Finasteride is a potent, reversible inhibitor of the rat type 1 5 alpha-reductase with Ki of 10.2 nM, used in the treatment of benign prostatic hyperplasia (BPH) and male pattern baldness (MPB).
Steroid 5α-reductase (5αR) is the NADPH-dependent enzyme required for the conversion of testosterone (T) to dihydrotestosterone (DHT) [7]. Finasteride is an orally active testosterone 5-α-reductase inhibitor (Ki= 10 nM) [8]. In COS cells expressing rat types 1 or 2 5αR, finasteride displays reversible inhibition of rat type 1 5αR and time-dependent inhibition of rat type 2 5αR, and it is a potent inhibitor of both isozymes with IC50 values of 13 nM and 1 nM, respectively [7]. The growth rate of the LnCap cell line can be dose-dependently inhibited by finasteride in vitro, in defined conditions [9]. Binding of LNCaP cell nuclear proteins to steroid receptor-binding consensus (SRBC) was diminished when the cells were exposed to 25 microM finasteride, at which concentration 50% of both prostate-specific antigen (PSA) mRNA and protein were inhibited [10]. Finasteride treatment induced dosage-related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation) [11].
作用机制
It is now clear that the mechanism of inhibition of the 5αRs involves reduction of the A-ring of the azasteroid and subsequent adduct formation with NADP+[7].
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