Identification of 7(8) and 8(9) unsaturated adrenal steroid metabolites produced by patients with 7-dehydrosterol-Δ7-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-delta(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 delta(7) and delta(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, 3beta-hydroxysteroid dehydrogenase, 3alpha-hydroxysteroid dehydrogenase, 17beta-hydroxysteroid dehydrogenase, 20alpha-hydroxysteroid dehydrogenase and 5beta-reductase. We have yet to prove the activity of adrenal 21-hydroxylase, 11beta-hydroxylase or 5alpha-reductase towards 7- or 8-dehydroprecursors.
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In Smith-Lemli-Opitz syndrome, deficiency of 7-dehydrocholesterol reductase leads to UVA photosensitivity of the skin and to formation of atypical steroids.
“Firstly, the 7-Δ reductase deficiency observed in Smith–Lemli–Opitz syndrome (SLOS), in an addition to severe malformations, results in development of skin photosensitivity to UVA [158, 159] and production a series of unusual steroids [79, 160, 161].”
From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [160]
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Cites
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- Authors
- Shackleton, C., Roitman, E., Guo, L.-W., Wilson, W. K., & Porter, F. D.
- Affiliations
- Rice University (US)
- National Institutes of Health (US)
- Corresponding author
- Shackleton, Cedric
- Venue
- The Journal of Steroid Biochemistry and Molecular Biology
- Publisher
- Elsevier BV
- Published
- 2002-10
- Volume
- 82
- Issue
- 2-3
- Pages
- 225-232
- ISSN
- 0960-0760 (ISSN-L)
- OpenAlex
- W1989168127
- Cited by
- 56
- References
- 5
- Citations by year
- 2026: 1 · 2025: 1 · 2022: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 2 · 2016: 2 · 2015: 1 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 1.39
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Steroid Biochemistry and Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r03hd039707-02)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD-39707)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- Smith-Lemli-Opitz syndrome, 7-dehydrocholesterol, 8-dehydrocholesterol, steroid metabolites, pregnanetriol, steroidogenesis, adrenal steroidogenesis
- MeSH terms
- Adolescent, Adrenal Glands, Adult, Child, Child, Preschool, Chromatography, High Pressure Liquid, Chromatography, Ion Exchange, Humans, Infant, Steroids, Smith-Lemli-Opitz Syndrome
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