Lumisterol is metabolized by CYP11A1: discovery of a new pathway
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Lumisterol3 (L3) is produced by photochemical transformation of 7-dehydrocholesterol (7-DHC) during exposure to high doses of ultraviolet B radiation. It has been assumed that L3 is biologically inactive and is not metabolized in the body. However, some synthetic derivatives of L3 display biological activity. The aim of this study was to test the ability of CYP11A1 to metabolize L3. Incubation of L3 with bovine or human CYP11A1 resulted in the formation of three major and a number of minor products. The catalytic efficiency of bovine CYP11A1 for metabolism of L3 dissolved in 2-hydroxypropyl-β-cyclodextrin was approximately 20% of that reported for vitamin D3 and cholesterol. The structures of the three major products were identified as 24-hydroxy-L3, 22-hydroxy-L3 and 20,22-dihydroxy-L3 by NMR. 22-Hydroxy-L3 was further metabolized by bovine CYP11A1 to 20,22-dihydroxy-L3. Both 22-hydroxy-L3 and 20,22-dihydroxy-L3 gave rise to a minor metabolite identified from authentic standard and mass spectrometry as pregnalumisterol (pL) (product of C20-C22 side chain cleavage of L3) and two trihydroxy-L3 products. The capability of tissues expressing CYP11A1 to metabolize L3 was demonstrated using pig adrenal fragments where 20,22-dihydroxy-L3, 22-hydroxy-L3, 24-hydroxy-L3 and pL were detected by LC/MS. Thus, we have established that L3 is metabolized by CYP11A1 to 22- and 24-hydroxy-L3 and 20,22-dihydroxy-L3 as major products, as well as to pL and other minor products. The previously reported biological activity of pL and the presence of CYP11A1 in skin suggest that this pathway may serve to produce biologically active products from L3, emphasizing a novel role of CYP11A1 in sterol metabolism.
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CYP11A1 initiates lumisterol (L3) metabolism through sequential hydroxylation of its side chain.
“CYP11A1 also initiates lumisterol (L3) metabolism through sequential hydroxylation of its side chain [23,[43], [44], [45], [46]].”
CYP11A1-initiated lumisterol metabolism leads to cutaneous production of several hydroxy forms of L3, including 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3.
“This leads to the cutaneous production of several hydroxy forms of L3, including 20(OH)L3, 22(OH)L3, 20,22(OH)2L3, and 24(OH)L3 [23,[43], [44], [45]].”
CYP11A1 initially hydroxylates lumisterol 3 at C22 or C24; 22-hydroxylumisterol is then hydroxylated at C20 producing 20,22-dihydroxylumisterol 3, and some undergoes cleavage to pregnalumisterol.
“CYP11A1 initially hydroxylates lumisterol 3 at C22 or C24. 22-Hydroxylumisterol is then hydroxylated at C20 producing 20,22-dihydroxylumisterol 3 and some of this undergoes hydroxylation at other sites while some undergoes cleavage to pregnalumisterol [31].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [31]
Purified bovine and human CYP11A1 metabolize lumisterol 3 with a catalytic efficiency approximately 20% of that for cholesterol.
“Recently, it has been reported that purified bovine and human CYP11A1 can metabolize lumisterol 3 with a catalytic efficiency approximately 20% of that for cholesterol [31].”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [31]
CYP11A1 can hydroxylate L3, with major products 20-(OH)L3, 22-(OH)L3, 24(OH)L3 and 20,22-(OH)2L3, plus small pregnalumisterol.
“Major products were identified as 20-(OH)L3, 22-(OH)L3, 24(OH)L3 and 20,22-(OH)2L3, with a small amount of the C20-C22 cleavage product, pregnalumisterol (pL) [184, 225].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [184]
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- Authors
- Tuckey, R. C., Slominski, A. T., Cheng, C. Y. S., Chen, J., Kim, T.-K., Xiao, M., & Li, W.
- Affiliations
- The University of Western Australia (AU)
- University of Tennessee Health Science Center (US)
- Corresponding author
- Tuckey, Robert C.
- Venue
- The International Journal of Biochemistry & Cell Biology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 55
- Pages
- 24-34
- ISSN
- 1357-2725 (ISSN-L)
- PMC
- PMC4252613
- OpenAlex
- W1985579241
- Cited by
- 43
- References
- 42
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 4 · 2023: 5 · 2022: 5 · 2021: 8 · 2020: 5 · 2019: 1 · 2018: 4 · 2017: 4 · 2016: 1 · 2015: 2 · 2014: 2
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The International Journal of Biochemistry & Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UWA Profiles and Research Repository (University of Western Australia) (submittedVersion)
- Funders
- The University of Western Australia
- NIH (2R01AR052190-A6, 1R01AR056666-01A2, 1R21AR063242-01A1, 1S10OD010678-01, 1S10RR026377-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Steroid Chemistry and Biochemistry
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- lumisterol, CYP11A1, sterol metabolism, 7-dehydrocholesterol, UV-B radiation, side-chain cleavage, adrenal gland
- MeSH terms
- Adrenal Glands, Animals, Cattle, Cholesterol Side-Chain Cleavage Enzyme, Chromatography, High Pressure Liquid, Ergosterol, Female, Humans, Models, Chemical, Magnetic Resonance Spectroscopy, Swine, Molecular Structure, Spectrometry, Mass, Electrospray Ionization, Metabolic Networks and Pathways
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