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Cited by 61Metabolism and Genetic DisordersSteroid Chemistry and BiochemistryCholesterol and Lipid Metabolism

Role of a disordered steroid metabolome in the elucidation of sterol and steroid biosynthesis

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Shackleton, Cedric H. L.·2012·Lipids
DOI 10.1007/s11745-011-3605-6PMC PMC3564490
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Abstract

In 1937 Butler and Marrian found large amounts of the steroid pregnanetriol in urine from a patient with the adrenogenital syndrome, a virilizing condition known to be caused by compromised adrenal secretion even in this pre-cortisol era. This introduced the concept of the study of altered excretion of metabolites as an in vivo tool for understanding sterol and steroid biosynthesis. This approach is still viable and has experienced renewed significance as the field of metabolomics. From the first cyclized sterol lanosterol to the most downstream product estradiol, there are probably greater than 30 steps. Based on a distinctive metabolome clinical disorders have now been attributed to about seven post-squalene cholesterol (C) biosynthetic steps and around 15 en-route to steroid hormones or needed for further metabolism of such hormones. Forty years ago it was widely perceived that the principal steroid biosynthetic defects were known but interest rekindled as novel metabolomes were documented. In his career this investigator has been involved in the study of many steroid disorders, the two most recent being P450 oxidoreductase deficiency and apparent cortisone reductase deficiency. These are of interest as they are due not to mutations in the primary catalytic enzymes of steroidogenesis but in ancillary enzymes needed for co-factor oxido-reduction A third focus of this researcher is Smith-Lemli-Opitz syndrome (SLOS), a cholesterol synthesis disorder caused by 7-dehydrocholesterol reductase mutations. The late George Schroepfer, in whose honor this article has been written, contributed greatly to defining the sterol metabolome of this condition. Defining the cause of clinically severe disorders can lead to improved treatment options. We are now involved in murine gene therapy studies for SLOS which, if successful could in the future offer an alternative therapy for this severe condition.

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  • CYP11A1 action on 7DHC in vivo is supported by detection of Δ7-steroids in Smith-Lemli-Opitz syndrome patients.

    “CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients.”

    From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [61]

  • The production of 7DHP in SLOS and during equilin synthesis is attributed to CYP11A1 action on 7DHC.

    “The production of 7DHP in SLOS and during the synthesis of equilin is attributed to CYP11A1 action on 7DHC [61].”

    From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [61]

  • Mutations in genes encoding skin steroidogenic enzymes may cause local formation of atypical steroids.

    “In addition, mutation of any gene encoding enzymes involved in steroidogenesis in the skin may result in local formation of unusual steroids, as extensively reviewed recently [157].”

    From Steroidogenesis in the skin: Implications for local immune functions (2013) · cites this paper as [157]

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Authors
Shackleton, C. H. L.
Affiliations
University of Birmingham (GB)
Corresponding author
Shackleton, Cedric H. L.
Venue
Lipids
Publisher
Wiley
Published
2011-08-27
Volume
47
Issue
1
Pages
1-12
ISSN
  • 0024-4201 (ISSN-L)
  • 1558-9307
DOI
10.1007/s11745-011-3605-6
PMC
PMC3564490
OpenAlex
W1969468842
Cited by
61
References
62
Citations by year
2025: 1 · 2024: 4 · 2023: 10 · 2022: 2 · 2021: 2 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 4 · 2016: 4 · 2015: 6 · 2014: 5 · 2013: 5 · 2012: 2
FWCI
0.46
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Lipids (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Child Health and Human Development (5R01HD053036)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
Keywords
steroidogenesis, steroidogenesis disorders, adrenogenital syndrome, pregnanetriol, lanosterol, cholesterol biosynthesis, Smith-Lemli-Opitz syndrome, P450 oxidoreductase deficiency, metabolomics, gene therapy
MeSH terms
Adrenal Glands, Animals, Hirsutism, Humans, Mutation, Oxidoreductases, Pregnanetriol, Sterols, Smith-Lemli-Opitz Syndrome, 11-beta-Hydroxysteroid Dehydrogenases, Steroid Metabolism, Inborn Errors, Oxidoreductases Acting on CH-CH Group Donors, Adrenogenital Syndrome, Lipogenesis, Mice, Metabolome, 46, XX Disorders of Sex Development

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