5-alpha-reductase inhibitor

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5α-Reductase inhibitors (or 5-alpha-reductase inhibitors) are a group of drugs with antiandrogenic activity, used in the treatment of benign prostatic hyperplasia and androgenic (or androgenetic) alopecia. These drugs decrease the levels of available 5α-reductase prior to testosterone's binding with the enzyme, thus reducing levels of dihydrotestosterone that derives from such a bond.

Contents

[edit] Clinical use

[edit] Indications

5α-Reductase inhibitors are clinically used in the treatment of conditions that are exacerbated by dihydrotestosterone. To be specific, these indications may include:[1]

[edit] Adverse drug reactions

In general, adverse drug reactions (ADRs) experienced with 5α-reductase inhibitors are dose-dependent. Common ADRs include impotence, decreased libido, decreased ejaculate volume, depression, and anxiety. Rare ADRs include breast tenderness and enlargement (gynecomastia), and allergic reaction.[1][2]

The FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-alpha reductase inhibitor (5-ARI) class of drugs has been revised to include new safety information about the increased risk of being diagnosed with a more serious form of prostate cancer (high-grade prostate cancer).[3]

[edit] Pharmacology

The enzyme 5α-reductase is involved in the conversion of testosterone to the active form dihydrotestosterone (DHT) by reducing the Δ4,5 double-bond. In benign prostatic hyperplasia, dihydrotestosterone acts as a potent cellular androgen and promotes prostate growth; therefore, inhibiting the enzyme reduces the excessive prostate growth. In alopecia, male-pattern baldness is one of the effects of androgenic receptor activation. Thus, reducing the levels of dihydrotestosterone reduces alopecia.

Results of an enzyme assay conducted with an extract of Ganoderma lucidum (Reishi) and the enzyme 5-alpha reductase.[4][vague]

[edit] Examples


Zinc,[5] azelaic acid,[5] β-sitosterol,[6] certain unsaturated aliphatic fatty acids such as gamma-linolenic acid, alpha-linolenic acid, linoleic acid, and oleic acid,[7] and a variety of polyphenols[8] have been found to inhibit 5α-reductase activity to varying degrees.

Certain pesticides are able to disturb the sex steroid hormone system and to act as antiandrogens.[9]

[edit] Herbs

Many chemical compounds in nature are able to inhibit 5α-reductase, such as those found in the Reishi mushroom Ganoderma lucidum.[4][10][11] Ganoderic acid[12] or organoderol B may be the active compounds.[13]

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.[14]

Other herbs include:

None of these plants have been tested in human clinical trials and their potential for the treatment of BPH and related conditions is unknown.

