Rat CYP24A1 acts on 20-hydroxyvitamin D3 producing hydroxylated products with increased biological activity
Open accessAbstract
20-Hydroxyvitamin D(3) (20(OH)D(3)), the major product of CYP11A1 action on vitamin D(3), is biologically active and is produced in vivo. As well as potentially having important physiological actions, it is of interest as a therapeutic agent due to its lack of calcemic activity. In the current study we have examined the ability of CYP24A1, the enzyme that inactivates 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), to metabolize 20(OH)D(3). Rat CYP24A1 was expressed in Escherichia coli, purified by Ni-affinity chromatography and assayed with substrates incorporated into phospholipid vesicles which served as a model of the inner mitochondrial membrane. In this system CYP24A1 metabolized 1,25(OH)(2)D(3) with a catalytic efficiency 1.4-fold higher than that seen for 25-hydroxyvitamin D(3) (25(OH)D(3)). CYP24A1 hydroxylated 20(OH)D(3) to several dihydroxy-derivatives with the major two identified by NMR as 20,24-dihydroxyvitamin D(3) (20,24(OH)(2)D(3)) and 20,25-dihydroxyvitamin D(3) (20,25(OH)(2)D(3)). The catalytic efficiency of CYP24A1 for 20(OH)D(3) metabolism was more than 10-fold lower than for either 25(OH)D(3) or 1,25(OH)(2)D(3) and no secondary metabolites were produced. The two major products, 20,24(OH)(2)D(3) and 20,25(OH)(2)D(3), caused significantly greater inhibition of colony formation by SKMEL-188 melanoma cells than either 1,25(OH)(2)D(3) or the parent 20(OH)D(3), showing that CYP24A1 plays an activating, rather than an inactivating role on 20(OH)D(3).
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Rat CYP24A1 hydroxylates 20(OH)D3 at C24, producing 20,24(OH)2D3 as the major product, and at C25, producing 20,25(OH)2D3.
“Rat CYP24A1 was observed to hydroxylate 20(OH)D3 at C24, as it does with 1,25(OH)2D3, producing 20,24(OH)2D3 as the major product. It was also found to hydroxylate 20(OH)D3 at C25 producing 20,25(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 [56]
CYP27A1 and CYP24A1 can metabolize 20(OH)D3.
“both CYP27A1 which acts as a 25-hydroxylase on vitamin D3 and a 26-hydroxylase on cholesterol, and CYP24A1 which inactivates 1,25(OH)2D3, can also metabolize 20(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 [56]
In the case of CYP24A1, the increased potency of its 20(OH)D3 products indicates that the enzyme plays an activating role, rather than the inactivation seen with 1,25(OH)2D3.
“In the case of CYP24A1, the increased potency of the products indicates that the enzyme plays an activating role, rather than the inactivation seen with 1,25(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 [56]
The in vitro results challenge the dogma that CYP24A1 is always an inactivating enzyme.
“but the in vitro results challenge the dogma that CYP24A1 is always an inactivating enzyme”
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 [56]
20,24(OH)2D3, 20,25(OH)2D3, and 20,26(OH)2D3 display stronger inhibition of colony formation by SKMEL-188 melanoma cells than the parent 20(OH)D3.
“Initial tests performed on 20,24(OH)2D3, 20,25(OH)2D3 and 20,26(OH)2D3, products of 20(OH)D3 hydroxylation by CYP24A1 [56] and/or CYP27A1 [55] (Fig. 1), revealed that they display stronger inhibition of colony formation by SKMEL-188 melanoma cells than the parent 20(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 [56]
There is sufficient experimental data to justify further preclinical testing of these novel secosteroids in melanoma.
“In the case of melanoma, there is already sufficient experimental data to justify further preclinical testing of these novel secosteroids [53,56,59,63–65,71,73,77,78,80,81,91,92].”
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 [56]
For 20S(OH)D3, CYP24A1 may activate by C24 or C25 hydroxylation, giving products more potent than 20S(OH)D3 and 1α,25(OH)2D3 for inhibiting melanoma colony formation.
“For 20S(OH)D3, CYP24A1 may play an activating role since hydroxylation at C24 or C25 by this enzyme gives products more potent than 20S(OH)D3 (and 1α,25(OH)2D3) for the inhibition of colony formation by melanoma cells [208].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [208]
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References 56 · Cited by 44
- Authors
- Tieu, E. W., Tang, E. K. Y., Chen, J., Li, W., Nguyen, M. N., Janjetovic, Z., Slominski, A., & Tuckey, R. C.
- Affiliations
- The University of Western Australia (AU)
- University of Tennessee Health Science Center (US)
- Corresponding author
- Tuckey, Robert C.
- Venue
- Biochemical Pharmacology
- Publisher
- Elsevier BV
- Published
- 2012-12
- Volume
- 84
- Issue
- 12
- Pages
- 1696-1704
- ISSN
- 0006-2952 (ISSN-L)
- PMC
- PMC3501553
- OpenAlex
- W2071882832
- Cited by
- 44
- References
- 56
- Citations by year
- 2025: 2 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 5 · 2017: 4 · 2016: 5 · 2015: 6 · 2014: 5 · 2013: 3
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biochemical Pharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (University of Western Australia) (submittedVersion)
- Funders
- NIH (R01AR052190)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Keywords
- CYP24A1, vitamin D metabolism, 1,25-dihydroxyvitamin D3, 25-hydroxyvitamin D3, antiproliferative activity, phospholipid vesicles
- MeSH terms
- Animals, Calcifediol, Hydroxylation, Magnetic Resonance Spectroscopy, Steroid Hydroxylases, Spectrometry, Mass, Electrospray Ionization, Rats, Vitamin D3 24-Hydroxylase
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