Steroid 11β-hydroxylase (
CYP11B1; EC 1.14.15.4) is a mitochondrial
enzyme located in the zona fasciculata of the adrenal cortex and also in the brain that mediates the conversion of
11-deoxycortisol to
cortisol and 11-deoxycorticosterone (DOC) to
corticosterone. Inhibitors of
CYP11B1, such as
metyrapone and
etomidate, reduce
glucocorticoid synthesis and raise levels of DOC providing greater availability for metabolic conversion to the
GABA(A) receptor modulating
neurosteroid allotetrahydrodeoxycorticosterone (
THDOC). Because
THDOC is a potent
anticonvulsant, it is plausible that
CYP11B1 inhibitors could protect against
seizures. Here we demonstrate that
metyrapone affords dose-dependent protection against 6-Hz
seizures 30 min after injection (ED(50), 191 mg/kg), but is markedly more potent at 6 h (ED(50), 30 mg/kg). Similarly,
etomidate is also protective at 30 min and 6 h (ED(50) values, 4.5 and 1.7 mg/kg).
Finasteride, an inhibitor of
neurosteroid synthesis, attenuated the
anticonvulsant effects of both
CYP11B1 inhibitors at 6 h, but not 30 min following their injection. Plasma
THDOC levels measured by liquid chromatography-mass spectrometry were markedly increased 6 h after injection of both
CYP11B1 inhibitors and this increase was attenuated by
finasteride pretreatment. We conclude that inhibition of
CYP11B1 causes delayed seizure protection due to slow build-up of
neurosteroids. Early seizure protection is independent of
neurosteroids.