The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism

Slominski, Andrzej; Semak, Igor; Zjawiony, Jordan; Wortsman, Jacobo; Li, Wei; Szczesniewski, Andre; Tuckey, Robert C.

doi:10.1111/j.1742-4658.2005.04819.x

Cited by 155Vitamin D Research StudiesSteroid Chemistry and BiochemistryPharmacogenetics and Drug Metabolism

The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism

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Slominski, Andrzej, Semak, Igor, Zjawiony, Jordan, Wortsman, Jacobo, Li, Wei, Szczesniewski, Andre, Tuckey, Robert C.·2005·The FEBS Journal

DOI 10.1111/j.1742-4658.2005.04819.xPMC PMC2234577

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Abstract

We show that cytochrome P450scc (CYP11A1) in either a reconstituted system or in isolated adrenal mitochondria can metabolize vitamin D3. The major products of the reaction with reconstituted enzyme were 20‐hydroxycholecalciferol and 20,22‐dihydroxycholecalciferol, with yields of 16 and 4%, respectively, of the original vitamin D3 substrate. Trihydroxycholecalciferol was a minor product, likely arising from further metabolism of dihydroxycholecalciferol. Based on NMR analysis and known properties of P450scc we propose that hydroxylation of vitamin D3 by P450scc occurs sequentially and stereospecifically with initial formation of 20(S)‐hydroxyvitamin D3. P450scc did not metabolize 25‐hydroxyvitamin D3, indicating that modification of C25 protected it against P450scc action. Adrenal mitochondria also metabolized vitamin D3 yielding 10 hydroxyderivatives, with UV spectra typical of vitamin D triene chromophores. Aminogluthimide inhibition showed that the three major metabolites, but not the others, resulted from P450scc action. It therefore appears that non‐P450scc enzymes present in the adrenal cortex to some extent contribute to metabolism of vitamin D3. We conclude that purified P450scc in a reconstituted system or P450scc in adrenal mitochondria can add one hydroxyl group to vitamin D3 with subsequent hydroxylation being observed for reconstituted enzyme but not for adrenal mitochondria. Additional vitamin D3 metabolites arise from the action of other enzymes in adrenal mitochondria. These findings appear to define novel metabolic pathways involving vitamin D3 that remain to be characterized.

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CYP11A1 hydroxylates the vitamin D3 side chain at carbons 17, 20, 22, and 23, yielding at least ten metabolites.
“CYP11A1 can hydroxylate the side chain of vitamin D3 at carbons 17, 20, 22 and 23 to produce at least 10 metabolites”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [46]
The main products of CYP11A1 action on vitamin D3 include 20(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 17,20(OH)2D3, and 17,20,23(OH)3D3.
“with 20(OH)D3, 20,23(OH)2D3, 20,22(OH)2D3, 17,20(OH)2D3 and 17,20,23(OH)3D3 being the main products”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [46]
CYP11A1 does not act on 25(OH)D3.
“However, CYP11A1 does not act on 25(OH)D3.”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [46]
CYP11A1 only hydroxylates the vitamin D3 side chain and cannot cleave it.
“CYP11A1 only catalyses hydroxylation of the side chain of vitamin D3 and cannot cleave it”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [46]
The favored hydroxylation site on vitamin D3 by CYP11A1 is C20 rather than C22, with 20(OH)D3 as the major metabolite.
“The favored site of hydroxylation is at C20 rather than C22, with 20(OH)D3 being the major metabolite”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [46]

