5 Alpha-reductase

Russell DW, Wilson JD Steroid 5 alpha-reductase two genes/two enzymes. Annu Rev Biochem 1994 63 25. 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

Heinrich, M., H. Rimpler, and N. A. Barrera. Indigenous phytotherapy of gastrointestinal disorders in a lowland Mixe community (Oaxaca, Mexico) Ethnopharmacologic evaluation. J Ethnopharmacol 1992 36(1) 63—80. Liao, Z. K., J. Jiang, and X. P. Xu. The technical method for preparation of phytic acid and oryzenin. Huaxi Yaoxue Zazhi 1996 11(1) 46-70. Tokuyama, T. 5-Alpha-reductase inhibitor from rice for therapeutic use. Patent-Japan Kokai Tokkyo Koho-07 157,436 1993 7 pp. 

SR018 Prager, N., K. Bickett, N. French, and G. Marcovici. A randomized, doubleblind, placebo-controlled trial to determine the effectiveness of botanically derived inhibitors of 5-alpha-reductase in the treatment of androgenetic alopecia. J Altem Complement Med 2002 8(2) 143-152. 

SR039 lehle, C., S. Delos, O. Guirou, R. Tate, ]. P. Raynaud, and P. M. Martin. Human prostatic steroid 5 alpha-reductase isoforms—a comparative study of selective inhibitors. J Steroid Biochem Mol Biol 1995 54(5-6) 273-279. 

SR040 Delos, S., C. lehle, P. M. Martin, and ]. P. Raynaud. Inhibition of the activity of basic 5 alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells. J Steroid Biochem Mol... 

SR041 Strauch, G., P. Perles, G. Vergult, et al. Comparison of finasteride (Proscar) and Serenoa repens (Permixon) in the inhibition of 5-alpha reductase in healthy male volunteers. Eur Urol 1994 26(3) 247-252. 

Bayne, C. W., F. Donnelly, M. Ross, and F. K. Habib. Serenoa repens (Permixon) 5-alpha-reductase types 1 and 11 inhibitor-new evidence in a coculture model of BPH. Prostate 1999 40(4) 232-241. 

Niederprum, H. ]., H. U. Schweikert, and K. S. Zanker. Testosterone 5-al-pha-reductase inhibition by free fatty acids from Sabal serrulata fruits. Phytomedicine 1994 1(2) 127—133. Hagenlocher, M., G. Romalo, and H. U. Schweikert. Specific inhibition of 5-alpha reductase by a new extract of Sabal serrulata. Akt Urol 1993 24 146-149. 

SRI 10 Duker, E. M., and L. Kopanski. Inhibition of 5-alpha-reductase activity by extracts from Sabal serrulata. Planta Med 1989 55(6) 587. 

Geriatric Considerations - Summary Alpha-adrenergic blockers are modestly effective alone, and in combination with 5-alpha reductase inhibitors (e,g, finasteride) in the treatment of urinary obstructive symptoms related to benign prostatic hyperplasia. Alfuzosin is a "uroselective" alpha-blockerwhich appears to cause less orthostatic hypotension than nonselective alpha-blockers such as terazosin, prazosin, and doxazosin. 

Mechanism of Action An androgen hormone inhibitor that inhibits 5-alpha reductase, an intracellular enzyme that converts testosterone into dihydrotestosterone (DHT) in the prostate gland, resulting in a decreased serum DHT level. Therapeutic Effect Reduces size of the prostate gland. 

It is a inhibitor of 5-alpha reductase and blocks the conversion of testosterone to dehydrotesto-sterone. It prevents further hair loss in the significant proportion of men in the androgenic alopecia. 

The investigators found that the described 10 SNP variants of SRD5A2 differ in their biologic effects, not only in how much they affect levels of DHT, but also in their response to finasteride, a competitive inhibitor of 2,5-alpha reductase. Finasteride (Proscar) is marketed for the treatment of BPH and is under investigation for the chemoprevention of prostate cancer. The investigators found a 200-fold range in activity of the enzymes encoded by these gene variants and as much as a 60-fold difference in the ability of finasteride to inhibit the enzyme s activity. 