[edit] References

  1. ^ a b Rossi S (Ed.) (2004). Australian Medicines Handbook 2004. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-4-2
  2. ^ Rahimi-Ardabili B, Pourandarjani R, Habibollahi P, Mualeki A (2006). "Finasteride induced depression: a prospective study". BMC Clinical Pharmacology 6: 7. doi:10.1186/1472-6904-6-7. PMC 1622749. PMID 17026771. http://www.biomedcentral.com/1472-6904/6/7. 
  3. ^ http://www.drugs.com/fda/5-alpha-reductase-inhibitors-5-aris-label-change-increased-risk-prostate-cancer-12977.html
  4. ^ a b Liu J, Kurashiki K, Shimizu K, Kondo R (February 2006). "5alpha-reductase inhibitory effect of triterpenoids isolated from Ganoderma lucidum". Biol. Pharm. Bull. 29 (2): 392–5. doi:10.1248/bpb.29.392. PMID 16462054. 
  5. ^ a b 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. 
  6. ^ 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. 
  7. ^ Liang T, Liao S (July 1992). "Inhibition of steroid 5 alpha-reductase by specific aliphatic unsaturated fatty acids". The Biochemical Journal 285 (2): 557–62. PMC 1132824. PMID 1637346. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1132824. 
  8. ^ Hiipakka RA, Zhang HZ, Dai W, Dai Q, Liao S (March 2002). "Structure-activity relationships for inhibition of human 5alpha-reductases by polyphenols". Biochemical Pharmacology 63 (6): 1165–76. 
  9. ^ Lo, S; King, I; Alléra, A; Klingmüller, D (2007). "Effects of various pesticides on human 5alpha-reductase activity in prostate and LNCaP cells.". Toxicology in vitro : an international journal published in association with BIBRA 21 (3): 502–8. doi:10.1016/j.tiv.2006.10.016. PMID 17218080. 
  10. ^ Liu, J; Tamura, S; Kurashiki, K; Shimizu, K; Noda, K; Konishi, F; Kumamoto, S; Kondo, R (2009). "Anti-androgen effects of extracts and compounds from Ganoderma lucidum.". Chemistry & biodiversity 6 (2): 231–43. doi:10.1002/cbdv.200800019. PMID 19235153. 
  11. ^ Noguchi, M; Kakuma, T; Tomiyasu, K; Yamada, A; Itoh, K; Konishi, F; Kumamoto, S; Shimizu, K et al. (2008). "Randomized clinical trial of an ethanol extract of Ganoderma lucidum in men with lower urinary tract symptoms.". Asian journal of andrology 10 (5): 777–85. doi:10.1111/j.1745-7262.2008.00361.x. PMID 18097505. 
  12. ^ Liu, J; Shiono, J; Shimizu, K; Kukita, A; Kukita, T; Kondo, R (2009). "Ganoderic acid DM: anti-androgenic osteoclastogenesis inhibitor.". Bioorganic & medicinal chemistry letters 19 (8): 2154–7. doi:10.1016/j.bmcl.2009.02.119. PMID 19289282. 
  13. ^ Liu, J; Shimizu, K; Konishi, F; Kumamoto, S; Kondo, R (2007). "The anti-androgen effect of ganoderol B isolated from the fruiting body of Ganoderma lucidum.". Bioorganic & medicinal chemistry 15 (14): 4966–72. doi:10.1016/j.bmc.2007.04.036. PMID 17499997. 
  14. ^ Liu, J; Shimizu, K; Kondo, R (2009). "Anti-androgenic activity of fatty acids.". Chemistry & biodiversity 6 (4): 503–12. doi:10.1002/cbdv.200800125. PMID 19353546. 
  15. ^ Plants for a Future: Angelica koreana
  16. ^ Seo, EK; Kim, KH; Kim, MK; Cho, MH; Choi, E; Kim, K; Mar, W (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. 
  17. ^ Oku H. Ishiguro K.,"Cyclooxygenase-2 inhibitory 1,4-naphthoquinones from Impatiens balsamina L.", Biological & Pharmaceutical Bulletin. 25(5):658-60, 2002 May
  18. ^ Li, YH; Yang, YF; Li, K; Jin, LL; Yang, NY; Kong, DY (2009). "5 alpha-reductase and aromatase inhibitory constituents from Brassica rapa L. pollen.". Chemical & pharmaceutical bulletin 57 (4): 401–4. PMID 19336936. 
  19. ^ Pandit S. Chauhan NS. Dixit VK."Effect of Cuscuta reflexa Roxb on androgen-induced alopecia." Journal of Cosmetic Dermatology. 7(3):199-204, 2008 Sep.
  20. ^ Flora of China: Euphorbia jolkinii
  21. ^ Park, SH; Kim, JA; Hua, XG (2005). "Isolation of 5α-reductase inhibitors from Euphorbia jolkinii". Korean Journal of Pharmacognosy 36 (1): 9–16. 
  22. ^ Fujita R. Liu J. Shimizu K. Konishi F. Noda K. Kumamoto S. Ueda C. Tajiri H. Kaneko S. Suimi Y. Kondo R."Anti-androgenic activities of Ganoderma lucidum.", Journal of Ethnopharmacology. 102(1):107-12, 2005 Oct 31.
  23. ^ Cho, CH; Bae, JS; Kim, YU (2010). "5alpha-reductase inhibitory components as antiandrogens from herbal medicine.". Journal of acupuncture and meridian studies 3 (2): 116–8. doi:10.1016/S2005-2901(10)60021-0. PMID 20633525. 
  24. ^ Hirata, N; Tokunaga, M; Naruto, S; Iinuma, M; Matsuda, H (2007). "Testosterone 5alpha-reductase inhibitory active constituents of Piper nigrum leaf.". Biological & pharmaceutical bulletin 30 (12): 2402–5. PMID 18057734. 
  25. ^ Edgar AD. Levin R. Constantinou CE. Denis L. "A critical review of the pharmacology of the plant extract of Pygeum africanum in the treatment of LUTS.Neurourology & Urodynamics. 26(4):458-63; discussion 464, 2007" [Review]
  26. ^ Raynaud, JP; Cousse, H; Martin, PM (2002). "Inhibition of type 1 and type 2 5alpha-reductase activity by free fatty acids, active ingredients of Permixon.". The Journal of steroid biochemistry and molecular biology 82 (2-3): 233–9. doi:10.1016/S0960-0760(02)00187-5. PMID 12477490. 
  27. ^ Pais, P (2010). "Potency of a novel saw palmetto ethanol extract, SPET-085, for inhibition of 5alpha-reductase II.". Advances in therapy 27 (8): 555–63. doi:10.1007/s12325-010-0041-6. PMID 20623347. 
  28. ^ Abe, M; Ito, Y; Oyunzul, L; Oki-Fujino, T; Yamada, S (2009). "Pharmacologically relevant receptor binding characteristics and 5alpha-reductase inhibitory activity of free Fatty acids contained in saw palmetto extract.". Biological & pharmaceutical bulletin 32 (4): 646–50. doi:10.1248/bpb.32.646. PMID 19336899. 
  29. ^ Roh, SS; Park, MK; Kim, YU (2010). "Abietic acid from Resina Pini of Pinus species as a testosterone 5α-reductase inhibitor". Journal of Health Science 56 (4): 451–455. doi:10.1248/jhs.56.451. 
  30. ^ Roh, SS; Kim, CD; Lee, MH; Hwang, SL; Rang, MJ; Yoon, YK (2002). "The hair growth promoting effect of Sophora flavescens extract and its molecular regulation.". Journal of dermatological science 30 (1): 43–9. PMID 12354419. 
  31. ^ Park, WS; Son, ED; Nam, GW; Kim, SH; Noh, MS; Lee, BG; Jang, IS; Kim, SE et al. (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. 
  32. ^ Park, WS; Lee, CH; Lee, BG; Chang, IS (2003). "The extract of Thujae occidentalis semen inhibited 5alpha-reductase and androchronogenetic alopecia of B6CBAF1/j hybrid mouse.". Journal of dermatological science 31 (2): 91–8. PMID 12670719. 
  33. ^ Matsuda H., Yamazaki M., Naruto S., Asanuma Y., Kubo M. "Anti-androgenic and hair growth promoting activities of Lygodii Spora (spore of Lygodium japonicum) I. Active constituents inhibiting testosterone 5α-reductase " Biological and Pharmaceutical Bulletin 2002 25:5 (622-626)
Class
Substrate
Hydrolase (EC 3)
Lyase (EC 4)
5α-reductase inhibitors
Alpha blockers (α1)
Herbals
Other
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