CYP11A1 does not hydroxylate 25(OH)D3, so it does not compete with CYP27B1 for activation of 25-hydroxyvitamin D3.
“It is important to note that CYP11A1 does not hydroxylate 25(OH)D3 [46] so that the CYP11A1 does not compete with CYP27B1 for activation of 25-hydroxyvitamin D3.”
From The role of CYP11A1 in the production of vitamin D metabolites and their role in the regulation of epidermal functions (2014) · cites this paper as [46]
7DHC, ergosterol, lumisterol 3, and vitamins D3 and D2 serve as substrates for CYP11A1.
“Studies, initially with purified enzyme, reveal that 7-dehydrocholesterol (7DHC), ergosterol, lumisterol 3, and vitamins D3 and D2 also serve as substrates for CYP11A1, with 7DHC being better and vitamins D3 and D2 being poorer substrates than cholesterol.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [24]
The activity of CYP11A1 is affected by substrate structure: sterols with steroidal or Δ7-steroidal structures undergo side chain cleavage following hydroxylations at C22 and C20, whereas vitamin D metabolism involves sequential hydroxylations starting at C20 without cleavage.
“The activity of CYP11A1 is affected by the structure of the substrate with sterols having steroidal or Δ7-steroidal structures undergoing side chain cleavage following hydroxylations at C22 and C20. In contrast, metabolism of vitamin D involves sequential hydroxylations that start at C20 but do not lead to cleavage.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [24]
Catalytic activity of CYP11A1 on non-traditional substrates such as vitamin D and ergosterol does not result in side chain cleavage, but involves sequential hydroxylations of the side chain including at C17.
“Importantly, catalytic activity on non-traditional substrates such as vitamin D and ergosterol does not result in side chain cleavage, but involves sequential hydroxylations of the side chain including at C17 [[10,24–30], and see below].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [24]
CYP11A1 does not metabolize 25-hydroxyvitamin D3, indicating that hydroxylation at C25 protects the secosteroid against side chain hydroxylation by CYP11A1, and therefore this enzyme does not compete with CYP27B1 for activation of 25(OH)D3.
“Importantly, CYP11A1 does not metabolize 25-hydroxyvitamin D3 indicating that hydroxylation at C25 protects the secosteroid against hydroxylation of the side chain by CYP11A1 [24] and therefore, that this enzyme does not compete with CYP27B1 for activation of 25(OH)D3 [103].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [24]
CYP11A1 favors initial hydroxylation of vitamin D3 at C20 over C22 (or C23), with 20(OH)D3 as the first and major metabolite.
“Subsequent enzymatic analysis revealed that CYP11A1 favors initial hydroxylation of D3 at C20 over C22 (or C23), with 20(OH)D3 representing the first and major metabolite.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [24]
C23 and C17 are also major hydroxylation sites for CYP11A1 acting on vitamin D3, and no side-chain cleavage occurs.
“We extended these observations showing that C23 and C17 were also major sites of hydroxylation, but that no cleavage of the side chain occurred [119–121], leading to the pathway described in Fig. 4.”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [119]
The two main mono-hydroxylated D3 species produced by CYP11A1 are 20S(OH)D3 and 22(OH)D3.
“The two main mono-hydroxylated species produced from D3 are 20S(OH)D3 and 22(OH)D3 [118–122].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [119]
CYP11A1 can hydroxylate the side chains of vitamin D2 and D3.
“CYP11A1, the enzyme that catalyzes the first step in steroid hormone synthesis by hydroxylating then cleaving the side chain of cholesterol to produce pregnenolone, can also hydroxylate the side chains of vitamin D2 and D3”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [119]

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Authors: Slominski, A., Semak, I., Zjawiony, J., Wortsman, J., Li, W., Szczesniewski, A., & Tuckey, R. C.
Affiliations: University of Tennessee Health Science Center (US)
Belarusian State University (BY)
University of Mississippi (US)
SIU Medicine (US)
Agilent Technologies (United States) (US)
The University of Western Australia (AU)
ORCID: Slominski, Andrzej
Semak, Igor
Zjawiony, Jordan
Tuckey, Robert C.
Venue: The FEBS Journal
Publisher: Wiley
Published: 2005-08
Volume: 272
Issue: 16
Pages: 4080-4090
ISSN: 1742-464X (ISSN-L)
1742-4658
DOI: 10.1111/j.1742-4658.2005.04819.x
PMC: PMC2234577
OpenAlex: W1887054657
Cited by: 155
References: 48
Citations by year: 2025: 4 · 2024: 8 · 2023: 8 · 2022: 10 · 2021: 9 · 2020: 12 · 2019: 6 · 2018: 8 · 2017: 6 · 2016: 15 · 2015: 14 · 2014: 12 · 2013: 5 · 2012: 10
FWCI: 2.23
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3 d)
Locations: FEBS Journal (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
UWA Profiles and Research Repository (UWA) (submittedVersion)
Funders: National Institutes of Health
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR 047079, R01AR047079)
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: vitamin D3 metabolism, cytochrome P450scc, CYP11A1, adrenal mitochondria, hydroxylation, stereospecificity, 25-hydroxyvitamin D3, adrenal cortex
MeSH terms: Adrenal Glands, Animals, Cattle, Cholecalciferol, Cholesterol Side-Chain Cleavage Enzyme, Chromatography, High Pressure Liquid, Chromatography, Thin Layer, Male, Mitochondria, Mass Spectrometry, Rats, Wistar, Nuclear Magnetic Resonance, Biomolecular, Rats

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The cytochrome P450scc system opens an alternate pathway of vitamin D3 metabolism

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