Cutaneous Secosteroidal System

Abstract

Few years ago, it was shown that the P450scc system cleaves the side chain of 7-dehydrocholesterol (7DHC, provitamin D3) to produce 7-dehydropregnenolone (7DHP) (Guryev et al. 2003; Slominski et al. 2004d). 7DHP is a substrate for a novel metabolic pathway for the synthesis of steroids with two double bonds in 5 and 7 positions, collectively called steroidal 5,7-dienes (Fig. 8.1), which, hypothetically, may be produced in the skin since cutaneous CYP11A1 (P450scc) expression was confirmed (Slominski et al. 2004d). The role of this new pathway was supported ex vivo by demonstrating the efficient metabolic transformation of 7-dehydrocholesterol to 7DHP by adrenal glands and by mitochondria isolated from rat skin (Slominski et al. 2009c). HPLC separations, UV spectra, and mass spectrometry identified 7DHP, 22-hydroxy-7DHC, and 20,22-dihydroxy-7DHC as the major products with additional minor products defined as 17-hydroxy-7DHP and 7-dehydroprogesterone (Slominski et al. 2009c). These findings defined a novel steroidogenic pathway: 7DHC → 22(OH)7DHC → 20,22(OH)₂7DHC → 7DHP, with potential further metabolism of 7DHP mediated by 3β-HSD or CYP17 along the Δ⁴ and Δ⁵ steroidogenic pathways, with the production of 7-dehydroprogesterone and 17(OH)7DHP as intermediates (Slominski et al. 2009d). The existence of this synthetic pathway is documented by the accumulation of pregna- and androsta-5,7-dienes and their hydroxylated derivatives in the Smith–Lemli–Opitz syndrome (SLOS), characterized by 7DHC Δ-reductase deficiency, an enzyme responsible for the conversion of 7DHC to cholesterol (Marcos et al. 2004; Shackleton et al. 1999, 2002; Tint et al. 1994). Most recently, we have found that human placenta ex utero can transform 7DHC to 7DHP and further to 7-dehydroprogesterone (Slominski et al. submitted for publication).