List of 5α-reductase inhibitors

This is a list of 5α-reductase inhibitors (5α-RIs), drugs which inhibit one or more isoforms of the enzyme 5α-reductase. This enzyme is responsible for the conversion of the androgen hormone testosterone into the more potent dihydrotestosterone (DHT) and is essential for the production of neurosteroids like allopregnanolone, tetrahydrodeoxycorticosterone (THDOC), and 3α-androstanediol from progesterone, deoxycorticosterone, and DHT, respectively. 5α-Reductase inhibitors have medical applications in the treatment of benign prostatic hyperplasia, androgenic alopecia (pattern hair loss), and hirsutism (excessive hair growth).

Pharmaceutical drugs

5α-RIs that are used in medicine include the following:

Experimental drugs

5α-RIs that were under development for potential clinical use but were never marketed or are used in research include the following:

  • 4-MA – inhibits types 1 and 2 (IC50 = 8.5 nM), but also 3β-HSD inhibitor, investigated extensively but found to be hepatotoxic[1]
  • 17β-Carboxy-4-androsten-3-one[2][3]
  • AS-97004
  • Azelaic Acid[4]
  • Bexlosteride (LY-300502) – inhibits type 1
  • CGP-53153
  • Efomycin G (SNA 4606-2)
  • EM-402
  • FCE-28260 – inhibits types 1 and 2
  • FK-143
  • FR-146687
  • G-20000
  • Izonsteride (LY-320236) – inhibits types 1 and 2
  • L-10
  • L-39
  • L-697818
  • L-751788 (16-((4-chlorophenyl)oxy)-4,7-dimethyl-4-azaandronstan-3-one)
  • Lapisteride (CS-891) – inhibits types 1 and 2
  • LY-191704
  • LY-266111
  • MK-386 (L-733692) – inhibits type 1
  • MK-434 – inhibits type 2[5]
  • MK-963 (L-654066) – inhibits type 2
  • ONO-3805 (ONO-RI-3805)
  • PHL-00801 (Prostatonin; PY 102/UR 102; Pygeum africanum/Urtica dioica extract)
  • PNU-157706 – inhibits types 1 and 2[6]
  • Steroidal oximes[7][3]
  • Turosteride (FCE-26073) – inhibits type 2 and to a 15-fold lesser extent type 1
  • Z-350 – also an α1-adrenergic receptor antagonist[8]

Herbs and other inhibitors

Many plants, as well as their associated phytochemical constituents, have inhibitory effects on 5α-reductase.[9] In addition, many of these compounds are also phytoestrogens.[10] Examples include the following:

  • Alizarin,.
  • Angelica koreana [11][12]
  • Astaxanthin[13]
  • Azelaic acid,[4] (sometimes combined with minoxidil hair solution).
  • Black Pepper leaf extract (Piper nigrum) [14]
  • β-Sitosterol,[15] one of many phytosterols.
  • Chinese knotweed (Reynoutria multiflora, syn. Polygonum multiflorum),[16] contains resveratrol-like Stilbenoids.
  • Curcumin,[17][18][19] the principal curcuminoid of turmeric.
  • Dodder (Cuscuta reflexa)[20]
  • Eastern arborvitae, northern whitecedar (Thuja occidentalis)[21]
  • Euphorbia jolkinii[22][23]
  • Fatty acids: The relative inhibitory potencies of unsaturated fatty acids are, in decreasing order: Gamma-Linolenic acid, alpha-linolenic acid, linoleic acid, palmitoleic acid, oleic acid, and myristoleic acid.[24][25]
    • Medium chain fatty acids such as those found in coconut and the kernel of many palm fruits have also been found to inhibit 5α-reductase.[26]
  • Garden balsam or rose balsam (Impatiens balsamina)[27]
  • Green tea catechins, including (-)-epicatechin-3-gallate, and (-)-epigallo-catechin-3-gallate (EGCG).[28] However, another research found that green tea may actually increase DHT levels.[29]
  • Black tea theaflavins [30][31]
  • Japanese hedge parsley (Torilis japonica)[32]
  • Ku Shen or Bitter root (Sophora flavescens)[33]
  • Lingzhi mushroom or Reishi mushroom (Ganoderma lucidum)[34][35][36][37]
    • Ganoderic acid,[38] or Ganoderol B are thought to be the compounds in the mushroom that are specifically active.[39]
  • Pesticides: Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens.[40]
  • Phyllanthus emblica[41]
  • Pine (Pinus sp. resin, active substance abietic acid)[42]
  • Pollen of Turnip, turnip rape, fast plants, field mustard, or turnip mustard (Brassica rapa)[43]
  • Polyphenols[44]
  • Red stinkwood (Pygeum africanum)[45]
  • Riboflavin (vitamin B2).[46]
  • Saw palmetto (Serenoa repens, active substance possibly lauric acid[47])[48][49]
    • The berries of saw palmetto, a small palm native to the south east United States, possess a dual but weak 5a-reductase inhibition activity, due to their high content of phytosterols: β-sitosterol, stigmasterol, lupeol, lupenone, and cycloartenol. The lipido-sterol extract markedly inhibits both the human isoenzymes. Type 1 isoenzyme is noncompetitively (Ki = 7.2 μg/mL) and type 2 isoenzyme uncompetitively (Ki = 4.9 μg/mL) inhibited.[50] In vitro studies revealed a 5a-reductase inhibition activity of 1:5600 compared to finasteride but is at minimum 1:18000 in vivo. Meaning the 5a-reductase inhibition activity of 1mg finasteride is equal to 18000mg saw palmetto.[51]
  • Spore of Japanese climbing fern (Lygodium japonicum)[52]
  • Valoneic acid dilactone and gallagyldilactone are two hydrolysable tannin polyphenols isolated from the heartwood of Shorea laeviforia[53] and the North American white oak (Quercus alba) and European red oak (Quercus robur) and are inhibitory.[54]
  • Zinc.[4]

