Production of 22-hydroxy metabolites of vitamin D3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells
Open accessAbstract
Cytochrome P450scc (CYP11A1) can hydroxylate vitamin D(3), producing 20S-hydroxyvitamin D(3) [20(OH)D(3)] and 20S,23-dihydroxyvitamin D(3) [20,23(OH)(2)D(3)] as the major metabolites. These are biologically active, acting as partial vitamin D receptor (VDR) agonists. Minor products include 17-hydroxyvitamin D(3), 17,20-dihydroxyvitamin D(3), and 17,20,23-trihydroxyvitamin D(3). In the current study, we have further analyzed the reaction products from cytochrome P450scc (P450scc) action on vitamin D(3) and have identified two 22-hydroxy derivatives as products, 22-hydroxyvitamin D(3) [22(OH)D(3)] and 20S,22-dihydroxyvitamin D(3) [20,22(OH)(2)D(3)]. The structures of both of these derivatives were determined by NMR. P450scc could convert purified 22(OH)D(3) to 20,22(OH)(2)D(3). The 20,22(OH)(2)D(3) could also be produced from 20(OH)D(3) and was metabolized to a trihydroxyvitamin D(3) product. We compared the biological activities of these new derivatives with those of 20(OH)D(3), 20,23(OH)(2)D(3), and 1α,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)]. 1,25(OH)(2)D(3), 20(OH)D(3), 22(OH)D(3), 20,23(OH)(2)D(3), and 20,22(OH)(2)D(3) significantly inhibited keratinocyte proliferation in a dose-dependent manner. The strongest inducers of involucrin expression (a marker of keratinocyte differentiation) were 20,23(OH)(2)D(3), 20,22(OH)(2)D(3), 20(OH)D(3), and 1,25(OH)(2)D(3), with 22(OH)D(3) having a heterogeneous effect. Little or no stimulation of CYP24 mRNA expression was observed for all the analogs tested except for 1,25(OH)(2)D(3). All the compounds stimulated VDR translocation from the cytoplasm to the nucleus with 22(OH)D(3) and 20,22(OH)(2)D(3) having less effect than 1,25(OH)(2)D(3) and 20(OH)D(3). Thus, we have identified 22(OH)D(3) and 20,22(OH)(2)D(3) as products of CYP11A1 action on vitamin D(3) and shown that, like 20(OH)D(3) and 20,23(OH)(2)D(3), they are active on keratinocytes via the VDR, however, showing a degree of phenotypic heterogeneity in comparison with other P450scc-derived hydroxy metabolites of vitamin D(3).
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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 [48]
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 [48]
22(OH)D3 and 20,22(OH)2D3, as well as secosteroids with a short or no side chain, have antiproliferative and prodifferentiation effects but lower potency than 20(OH)D3 and 20,23(OH)2D3.
“22(OH)D3 and 20,22(OH)2D3, as well as secosteroids with a short or no side chain, showed antiproliferative and prodifferentiation effects, however, with lower potency than 20(OH)D3 and 20,23(OH)2D3.”
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 [48]
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 [48]
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 [48]
22(OH)2D3 and 20,22(OH)2D3 show antiproliferative and prodifferentiation effects but are less potent than 20(OH)D3 and 20,23(OH)2D3.
“The CYP11A1-derived secosteroids with a 22-hydroxyl group, 22(OH)2D3 and 20,22(OH)2D3, also show both antiproliferative and prodifferentiation effects, but are less potent than 20(OH)D3 and 20,23(OH)2D3”
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 [48]
The phenotypic effects of these secosteroids correlate with ligand-induced translocation of the vitamin D receptor to the nucleus.
“Also, the phenotypic effects correlate well with ligand-induced translocation of the VDR to the nucleus [48,59,73,78].”
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 [48]
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 [26]
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 [26]
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 [26]
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 [121]
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 [121]
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 [121]
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Non-Musculoskeletal Benefits of Vitamin D beyond the Musculoskeletal System
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Vitamin D derivatives enhance cytotoxic effects of H2O2 or cisplatin on human keratinocytes
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Self-citationLumisterol is metabolized by CYP11A1: discovery of a new pathway
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Self-citationHydroxylation of CYP11A1-derived products of vitamin D3 metabolism by human and mouse CYP27B1
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Self-citationDetection of 7-Dehydrocholesterol and Vitamin D3 Derivatives in Honey
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Self-citationHuman cytochrome P450scc (CYP11A1) catalyzes epoxide formation with ergosterol
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Self-citationNeurosteroidogenic enzymes: CYP11A1 in the central nervous system
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Design, Synthesis, and Biological Action of 20R-Hydroxyvitamin D3
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Self-citationAntifibrogenic Activities of CYP11A1-derived Vitamin D3-hydroxyderivatives Are Dependent on RORγ
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Self-citationExpression of human CYP27B1 in Escherichia coli and characterization in phospholipid vesicles
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Self-citationNovel DNA Aptamer for CYP24A1 Inhibition with Enhanced Antiproliferative Activity in Cancer Cells
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Self-citationHydroxylation of 20-hydroxyvitamin D3 by human CYP3A4
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Self-citationUpdates on Mechanisms of Cytochrome P450 Catalysis of Complex Steroid Oxidations
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“Human AdR (25), P450 11B1, and P450 11B2 were expressed in C41(DE3) with pGro7 and purified as described (26).”
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Genetic Disorders Of Vitamin D Synthesis and Action
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- Authors
- Tuckey, R. C., Li, W., Shehabi, H. Z., Janjetovic, Z., Nguyen, M. N., Kim, T.-K., Chen, J., Howell, D. E., Benson, H. A. E., Sweatman, T., Baldisseri, D. M., & Slominski, A.
- Affiliations
- The University of Western Australia (AU)
- University of Tennessee Health Science Center (US)
- ORCID
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 39
- Issue
- 9
- Pages
- 1577-1588
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC3164270
- OpenAlex
- W2127898028
- Cited by
- 88
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 7 · 2022: 5 · 2021: 11 · 2020: 5 · 2019: 1 · 2018: 7 · 2017: 6 · 2016: 10 · 2015: 9 · 2014: 9 · 2013: 4 · 2012: 8
- FWCI
- 5.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (University of Western Australia) (submittedVersion)
- eSpace (Curtin University) (submittedVersion)
- Funders
- National Institutes of Health
- Health Science Center, University of Tennessee
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR052190)
- 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 metabolites, cytochrome P450scc, CYP11A1, vitamin D hydroxylation, keratinocyte proliferation, 1,25-dihydroxyvitamin D3
- MeSH terms
- Calcifediol, Cells, Cultured, Cholecalciferol, Cholesterol Side-Chain Cleavage Enzyme, Dihydroxycholecalciferols, Humans, Hydroxycholecalciferols, Magnetic Resonance Spectroscopy, Protein Precursors, Skin, Steroid Hydroxylases, 25-Hydroxyvitamin D3 1-alpha-Hydroxylase, Keratinocytes, Receptors, Calcitriol, Protein Transport, Cell Proliferation, Vitamin D3 24-Hydroxylase
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