Effects of anticonvulsants on human p450c17 (17alpha-hydroxylase/17,20 lyase) and 3beta-hydroxysteroid dehydrogenase type 2.
OBJECTIVE
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 3beta HSDII (3beta-hydroxysteroid dehydrogenase) and P450c17 (17alpha-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 3beta HSDII and P450c17, we added them to yeast expressing human P450c17 or 3beta HSDII and assayed enzymatic activities in the microsomal fraction.


RESULTS
Concentrations of VPA < or = 10 mM had no effect on activities of P450c17; however, VPA inhibited 3beta 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 3beta HSDII or P450c17 activities at typical reference serum unbound concentrations, but did inhibit 3beta HSDII and P450c17 at concentrations >10-fold higher.


CONCLUSIONS
None of the tested AEDs influenced 3beta HSDII or P450c17 activities at concentrations normally used in AED therapy. However, VPA started to inhibit 3beta HSDII activity at concentrations 3 times above the typical reference serum unbound concentration. Because inhibition of 3beta 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 3beta HSDII and P450c17 only at toxic concentrations.
Flück
Christa E
CE
Department of Pediatrics and The Metabolic Research Unit, University of California San Francisco, San Francisco, California, USA. christa.flueck@dkf.unibe.ch
Yaworsky
Dustin C
DC
Miller
Walter L
WL
D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis; D000728:Androgens / Q000096:biosynthesis; D000927:Anticonvulsants / Q000493:pharmacokinetics*; D002220:Carbamazepine / Q000493:pharmacokinetics; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006801:Humans; D007700:Kinetics; D000077213:Lamotrigine; D008861:Microsomes / Q000201:enzymology; D008901:Mineralocorticoids / Q000096:biosynthesis; D011085:Polycystic Ovary Syndrome / Q000201:enzymology; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D013379:Substrate Specificity; D000077236:Topiramate; D014227:Triazines / Q000493:pharmacokinetics; D014635:Valproic Acid / Q000493:pharmacokinetics
D000305:Adrenal Cortex Hormones; D000728:Androgens; D000927:Anticonvulsants; D008901:Mineralocorticoids; D014227:Triazines; D000077236:Topiramate; D005632:Fructose; D002220:Carbamazepine; D014635:Valproic Acid; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase; D013254:Steroid 17-alpha-Hydroxylase; D000077213:Lamotrigine