These supplements have limited testing in human clinical trials, and their potential for the treatment of BPH, androgenic alopecia, and related conditions is unknown.


References

  1. ↑ Guarna A, Occhiato EG, Danza G, Conti A, Serio M (1998). "5 alpha-reductase inhibitors, chemical and clinical models". Steroids. 63 (5–6): 355–61. doi:10.1016/S0039-128X(98)00020-8. PMID 9618802. S2CID 54357911.
  2. ↑ Hsia SL, Voigt W (March 1974). "Inhibition of dihydrotestosterone formation: an effective means of blocking androgen action in hamster sebaceous gland". The Journal of Investigative Dermatology. 62 (3): 224–7. doi:10.1111/1523-1747.ep12676791. PMID 4361987.
  3. 1 2 Flores E, Bratoeff E, Cabeza M, Ramirez E, Quiroz A, Heuze I (May 2003). "Steroid 5α-Reductase Inhibitors". Mini Reviews in Medicinal Chemistry. 3 (3): 225–37. doi:10.2174/1389557033488196. PMID 12570838.
  4. 1 2 3 Stamatiadis D, Bulteau-Portois MC, Mowszowicz I (November 1988). "Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid". The British Journal of Dermatology. 119 (5): 627–32. doi:10.1111/j.1365-2133.1988.tb03474.x. PMID 3207614. S2CID 28506969.
  5. ↑ Cohen SM, Werrmann JG, Rasmusson GH, Tanaka WK, Malatesta PF, Prahalada S, Jacobs JG, Harris G, Nett TM (February 1995). "Comparison of the effects of new specific azasteroid inhibitors of steroid 5 alpha-reductase on canine hyperplastic prostate: suppression of prostatic DHT correlated with prostate regression". The Prostate. 26 (2): 55–71. doi:10.1002/pros.2990260202. PMID 7531846. S2CID 40758833.
  6. ↑ di Salle E, Giudici D, Radice A, Zaccheo T, Ornati G, Nesi M, Panzeri A, Délos S, Martin PM (February 1998). "PNU 157706, a novel dual type I and II 5alpha-reductase inhibitor". The Journal of Steroid Biochemistry and Molecular Biology. 64 (3–4): 179–86. doi:10.1016/S0960-0760(97)00158-1. PMID 9605412. S2CID 54300283.
  7. ↑ Hartmann RW, Hector M, Haidar S, Ehmer PB, Reichert W, Jose J (November 2000). "Synthesis and evaluation of novel steroidal oxime inhibitors of P450 17 (17 alpha-hydroxylase/C17-20-lyase) and 5 alpha-reductase types 1 and 2". Journal of Medicinal Chemistry. 43 (22): 4266–77. doi:10.1021/jm001008m. PMID 11063622.
  8. ↑ Fukuta Y, Fukuda Y, Higashino R, Yoshida K, Ogishima M, Tamaki H, Takei M (September 1999). "Z-350, a novel compound with alpha 1-adrenoceptor antagonistic and steroid 5 alpha-reductase inhibitory actions: pharmacological properties in vivo". The Journal of Pharmacology and Experimental Therapeutics. 290 (3): 1013–8. PMID 10454472.
  9. ↑ Nahata A, Dixit VK (August 2014). "Evaluation of 5α-reductase inhibitory activity of certain herbs useful as antiandrogens". Andrologia. 46 (6): 592–601. doi:10.1111/and.12115. PMID 23710567. S2CID 36474953.
  10. ↑ Stansbury, Jillian E. "Phytoestrogen review" (PDF).
  11. ↑ Plants for a Future: Angelica koreana Archived 2011-07-10 at the Wayback Machine
  12. ↑ Seo EK, Kim KH, Kim MK, Cho MH, Choi E, Kim K, Mar W (February 2002). "Inhibitors of 5alpha -reductase type I in LNCaP cells from the roots of Angelica koreana". Planta Medica. 68 (2): 162–3. doi:10.1055/s-2002-20258. PMID 11859469.
  13. ↑ Anderson, Mark L. (2005). "A preliminary investigation of the enzymatic inhibition of 5alpha-reduction and growth of prostatic carcinoma cell line LNCap-FGC by natural astaxanthin and Saw Palmetto lipid extract in vitro". Journal of Herbal Pharmacotherapy. 5 (1): 17–26. ISSN 1522-8940. PMID 16093232.
