1. Figure 2 Pathways of androgen synthesis and abiraterone metabolism
Figure 2 | Pathways of androgen synthesis and abiraterone metabolism. a | All pathways of extragonadal dihydrotestosterone (DHT) synthesis depend on 3β-hydroxysteroid dehydrogenase/Δ5→4 isomerase 1 (3β-HSD1) activity. In prostate tumours, conversion of androgen precursors to DHT can occur through the canonical, 5α-dione, and backdoor pathways. (Not all steps of the backdoor pathways are shown). All three pathways depend on the 3β-hydroxyl 3-keto activity and Δ5 → Δ4 isomerization activity of 3β-HSD1. Cholesterol and the 3β-HSD1 substrates pregnenolone, 17α-hydroxypregnenolone, dehydroepiandrosterone, and androstenediol all have a 3β-hydroxyl, Δ5 structure, which must be converted to the 3-keto, Δ4 structure to enable further conversion to testosterone and DHT. b | The 17α-hydroxylase/17,20-lyase (CYP17A1) inhibitor abiraterone is converted to steroidal metabolites that also have effects on androgen synthesis and signalling. Abiraterone is converted by 3β-HSD1 to Δ4-abiraterone, which inhibits 3β-HSD1 and is also a potent androgen receptor antagonist. Δ4-Abiraterone is converted by steroid-5α-reductase (SRD5A) to 3-keto-5α-abiraterone, which, by contrast, is an androgen receptor agonist. AKR1C3, aldo-keto reductase family 1 member C3; CYP11A1, mitochondrial cholesterol side chain cleavage enzyme; 17β-HSD3, 17β-hydroxysteroid dehydrogenase 3.
Hettel, D. & Sharifi, N. (2017) HSD3B1 status as a biomarker of androgen deprivation resistance and implications for prostate cancer
Nat. Rev. Urol. doi: /nrurol