C19 steroid production when P450c17 activities are unchanged, very high doses of VPA may promote C19 steroid biosynthesis, thus resembling PCOS. CBZ, TPM, and LTG influenced 3 beta HSDII and P450c17 only at toxic concentrations.