Reactome | SRD5A2 binds SRD5A2 inhibitors

SRD5A2 binds SRD5A2 inhibitors

Stable Identifier

R-HSA-9705794

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol, endoplasmic reticulum membrane

ReviewStatus

5/5

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The conversion of testosterone (TEST) to the most potent androgen, 5-alpha-dihydrotestosterone (DHTEST), is catalyzed by microsomal 5alpha-steroid reductases 1-3 (SRD5A1-3). SRD5As are highly expressed in the prostate, the skin, and other androgen target sites. Benign prostatic hyperplasia (BPH) is a pathologic process that can lead to the development of lower urinary tract symptoms (LUTS) in men. BPH refers to stromal and glandular epithelial hyperplasia that occurs in the zone of the prostate that surrounds the urethra. This overgrowth is dependent mainly on androgens, particularly DHTEST. Since SRD5As are responsible for the production of DHTEST, SRD5A inhibitors can be used in the treatment of symptomatic BPH (Rasmusson et al. 1986, Gisleskog et al. 1998).

The azasteroids finasteride and dutasteride are approved for human use to treat BPH (Sandhu 2009). Dutasteride can block all three SRD5A isoforms and can decrease DHTEST levels in the blood by up to 98% (Keam & Scott 2008, Yamana et al. 2010). In contrast, finasteride (Hasinki et al. 1992) only inhibits type II and III isoenzymes so is able to achieve a reduction in circulating DHTEST of only 65 to 70% (Yamana et al. 2010, Aggarwal et al. 2010). However, these two drugs decrease DHTEST levels in the prostate gland to a similar level, where the SRD5A2 isoform predominates.

The dicarboxylic acid azelaic acid is a potent inhibitor of SRD5A in human skin and could be an effective agent in the treatment of androgen related pathology of human skin such as various types of acne and cutaneous hyperpigmentary disorders (Stamatiadis et al. 1998, Fitton & Goa 1991, Passi et al. 1989). Its exact mechanism is unknown.

Literature References

PubMed ID	Title	Journal	Year
19936164	Therapeutic options in the treatment of benign prostatic hyperplasia Sandhu, JS	Patient Prefer Adherence	2009
3207614	Inhibition of 5 alpha-reductase activity in human skin by zinc and azelaic acid Stamatiadis, D, Mowszowicz, I, Bulteau-Portois, MC	Br J Dermatol	1988
1712709	Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders Goa, KL, Fitton, A	Drugs	1991
2534550	[Mechanism of azelaic acid action in acne] Nazzaro-Porro, M, Picardo, M, Passi, S, De Luca, C	G Ital Dermatol Venereol	1989
18318566	Dutasteride: a review of its use in the management of prostate disorders Keam, SJ, Scott, LJ	Drugs	2008
9871428	A model for the turnover of dihydrotestosterone in the presence of the irreversible 5 alpha-reductase inhibitors GI198745 and finasteride Karlsson, MO, Hammarlund-Udenaes, M, Gisleskog, PO, Hermann, D	Clin Pharmacol Ther	1998
1279965	Finasteride for benign prostatic hyperplasia Rose, LI, Hasinski, S, Miller, JL	Am Fam Physician	1992
3783591	Azasteroids: structure-activity relationships for inhibition of 5 alpha-reductase and of androgen receptor binding Walton, E, Steinberg, NG, Rasmusson, GH, Cascieri, MA, Liang, T, Patel, GF, Cheung, AH, Reynolds, GF, Brooks, JR, Berman, C	J Med Chem	1986
19879888	An overview on 5alpha-reductase inhibitors Kumar, M, Bhardwaj, TR, Aggarwal, S, Verma, A, Thareja, S	Steroids	2010
25961201	Human type 3 5α-reductase is expressed in peripheral tissues at higher levels than types 1 and 2 and its activity is potently inhibited by finasteride and dutasteride Yamana, K, Luu-The, V, Labrie, F	Horm Mol Biol Clin Investig	2010