Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-Δ 7-reductase deficiency (Smith–Lemli–Opitz syndrome)

Abstract

Patients with Smith–Lemli–Opitz syndrome have impaired ability to synthesize cholesterol due to attenuated activity of 7-dehydrosterol-Δ 7-reductase which catalyses the final step in cholesterol synthesis. Accumulation of 7- and 8-dehydrocholesterol is a result of the disorder and potentially these sterols could be used as precursors of a novel class of Δ 7 and Δ 8 unsaturated adrenal steroids and their metabolites. In this study, we have analyzed urine from SLOS patients in the anticipation of characterizing such metabolites. Gas chromatography/mass spectrometry (GC/MS) was used in the identification of two major metabolites as 7- and 8-dehydroversions of the well-known steroid pregnanetriol. Other steroids, such as 8-dehydro dehydroepiandrosterone (8-dehydro DHEA) and 7- or 8-dehydroandrostenediol were also identified, and several more steroids are present in urine but remain uncharacterized. As yet, the study provides no evidence for the production of ring-B unsaturated metabolites of complex steroids, such as cortisol. We believe that the following transformations can utilize ring-B dehydroprecursors: StAR transport of cholesterol, p450 side chain cleavage, 17-hydroxylase/17,20-lyase, 3β-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, 17β-hydroxysteroid dehydrogenase, 20α-hydroxysteroid dehydrogenase and 5β-reductase. We have yet to prove the activity of adrenal 21-hydroxylase, 11β-hydroxylase or 5α-reductase towards 7- or 8-dehydroprecursors.