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  • br Acknowledgements MC and PD were funded

    2024-07-10


    Acknowledgements MC and PD were funded by the Michael J Fox Foundation (Grant ID 9969). We would like to thank Pierluigi Saba, Francesco Traccis and Barbara Tuveri for their technical assistance.
    Introduction In the prostate, androgens play a crucial role in normal, BPH and cancerous growth by acting through the androgen receptor (AR), a member of the steroid nuclear receptor superfamily. The natural ligand for the AR is testosterone (T), which is produced by the testes (95%) and adrenal glands (5%) and enters prostate epithelial cells by passive diffusion. Once ligand is bound to cytoplasmic AR, the receptor undergoes homodimerization resulting in a conformational change and is translocated to the nucleus. In the nucleus, AR acts by binding to specific recognition sequences, called androgen response elements (AREs), located in or near androgen-regulated genes and thereby directs transcription of genes necessary for growth and maintenance of the prostate [1]. Consequently, the androgenic pathway has become a target of therapeutic intervention in both benign and cancerous diseases [2]. In the prostate, T is converted to the more potent ligand dihydrotestosterone (DHT) by steroid 5 alpha-reductase (5AR) isoenzymes. There are three 5AR isoenzymes in prostate tissue; 5AR Types 1 and 2 (5AR-1 and 5AR-2) are found in normal, BPH and cancerous tissue, with distribution patterns specific to each tissue type [3]. 5AR Type 3 (5AR-3) has recently been detected and described in hormone refractory prostate cancer (HRPC) and is ubiquitous in mammals, being found also in non-androgenic tissues such pancreas and motilin receptor agonist [4]. One group, however, has identified 5AR-3 as a polyprenol reductase involved in N-linked protein glycosylation [5], as opposed to it being classified as a 5 alpha-reductase. While both T and DHT bind to the AR, DHT binds the receptor with approximately 2–10 times greater affinity, dissociates from motilin receptor agonist the receptor much more slowly and results in an AR conformation that is much more resistant to degradation [6]. High levels of 5AR enzymatic activity result in large amounts of the more potent ligand available to drive prostate growth, thus inhibition of 5AR activity is a valuable tool in reducing proliferation. Table 1A lists biochemical properties and characteristics of 5AR-1 and -2 isoenzymes.
    5ARIs in clinical use 5AR (3-oxo-steroid-4-ene dehydrogenase E.C. 1.3.99.5 ) isoenzymes are membrane-bound microsomal proteins that act by reducing the double bond at the 4–5 position of a number of C19 and C21 steroids, such as T. They catalyze the NADPH-dependent reduction of T to yield the more potent hormone DHT [7]. Various compounds have been developed in an effort to block this conversion and inhibit the effects of DHT in prostate disease. Neither isoenzyme has been purified due to its unstable nature, so isoenzyme inhibitors have been designed by targeting their substrates. Azasteroids are chemically altered steroids that have been produced by substituting a nitrogen atom for one of the carbons at different positions in the ring; a number of these compounds have been found to inhibit 5AR activity [8]. Finasteride (chemical name 4-azaandrost-1-ene-17-carboxamide, N-(1,1-dimethylethyl)-3-oxo, (5(alpha)), 17(beta))-) and dutasteride (chemical name (5α, 17β)-N 2,5,bis(trifluoromethyl) phenyl -3-oxo-4-azaandrost-1-ene-17-carboxamide) belong to a group of compounds designated as 17β-substituted-4-azasteroids, one of the most extensively studied classes of steroidal 5AR inhibitors[8]. Both drugs display characteristics of competitive inhibitors in short-term kinetic experiments, but analysis of long-term reactions reveals they are irreversible inhibitors due to formation of very stable enzyme-bound intermediates. Interactions between 4-azasteroids and 5AR isoenzymes are best described by the two-step mechanism:with K as the inhibition constant for the first step equilibrium (reached rapidly) and k3 the rate constant for the second, time-dependent step (reached more slowly) [9], [10].