Molecular Endocrinology of Hydroxysteroid Dehydrogenases
Mammalian 3-HSDs work in concert with the 5- and 5ß-reductases to reduce 3-ketosteroids to produce the 5,3- and 5ß,3-tetrahydrosteroids. Although these reactions are responsible for the metabolism of the majority of steroid hormones, they are not without consequence. In the prostate, 3-HSD works as a molecular switch and regulates occupancy of the androgen receptor. In this tissue the enzyme interconverts 5-DHT [dissociation constant (Kd) for the androgen receptor of 10-11 M] to 3-androstanediol [Kd for the androgen receptor of 10-6 M], thereby reducing the affinity of the steroid ligand for the androgen receptor by 5 orders of magnitude (96, 97, 98, 99) (Fig. 3). In the dog prostate, evidence has mounted that the enzyme works predominantly as a dehydrogenase and works in concert with 5-reductase to maintain high levels of 5-DHT, which is required for both the normal and abnormal growth of the prostate (100, 101). Inhibitors of prostatic 3-HSD would block the interconversion of 5-DHT to 3-androstanediol and may be useful in preventing the build-up of 5-DHT. Such inhibitors could be useful in combination with Finasteride for the treatment of benign prostatic hyperplasia and prostatic cancer.
In the brain, 3-HSD converts 5-reduced steroids (e.g. 5-dihydroprogesterone) to yield tetrahydrosteroids (e.g. 5,3-tetrahydroprogesterone), which are potent allosteric effectors of the -aminobutyric acid (GABA)a receptor (Fig. 3). These steroids do not bind to the GABAa receptor by themselves but, in the presence of GABA, nanomolar concentrations of these steroids increase the affinity of the receptor for this neurotransmitter. As a consequence, these neurosteroids increase GABA-dependent chloride conductance and have anxiolytic and anesthetic properties (102, 103, 104). The 3-hydroxysteroid, alphaxalone, was developed as an anesthetic based on this mechanism of action (105). Thus, 3-HSD regulates occupancy of steroid hormone receptors, whether they are members of the nuclear receptor superfamily, such as the androgen receptor, or a membrane-bound chloride-ion gated channel such as the GABAa receptor.
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