New frontiers in androgen biosynthesis and metabolism

Abstract

Purpose of review: To summarize recent advances in androgen biosynthesis and metabolism in peripheral tissues (e.g., liver and prostate) and how these can be exploited therapeutically.

Recent findings: Human liver catalyzes the reduction of circulating testosterone to yield four stereoisomeric tetrahydrosteroids. Recent advances have assigned the enzymes responsible for these reactions and elucidated their structural biology. Data also suggest that for 5alpha-dihydrotestosterone (5alpha-DHT), conjugation reactions (phase II) may precede ketosteroid reduction (phase I) reactions. Human prostate is the site of benign prostatic hyperplasia and prostate cancer, which occur in the aging male. Although the importance of local androgen biosynthesis in these diseases is accepted, recent advances have identified enzymes that regulate ligand access to the androgen-receptor; a 'backdoor pathway' to 5alpha-DHT that does not require testosterone acting as an intermediate; and the finding that castrate-resistant prostate cancer (CRPC) has undergone an adaptive response to androgen deprivation, which involves intratumoral testosterone and 5alpha-DHT biosynthesis that can be targeted using inhibitors of (CYP17-hydroxylase/17,20-lyase), aldo-keto reductase 1C3, and 5alpha-reductase type 1 and type 2.

Summary: Enzyme isoforms responsible for the biosynthesis and metabolism of androgens in liver and prostate have been identified and those responsible for the biosynthesis of androgens in CRPC can be therapeutically targeted.

Figure 1

Reductive androgen metabolism in human liver. The reductive enzymes responsible for the metabolism of testosterone to its four stereoisomeric tetrahydrosteroids are shown (genes are italicized). The inset shows the preferred pathway of 5α-DHT metabolism with glucuronidation (a phase II reaction) preceding 3-ketosteroid reduction (a phase I reaction). AKR1C4 is shown preferentially reducing 5α-DHTG to 3α-diol-17-G since it has the highest catalytic efficiency for this reaction among the AKR1C isoforms: 5α-DHT = 5α-dihydrotestosterone; 3α-diol = 5α-androstane-3α,17β-diol; 3α-diol-3G = 3α-diol-3α-glucuronide; 5α-DHTG = 5α-DHT-17β-glucuronide; 3α-diol-17G = 3α-diol-17β-glucuronide.

Figure 2

Structure and mechanism of human steroid 5β-reductase (AKR1D1). (A) (α/β)₈-Barrel structure of an AKR1D1•NADP⁺ binary complex. NADP⁺ is in a stick presentation, a water molecule (red ball) is hydrogen bonded to Y58 and E120 of the catalytic tetrad which also contains (D53 and K87); and the three loops A, B and C which comprise the steroid binding site are in blue. (B) Catalytic mechanism of steroid double bond reduction.

Figure 3

Androgen biosynthesis in the prostate. Traditional pathway converting DHEA to 5α-DHT is shown in blue. Arrows and genes in blue show altered expression in castrate resistant prostate cancer (CRPC). Arrows and genes in red show the molecular switch that regulates ligand access to the AR. AKR1C2 is also overexpressed in CRPC. Arrows in grey show de novo routes to DHEA and Δ⁴-androstene-3,17-dione that may contribute to adaptive androgen biosynthesis in CRPC. Open orange arrows show the backdoor pathway to 5α-DHT.