Mechanism-Based Inhibition of Human Steroid 5α-Reductase by Finasteride: Enzyme-Catalyzed Formation of NADP−Dihydrofinasteride, a Potent Bisubstrate Analog Inhibitor

• DOI: 10.1021/ja953069t
• Publication Date: 2002-07-26T05:36:48Z
• Authors: Herbert G. Bull; Margarita Garcia-...; Stefan Andersson; Walter F. Baginsky; H. Karen Chan; Dina E. Ellsworth; Randall R. Miller; Ralph A. Stearns; Raman K. Bakshi; Gary H. Rasmusson; Richard L. Tolman; Robert W. Myers; John W. Kozarich; Georgianna S. Harris
• Keywords: Enzyme Kinetics; Dissociation constant

Finasteride is employed in treatment of benign prostatic hyperplasia man, where its target enzyme steroid 5α-reductase. It a novel, potent mechanism-based inhibitor the human prostate (type 2) isozyme. Although it accepted as an alternate substrate and ultimately reduced to dihydrofinasteride, this proceeds through enzyme-bound NADP−dihydrofinasteride adduct. processed with second-order rate constant, ki/Ki = 1 × 106 M-1 s-1, that approaches kcat/Km for reduction testosterone, 3 essentially every catalytic event lethal (partition ratio ≤ 1.07). The membrane-bound enzyme−inhibitor complex formed from [3H]finasteride appears release [3H]dihydrofinasteride half-life month at 37 °C (k (2.57 ± 0.03) 10-7 s-1), identified by mass spectroscopy. intermediate adduct can be recovered intact denaturation has been purified. Free solution, likewise decomposes dihydrofinasteride (half-life 11 days). An extremely bisubstrate analog inhibitor, binds free constant equal turnover testosterone dissociation Ki 10-13 M. also skin 1) isozyme, but much smaller 103 which attenuates activity against isozyme vivo. mechanism explains exceptional potency specificity finasteride hyperplasia, concept may have application other pyridine nucleotide-linked enzymes.