5β-Dihydrosteroids: Formation and Properties

Abstract

5β-Dihydrosteroids are produced by the reduction of Δ⁴-3-ketosteroids catalyzed by steroid 5β-reductase (AKR1D1). By analogy with steroid 5α-reductase, genetic deficiency exists in AKR1D1 which leads to errors in newborn metabolism and in this case to bile acid deficiency. Also, like the 5α-dihydrosteroids (e.g., 5α-dihydrotestosterone), the 5β-dihydrosteroids produced by AKR1D1 are not inactive but regulate ligand access to nuclear receptors, can act as ligands for nuclear and membrane-bound receptors, and regulate ion-channel opening. For example, 5β-reduction of cortisol and cortisone yields the corresponding 5β-dihydroglucocorticoids which are inactive on the glucocorticoid receptor (GR) and provides an additional mechanism of pre-receptor regulation of ligands for the GR in liver cells. By contrast, 5β-pregnanes can act as neuroactive steroids at the GABA_A and NMDA receptors and at low-voltage-activated calcium channels, act as tocolytic agents, have analgesic activity and act as ligands for PXR, while bile acids act as ligands for FXR and thereby control cholesterol homeostasis. The 5β-androstanes also have potent vasodilatory properties and work through blockade of Ca²⁺ channels. Thus, a preference for 5β-dihydrosteroids to work at the membrane level exists via a variety of mechanisms. This article reviews the field and identifies gaps in knowledge to be addressed in future research.

Keywords: bile acids; farnesoid X receptor; neuroactive steroids; pregnane X receptor; smooth muscle relaxation; tocolysis.

Figure 1

Bent steroid configuration seen in 5β-dihydrosteroids.

Figure 2

Metabolism of Δ⁴-3-ketosteroids to tetrahydrosteroids. The sequential role of aldo-keto reductases is illustrated. Reproduced with permission from Endocrine Society [5].

Figure 3

AKR1D1 splice variants. Reproduced with permission from Steroids [14].

Figure 4

Control of ligand access to the glucocorticoid receptor in liver cells.

Figure 5

Biosynthesis of 5β-pregnanes from progesterone.

Figure 6

Bioactive 5β-dihydrosteroids.

Figure 7

Allopregnanolone, ent-allopregnanolone and pregnanolone, ent-pregnanolone. The plane of the page is the mirror plane with allopregnanolone and pregnanolone behind the plane of the page and the ent-allopregnanolone and ent-pregnanolone in front of the plane of the page. Overlay of the respective enantiomer pairs would superimpose the A and C rings as well as the 18 and 19 methyl groups in each enantiomer pair.

Figure 8

Properties of ent-steroids. The figure summarizes various effects where the enantiomers of AlloP (allopregnanolone) have been compared, including effects with enantioselectivity (nat > ent), and effects where the enantiomers are equivalent (nat = ent). Reproduced with permission from Neuroscience Biohav. Res [60].