  14. ↑ Hirata N, Tokunaga M, Naruto S, Iinuma M, Matsuda H (December 2007). "Testosterone 5alpha-reductase inhibitory active constituents of Piper nigrum leaf". Biological & Pharmaceutical Bulletin. 30 (12): 2402–5. doi:10.1248/bpb.30.2402. PMID 18057734.
  15. ↑ Cabeza M, Bratoeff E, Heuze I, Ramírez E, Sánchez M, Flores E (2003). "Effect of beta-sitosterol as inhibitor of 5 alpha-reductase in hamster prostate". Proceedings of the Western Pharmacology Society. 46: 153–5. PMID 14699915.
  16. ↑ Liu Y, Wang Q, Yang J, Guo X, Liu W, Ma S, Li S (April 2018). "Polygonum multiflorum Thunb.: A Review on Chemical Analysis, Processing Mechanism, Quality Evaluation, and Hepatotoxicity". Frontiers in Pharmacology. 9 (1): 364. doi:10.3389/fphar.2018.00364. PMC 5912012. PMID 29713283.
  17. ↑ Sk, Kim; H, Seok; Hj, Park; Hs, Jeon; Sw, Kang; Bc, Lee; J, Yi; Sy, Song; Sh, Lee (2015-10-22). "Inhibitory Effect of Curcumin on Testosterone Induced Benign Prostatic Hyperplasia Rat Model". BMC Complementary and Alternative Medicine. 15: 380. doi:10.1186/s12906-015-0825-y. PMC 4618860. PMID 26490686.
  18. ↑ Ide, Hisamitsu; Lu, Yan; Noguchi, Takahiro; Muto, Satoru; Okada, Hiroshi; Kawato, Suguru; Horie, Shigeo (April 2018). "Modulation of AKR1C2 by curcumin decreases testosterone production in prostate cancer". Cancer Science. 109 (4): 1230–1238. doi:10.1111/cas.13517. ISSN 1347-9032. PMC 5891173. PMID 29369461.
  19. ↑ Srivilai, Jukkarin; Rabgay, Karma; Khorana, Nantaka; Waranuch, Neti; Nuengchamnong, Nitra; Wisuitiprot, Wudtichai; Chuprajob, Thipphawan; Changtam, Chatchawan; Suksamrarn, Apichart; Chavasiri, Warinthorn; Sornkaew, Nilubon (2017-07-01). "Anti-androgenic curcumin analogues as steroid 5-alpha reductase inhibitors". Medicinal Chemistry Research. 26 (7): 1550–1556. doi:10.1007/s00044-017-1869-y. ISSN 1554-8120. S2CID 38952839.
  20. ↑ Pandit S, Chauhan NS, Dixit VK (September 2008). "Effect of Cuscuta reflexa Roxb on androgen-induced alopecia". Journal of Cosmetic Dermatology. 7 (3): 199–204. doi:10.1111/j.1473-2165.2008.00389.x. PMID 18789055. S2CID 23035110.
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  22. ↑ Flora of China: Euphorbia jolkinii
  23. ↑ Park SH, Kim JA, Hua XG (2005). "Isolation of 5α-reductase inhibitors from Euphorbia jolkinii". Korean Journal of Pharmacognosy. 36 (1): 9–16.
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  29. ↑ Soy Phytochemicals and Tea Bioactive Components Synergistically Inhibit Androgen-Sensitive Human Prostate Tumors in Mice Green tea tended to increase serum testosterone and DHT levels by 73.8% (P = 0.14) and 194% (P = 0.076), respectively
  30. ↑ Zhou, Jin-Rong; Yu, Lunyin; Zhong, Ying; Blackburn, George L. (February 2003). "Soy phytochemicals and tea bioactive components synergistically inhibit androgen-sensitive human prostate tumors in mice". The Journal of Nutrition. 133 (2): 516–521. doi:10.1093/jn/133.2.516. ISSN 0022-3166. PMC 2683253. PMID 12566493.
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  32. ↑ Park WS, Son ED, Nam GW, Kim SH, Noh MS, Lee BG, Jang IS, Kim SE, Lee JJ, Lee CH (May 2003). "Torilin from Torilis japonica, as a new inhibitor of testosterone 5 alpha-reductase". Planta Medica. 69 (5): 459–61. doi:10.1055/s-2003-39717. PMID 12802730.
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