3-beta-hydroxy-delta5-steroid dehydrogenase, delta-isomeric type 1 (3β-HSD1) (3β-HSD1)

3-beta-hydroxysteroid dehydrogenase type 1 (3β-HSD1) is a membrane-bound enzyme essential for the biosynthesis of all active steroid hormones, including progesterone, androgens, and estrogens (UniProt P14060). Unlike the type 2 isoenzyme found primarily in the adrenals and gonads, 3β-HSD1 is predominantly expressed in peripheral tissues such as the placenta, skin, and mammary glands, where it facilitates the intracrine conversion of adrenal-derived precursors like dehydroepiandrosterone (DHEA) into potent hormones (NCBI Gene 3283). In clinical oncology, 3β-HSD1 is a major driver of resistance in castration-resistant prostate cancer (CRPC) because it enables the tumor to synthesize its own dihydrotestosterone (DHT) despite low circulating testosterone levels (Chang et al., 2013, PMID: 23933607). A common germline polymorphism in the HSD3B1 gene (1245A>C) results in a more stable enzyme, leading to rapid androgen synthesis and poorer clinical outcomes in patients undergoing androgen deprivation therapy (Hearn et al., 2016, PMID: 27673061). Consequently, 3β-HSD1 has emerged as a high-priority therapeutic target, with research focusing on developing potent and selective inhibitors to block this bypass pathway of androgen production (DrugBank DB01106).

Other names

HSD3B13-beta-HSD 1Hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta-isomerase 1Progesterone reductaseTrophoblast antigen FDO-161

Inhibition of the enzymatic conversion of delta-5-3-beta-hydroxysteroids into delta-4-3-ketosteroids, thereby blocking the synthesis of active androgens and estrogens in peripheral tissues.