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  • The exact etiology of BPH is not completely

    2023-09-27

    The exact etiology of BPH is not completely understood, however this pathology has been associated with elevated Fluorescein-12-dUTP levels of the androgen DHT (10). Thus, a valuable strategy in BHP treatment is the reduction of DHT (10) levels, by inhibiting its biosynthetic production [6], [8]. An important pharmacological target in the reduction of DHT (10) levels is the enzyme 5α-reductase. For this reason, several 5α-reductase inhibitors have also been developed and two of them, finasteride (13) and dutasteride (14) (Fig. 1), are being used in the clinical practice [9], [10], [11]. In fact, clinical studies have been revealing that 5α-reductase inhibitors lead to a reduction in prostatic volume and in total serum prostate-specific antigen (PSA) levels as well as to an improvement in urinary flow rate and a LUTS reduction in BHP. These important pharmacotherapeutical properties as well as the fact that these compounds can also be beneficial in BHP prevention and even in PC prevention and treatment justify the intense research concerning the development of new and improved 5α-reductase inhibitors that has been performed over the last decades. PC is the most frequently diagnosed nonskin cancer and the second leading cause of cancer death in men residing in Europe and USA [12]. It is well understood that the initial growth of PC is dependent on androgens, as at least 80% of human PCs respond favorably to androgen ablation therapy [13], [14], [15]. This dependence of PC on androgen signaling has been known since the seminal studies of Huggins and Hodges, for about 70 years ago [16], [17]. For this reason, the use of strategies that effectively lower the levels of circulating androgens in PC patients has been the mainstay of PC therapy for several decades. Systemic ablation of androgen by castration, either surgical or chemical, is highly effective in treating PC when the disease is hormone-dependent [18]. Until the 1980s, T (9) suppression for men with advanced PC was managed surgically, with bilateral orchiectomy, or medically, with diethylstilbestrol, a drug that was associated with a problematic side effect profile [19]. A relevant disadvantage of this surgical and chemical castration is that they do not affect androgen synthesis in the adrenal glands. The introduction in the mid-1980s, of the luteinizing hormone-releasing hormone agonists followed by the gonadotropin-releasing hormone antagonists (e.g. degarelix), which showed a great effectiveness in the suppression of circulating T (9) levels and led to a significant shift away from surgical castration to medical management during the past 25 years [19]. However, for most PC patients showing an initial response to hormonal therapy, the disease will progress to a castration-insensitive phase, which carries a much poorer prognosis [20], [21], [22]. In castrate-resistant prostate cancer (CRPC) the disease becomes “androgen-refractory”. However, the AR axis remains active with continued activation of downstream genes, despite castrate androgen levels [23], [24], [25]. In fact, it was observed that PC can generate intracrine androgenic steroids and become hypersensitive to low steroidal levels, which is vital for disease progression [26], [27]. For these reasons, androgen biosynthesis inhibition and/or AR blockage has been considered a very relevant approach, even in CRPC. In this context, CYP17 is a key enzyme in androgen biosynthesis and its inhibition can lead to an almost complete androgen production.
    The enzyme 5α-reductase According to Scheme 1, the conversion of the Δ4-double bond of T (9) to the corresponding 3-oxo-5α-steroid DHT (10) is an irreversible reaction catalyzed by 5α-reductase enzymes. Although T (9) is the main substrate of 5α-reductase, a similar conversion can also occur with other endogenous steroids. 5α-Reductases are NADPH-dependent enzymes (NADPH=reduced form of nicotinamide adenine dinucleotide phosphate) whose mechanism involves the binding of the cofactor and then the substrate, forming a ternary complex. Then, an electrophilic residue in the active site of the enzyme activated the Δ4-3-ketone system of the steroidal substrate, e.g. T (9), originating a delocalized carbocation at C5. After that, a hydride transfer from NADPH to the α-face of this carbocation lead to the formation of an enolate of DHT (10) which is protonated at C4 on the β-face to afford DHT (10) [9], [11], [28].