Finasteride is a selective inhibitor of 5-alpha-reductase. It thereby reduces prostatic concentrations of dihydrotestosterone and so reduces prostatic size (6,7,8). It is therefore used to treat benign prostatic hyperplasia (9,10,11,12) and in the prevention and treatment of prostate cancer (13). It is poorly effective in patients with prostatic obstruction and small prostate glands (14), but in patients with glands larger than 40 ml it produces significant symptomatic improvement. 

The benefit of combining an alpha-adrenoceptor antagonist with a 5-alpha-reductase inhibitor has been assessed in men with benign prostatic hyperplasia (23). Modified-release alfuzosin was more effective than finasteride, with no additional benefit in combining the drugs. The adverse effects of alpha-blockade were postural hypotension, hypotension, headache, dizziness, and malaise the adverse effects of finasteride were ejaculatory disorders and impotence. 

Steiner JF. Finasteride a 5 alpha-reductase inhibitor. Clin Pharm 1993 12(l) 15-23. 

Reddy GK. Finasteride, a selective 5-alpha-reductase inhibitor, in the prevention and treatment of human prostate cancer. Clin Prostate Cancer 2004 2(4) 206-8. 

Gormley GJ, Stoner E, Rittmaster RS, Gregg H, Thompson DL, Lasseter KC, Vlasses PH, Stein EA. Effects of finasteride (MK-906), a 5 alpha-reductase inhibitor, on circulating androgens in male volunteers. J Clin Endocrinol Metab 1990 70(4) 1136-41. 

Saw palmetto relieves urinary symptoms and flow measures associated with an enlarged prostate it does not reduce the enlargement. Saw palmetto is chiefly employed to manage prostatic enlargement or benign prostatic hyperplasia (BPH). A hexane extract inhibits 5-alpha reductase, the enzyme needed for the conversion of testosterone into dihydrotestosterone (DHT). Saw palmetto further antagonizes DHT binding at prostatic receptor sites, which increases the metabolism and excretion of DHT. It is also used to treat BPH-related inflammation (see Chapter 55). 

Celotti, F., Melcangi, R. C., and Martini, L. (1992). The 5 alpha-reductase in the brain Molecular aspects and relation to brain function. Front. Neuroendocrinal. 13, 163—215. 

Wilson JD, Griffin JE, Russell DW (1993) Steroid 5 alpha-reductase 2 deficiency. Endocr Rev, 14 577-593. 

Katashima, M., Yamamoto, K., Tokuma, Y., Hata, T., Sawada, Y., and Iga, T., Pharmacokinetic and pharmacodynamic study of a new nonsteroidal 5 alpha-reductase inhibitor, 4-[3-[3-[Bis (4-isobutylphenyl)methylamino]benzoyl]-lH-indol-l-yl]-butyric acid, in rats, Journal of Pharmacoloqy and Experimental Therapeutics, Vol. 284, No. 3, 1998, pp. 914-920. 

Testosterone-5-alpha reductase inhibitors (finasteride, dutasteride)... 

R12. Ross, R. K., Bernstein, L., Lobo, R. A., Shimizu, H., Stanczyk, F. Z., etal., 5-Alpha-reductase activity and risk of prostate cancer among Japanese and US white and black males. Lancet 339, 887-889 (1992). 

A systematic review and meta-analysis of randomized trials of S. repens in men with benign prostatic hyperplasia showed that saw palmetto extracts improve urinary symptoms and flow measures to a greater extent than placebo, and similar improvements in urinary symptoms and flow measures to the 5-alpha-reductase inhibitor finasteride with fewer adverse effects (6). 

Category 5-alpha reductase inhibitor Androgen antagonist Half-life 3-5 weeks... 

Imperato-McGinley J, Guerrero L> Gautier T, Peterson RE, Steroid 5 alpha-reductase deficiency in man An inherited form of male pseudohermaphroditism. Science 1974 186 1213-15. 

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