Action of endogenous steroid inhibitors of brain aromatase relative to fadrozole

Abstract

To study mechanisms of aromatase inhibition in brain cells, a highly effective non-steroidal aromatase inhibitor (Fadrozole; 4-[5,6,7,8-tetra-hydroimidazo-(1,5- a)-pyridin-5-yl] benzonitrile HCl; CGS 16949A) was compared with endogenous C-19 steroids, known to be formed in the preoptic area, which inhibit oestrogen formation. Using a sensitive in vitro tritiated water assay for aromatase activity in avian (dove) preoptic tissue, the order of potency, with testosterone as substrate was: Fadrozole ( K i < 1 × 10 −9 M) > 4-androstenedione 5 α-androstanedione > 5 α-dihydrotestosterone ( K i = 6 × 10 −8 M) > 5 β-androstanedione > 5 β-dihydrotestosterone ( K i = 3.5 × 10 −7 M) > 5 α-androstane-3 α, 17 β-diol ( K i = 5 × 10 −6 M) > 5 β-androstane-3 β,17 β-diol. Five other steroids, 5β-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, progesterone, oestradiol and oestrone, showed no inhibition at 10 −4 M. The kinetics indicate that endogenous C-19 steroids show similar competitive inhibition of the aromatase as Fadrozole. Mouse (BALB/c) preoptic aromatase was also inhibited by Fadrozole. We conclude that endogenous C-19 metabolites of testosterone are effective inhibitors of the brain aromatase, and suggest that they bind competitively at the same active site as Fadrozole.