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  • All scientific data over the years

    2024-06-21

    All scientific data over the years points that 5α-reductase inhibitors undoubtedly are an effective treatment for BPH and associated LUTS, having a favorable risk-benefit profile. In contrast, although some studies indicated positive results, there is still no consensus about their use in BPH or PC prevention and probably more studies are needed. In fact, the Prostate Cancer Prevention Trial (PCPT) evidenced that in spite of the fact that the use of finasteride (13) reduced the risk of developing symptomatic BPH and also reduced PC incidence, a potential association with high-grade cancers was also observed. In the “Reduction by Dutasteride of Prostate Cancer Events” (REDUCE) trial, a risk reduction of developing PC was also observed with the use of dutasteride (14) as well as beneficial effects on BPH outcomes. However, it was also observed the development of high-grade PC in the dutasteride group versus the placebo group. In addition to the benefit/risk ratio of therapy, the possibility of undesirable sexual side effects and decreased quality of life is probably explaining why 5α-reductase inhibitors are still not universally adopted to reduce the risk of PC [6], [84]. As the expression of 5α-reductase type I is increased in PC and pre-clinical in vitro and in vivo studies have also demonstrated that inhibition of 5α-reductase isoenzymes by finasteride (13) or dutasteride (14) can kill PC thymidylate synthase and increase apoptosis [85], [86], it is not surprising that several clinical trials have been performed involving the use of finasteride (13) and dutasteride (14) in PC treatment [6], [31]. Until now, clinical trials involving the use of these drugs as monotherapy in patients with advanced PC showed no improvement of clinical end points. Other clinical studies evidenced, however, that dutasteride (14) in combination with ketoconazole and hydrocortisone reduced PSA levels and improved the median time to disease progression than in the ketoconazole plus hydrocortisone group in CRPC [6], [31]. More recently, the safety and efficacy of dutasteride (14) on PC progression in men with low-risk disease was evaluated and the authors concluded that this drug can provide a beneficial adjunct to active surveillance for men with this pathological situation [87]. Another study indicated that dutasteride (14) delayed the progression of PC in patients with biochemical failure after radical therapy [88]. In addition, other studies in this context are being performed [6] aiming the improvement on the knowledge about the therapeutical utility of finasteride (13) and dutasteride (14) in prostatic conditions evidencing the high interest of the development and clinical study of 5α-reductase inhibitors. > CYP17: a dual activity enzyme The eukaryotic class II cytochrome P450 enzyme CYP17 is an endoplasmic reticulum membrane bound multifunctional protein localized in the adrenal glands, testes, placenta and ovaries [89]. Human CYP17 is expressed from a single gene found on chromosome 10, in steroidogenic tissue [90], [91], [92]. CYP17 lies at the crossroads of corticosteroids and androgen biosynthesis and is responsible for the catalysis of two reaction engaged on a single active site (Scheme 1) [93], [94], [95], [96], [97], [98]. The first catalyzed reaction is a 17α-hydroxylation of its natural substrates, pregnenolone (1) and progesterone (2) (17α-hydroxylase activity), which is common for both pathways. The 17α-hydroxy-intermediates 4 and 5 can further suffer an acyl-carbon cleavage at position C17–C20 (C17,20-lyase activity), to give the androgen precursors, dehydroepiandrosterone (7 or DHEA) and androstenedione (8 or AD). Because the first step produces an intermediate for the synthesis of corticosteroids, it has been suggested that CYP17 inhibitors should ideally inhibit only its C17,20-lyase activity [75]. CYP17 is a monooxygenase enzyme containing a heme prosthetic group at the active site, with an iron-oxygen species responsible for the catalytic activity of the enzyme [89]. Cytochrome P450 reductase is necessary for both 17α-hydroxylase and C17,20-lyase activities to transfer electrons in the presence of nicotinamide adenine dinucleotide phosphate (NADPH). The dual catalytic activity of CYP17 has been explained by modulation of the enzyme's C17,20-lyase activity by several factors, such as the presence of the electron carrier P450 oxidoreductase (POR) [99], [100], cytochrome b5 (cyt. b5) [101], [102], [103], [104], the phosphorylation of serine/threonine residues [101], [105], [106], [107], and single amino acid mutations [108], [109], [110], [111].