17-Hydroxylase/C17, 20-lyase (CYP17) is not the enzyme responsible for side-chain cleavage of cortisol and its metabolites
Abstract
The question addressed in this study was the nature of the enzyme required to remove the side-chain of 17-hydroxycorticosteroids, leading in the case of cortisol to the excretion of 11beta-hydroxyandrosterone, 11-oxo-androsterone and the corresponding etiocholanolones. We questioned whether it could be CYP17, the 17-hydroxylase/17,20-lyase utilized in androgen synthesis. The conversion of exogenous cortisol to C(19) steroids in patients with complete 17-hydroxylase deficiency (17HD) was studied rationalizing that if CYP17 was involved no C(19) steroids would be formed. The urinary excretion of the four 11-oxy-C(19) steroids as well as many of the major C(21) cortisol metabolites were measured by GC/MS. Our results showed that the conversion of cortisol to C(19) steroids was normal in 17HD indicating that a currently unidentified enzyme must be responsible for this transformation. A secondary goal was to determine to what extent 11-oxy-C(19) steroids were metabolites of cortisol or adrenal synthesized 11beta-hydroxyandrostenedione. Since cortisol-treated 17HD patients cannot produce androstenedione, all C(19) 11-oxy-metabolites excreted must be derived from exogenous cortisol. The extent to which 17HD patients have lower relative excretion of C(19) steroids should reflect the absence of 11beta-hydroxyandrostenedione metabolites. Our results showed almost all of 11-oxo-etiocholanolone and 11beta-hydroxyetiocholanolone were cortisol metabolites, but in contrast the excretion of 11beta-hydroxyandrosterone was less than 10% that of normal individuals, indicating that in excess of 90% must be a metabolite of 11beta-hydroxyandrostenedione.
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The glucocorticoid contribution to urine 11β-OHAn is very low in healthy individuals, with the majority originating from the metabolism of the androgen 11OHA4.
“As a result, the glucocorticoid contribution to urine 11β-OHAn is very low in healthy individuals, with the majority originating from the metabolism of the androgen 11OHA4 (Section 4.3.2) [258].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [258]
Although 11β-OHAn can also derive from cortisol metabolism, this only contributes to approximately 5-10% of the measured levels, with at least 90% originating from 11OHA4.
“It should be noted that although 11β-OHAn can also derive from cortisol metabolism (Section 4.2.2), this only contributes to approximately 5–10% of the measured levels, with at least 90% originating from 11OHA4 [258].”
From Human steroid biosynthesis, metabolism and excretion are differentially reflected by serum and urine steroid metabolomes: a comprehensive review (2019) · cites this paper as [258]
Urinary 11-oxygenated ETIO is predominantly a product of glucocorticoid metabolism, while urinary 11-oxygenated AST results mainly from 11-oxygenated androgens.
“While urinary 11-oxygenated ETIO is predominantly a product of glucocorticoid metabolism, urinary 11-oxygenated AST results mainly from 11-oxygenated androgens (Jones et al., 2016, Shackleton et al., 2008).”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Shackleton et al., 2008
Urinary 11-oxygenated AST and 11-oxygenated ETIO originate from androgen and glucocorticoid metabolism, however in different ratios.
“Urinary 11-oxygenated AST and 11-oxygenated ETIO originate from androgen and glucocorticoid metabolism, however in different ratios.”
From Intracrine androgen biosynthesis, metabolism and action revisited (2018) · cites this paper as Shackleton et al., 2008
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Schiffer, L., Barnard, L., Baranowski, E. S., Gilligan, L. C., Taylor, A. E., Arlt, W., Shackleton, C. H. L., & Storbeck, K.-H. (2019) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2019.105439 · Cited by 450 · see citing works
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Self-citation
- Authors
- Shackleton, C. H. L., Neres, M. S., Hughes, B. A., Stewart, P. M., & Kater, C. E.
- Affiliations
- University of Birmingham (GB)
- Universidade Federal de São Paulo (BR)
- Corresponding author
- Shackleton, Cedric H.L.
- Venue
- Steroids
- Publisher
- Elsevier BV
- Published
- 2008-07
- Volume
- 73
- Issue
- 6
- Pages
- 652-656
- ISSN
- 0039-128X (ISSN-L)
- OpenAlex
- W2030667202
- Cited by
- 39
- References
- 22
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 1 · 2023: 1 · 2021: 4 · 2020: 4 · 2019: 5 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 0.82
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Steroids (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- UNIFESP Institutional Repository (Universidade Federal de São Paulo) (submittedVersion)
- Funders
- Wellcome Trust (066357)
- Universidade de São Paulo
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
- Keywords
- CYP17, cortisol metabolism, side-chain cleavage, 11β-hydroxyandrostenedione, 17-hydroxylase deficiency, adrenal steroidogenesis, urinary steroid excretion
- MeSH terms
- Adrenal Hyperplasia, Congenital, Humans, Hydrocortisone, Hydrolysis, Steroid 17-alpha-Hydroxylase
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