Metabolism of vitamin D2 to 17, 20,24-trihydroxyvitamin D2 by cytochrome p450scc (CYP11A1)
Open accessAbstract
As well as catalyzing the conversion of cholesterol to pregnenolone for steroid synthesis, cytochrome P450scc (P450scc) can also metabolize vitamins D2 (D2) and D3 (D3). Two products of D2 metabolism by P450scc, 20-hydroxyvitamin D2 and 17,20-dihydroxyvitamin D2, have been identified and shown to exert biological activity on cultured keratinocytes. The aim of this study was to fully characterize the metabolism of D2 by P450scc, including identifying additional products and determining the kinetics of D2 metabolism. Two new products were isolated by reverse-phase high-performance liquid chromatography: a dihydroxy metabolite with a hydroxyl group at C20 plus another unidentified position, and a trihydroxy metabolite identified by NMR as 17,20,24-trihydroxyvitamin D2. Kinetics of D2 metabolism was determined with substrate solubilized by 2-hydroxypropyl-beta-cyclodextrin or incorporated into phospholipid vesicles. In 2-hydroxypropyl-beta-cyclodextrin, D2 was hydroxylated at C20 with a k(cat)/K(m) 5-fold lower than that for cholesterol metabolism. 20-Hydroxyvitamin D2 was hydroxylated with a similar k(cat)/K(m) to D2, whereas 17,20-dihydroxyvitamin D2 was hydroxylated with a lower k(cat)/K(m) than that for D2 in 2-hydroxypropyl-beta-cyclodextrin. In vesicles, D2 displayed a high K(m) relative to that for cholesterol, but hydroxylation resulted in products that could be further hydroxylated with relatively low K(m) values. We conclude that P450scc catalyzes three sequential hydroxylations of D2 producing 20-hydroxyvitamin D2, 17,20-dihydroxyvitamin D2, and 17,20,24-trihydroxyvitamin D2, which dissociate from the active site of P450scc and accumulate in the reaction mixture. D2 metabolism occurs with lower efficiency (k(cat)/K(m)) than that observed for both cholesterol and D3 metabolism by P450scc.
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The major products of vitamin D2 metabolism by CYP11A1 are 20(OH)D2 and 17,20(OH)2D2, with lesser production of 17,20,24(OH)3D2 and an unidentified dihydroxyvitamin D2 metabolite.
“The major products were identified as 20(OH)D2 and 17,20(OH)2D2, with lesser production of 17,20,24(OH)3D2 and another unidentified dihydroxyvitamin D2 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 [57]
Purified CYP11A1 hydroxylates the vitamin D2 side chain without cleavage, with the preferred initial site at C20.
“purified CYP11A1 can also hydroxylate the side chain of vitamin D2 without its cleavage, with the preferred site for the initial hydroxylation being at C20”
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 [57]
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 [28]
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 [28]
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 [28]
Recombinant human CYP11A1 shows a similar sequence of reactions for vitamin D2, with 20(OH)D2 as the major product and lower production of 17,20(OH)2D2 and 17,20,24(OH)3D2 and another unidentified D2 metabolite.
“A similar sequence of reactions was seen for recombinant human CYP11A1 [9]. The major product was 20(OH)D2 with lower production of 17,20(OH)2D2 and 17,20,24 (OH)3D2 and another unidentified D2 metabolite [28,29].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [28]
Purified bovine CYP11A1 and adrenal mitochondria hydroxylate the side chain of vitamin D2 without cleavage, starting with hydroxylation at C20: D2→20(OH)D2→17,20(OH)2D2→17,20,24(OH)2D2.
“Purified bovine CYP11A1 and adrenal mitochondria hydroxylate the side chain of vitamin D2 without its cleavage, which starts with hydroxylation at C20: D2→20(OH)D2→17,20(OH)2D2→17,20,24(OH)2D2 [28,29]”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [28]
Initial CYP11A1 hydroxylation of vitamin D2 is at C20, producing 20S(OH)D2 as the major product, with 17,20(OH)2D2 and 17,20,24(OH)3D2 as other products.
“The initial hydroxylation is at C20 producing 20S(OH)D2 as the major product, with other products being 17,20(OH)2D2 and 17,20,24(OH)3D2 [180, 186, 187].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [186]
CYP11A1 acts on vitamin D2 as well as D3, producing biologically active products.
“CYP11A1 can act on vitamin D2 as well as D3, also producing biologically active products.”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [186]
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- Authors
- Nguyen, M. N., Slominski, A., Li, W., Ng, Y. R., & Tuckey, R. C.
- Affiliations
- The University of Western Australia (AU)
- University of Tennessee Health Science Center (US)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 2009-04
- Volume
- 37
- Issue
- 4
- Pages
- 761-767
- ISSN
- 0090-9556 (ISSN-L)
- PMC
- PMC2659330
- OpenAlex
- W2125720142
- Cited by
- 48
- References
- 31
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2020: 3 · 2018: 3 · 2017: 4 · 2016: 2 · 2015: 8 · 2014: 6 · 2013: 4 · 2012: 6
- FWCI
- 1.66
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UWA Profiles and Research Repository (UWA) (submittedVersion)
- Funders
- 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
- cytochrome P450scc, CYP11A1, substrate solubilization, hydroxypropyl-β-cyclodextrin, phospholipid vesicles, steroidogenic enzymes
- MeSH terms
- Cholesterol Side-Chain Cleavage Enzyme, Chromatography, High Pressure Liquid, Ergocalciferols, Kinetics, Magnetic Resonance Spectroscopy, 25-Hydroxyvitamin D 2
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