Biological Effects of CYP11A1-Derived Vitamin D and Lumisterol Metabolites in the Skin

Overview

Journal J Invest Dermatol

Publisher Elsevier

Specialty Dermatology

Date 2024 Jul 13

PMID 39001720

Authors

Andrzej T Slominski

Tae-Kang Kim

Zorica Janjetovic

Radomir M Slominski

Wei Li

Anton M Jetten

Arup K Indra

Rebecca S Mason

Robert C Tuckey

Affiliations

Soon will be listed here.

Abstract

Novel pathways of vitamin D3, lumisterol 3 (L3), and tachysterol 3 (T3) activation have been discovered, initiated by CYP11A1 and/or CYP27A1 in the case of L3 and T3. The resulting hydroxymetabolites enhance protection of skin against DNA damage and oxidative stress; stimulate keratinocyte differentiation; exert anti-inflammatory, antifibrogenic, and anticancer activities; and inhibit cell proliferation in a structure-dependent manner. They act on nuclear receptors, including vitamin D receptor, aryl hydrocarbon receptor, LXRα/β, RAR-related orphan receptor α/γ, and peroxisome proliferator-activated receptor-γ, with selectivity defined by their core structure and distribution of hydroxyl groups. They can activate NRF2 and p53 and inhibit NF-κB, IL-17, Shh, and Wnt/β-catenin signaling. Thus, they protect skin integrity and physiology.

Citing Articles

The Protective Role of Ambient Ultraviolet Radiation Against Dementia: An Ecological Analysis of Global Data.

You W Health Sci Rep. 2025; 8(1):e70302.

PMID: 39777281 PMC: 11705424. DOI: 10.1002/hsr2.70302.

Slit1 Promotes Hypertrophic Scar Formation Through the TGF-β Signaling Pathway.

Cui H, Zheng Y, Cho Y, Ro Y, Jeon K, Joo S Medicina (Kaunas). 2025; 60(12.

PMID: 39768930 PMC: 11678377. DOI: 10.3390/medicina60122051.

Beneficial Effects of Epigallocatechin Gallate in Preventing Skin Photoaging: A Review.

Sun J, Jiang Y, Fu J, He L, Guo X, Ye H Molecules. 2024; 29(22).

PMID: 39598619 PMC: 11596539. DOI: 10.3390/molecules29225226.

Short-Term Effects of Escalating Doses of Cholecalciferol on FGF23 and 24,25(OH) Vitamin D Levels: A Preliminary Investigation.

Pepe J, Colangelo L, Pilotto R, De Martino V, Ferrara C, Scillitani A Nutrients. 2024; 16(21).

PMID: 39519433 PMC: 11547203. DOI: 10.3390/nu16213600.

The Role of Retinoic-Acid-Related Orphan Receptor (RORs) in Cellular Homeostasis.

Nematisouldaragh D, Kirshenbaum E, Uzonna M, Kirshenbaum L, Rabinovich-Nikitin I Int J Mol Sci. 2024; 25(21).

PMID: 39518891 PMC: 11545807. DOI: 10.3390/ijms252111340.

References

Piotrowska A, Wierzbicka J, Rybarczyk A, Tuckey R, Slominski A, Zmijewski M . Vitamin D and its low calcemic analogs modulate the anticancer properties of cisplatin and dacarbazine in the human melanoma A375 cell line. Int J Oncol. 2019; 54(4):1481-1495. PMC: 6411347. DOI: 10.3892/ijo.2019.4725. View

Slominski A, Janjetovic Z, Kim T, Wasilewski P, Rosas S, Hanna S . Novel non-calcemic secosteroids that are produced by human epidermal keratinocytes protect against solar radiation. J Steroid Biochem Mol Biol. 2015; 148:52-63. PMC: 4369786. DOI: 10.1016/j.jsbmb.2015.01.014. View

Brozyna A, Hoffman R, Slominski A . Relevance of Vitamin D in Melanoma Development, Progression and Therapy. Anticancer Res. 2020; 40(1):473-489. PMC: 6948187. DOI: 10.21873/anticanres.13976. View

Gupta R, Dixon K, Deo S, Holliday C, Slater M, Halliday G . Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products. J Invest Dermatol. 2006; 127(3):707-15. DOI: 10.1038/sj.jid.5700597. View

Slominski A, Brozyna A, Skobowiat C, Zmijewski M, Kim T, Janjetovic Z . On the role of classical and novel forms of vitamin D in melanoma progression and management. J Steroid Biochem Mol Biol. 2017; 177:159-170. PMC: 5748362. DOI: 10.1016/j.jsbmb.2017.06.013. View

Slominski A, Kim T, Janjetovic Z, Tuckey R, Bieniek R, Yue J . 20-Hydroxyvitamin D2 is a noncalcemic analog of vitamin D with potent antiproliferative and prodifferentiation activities in normal and malignant cells. Am J Physiol Cell Physiol. 2010; 300(3):C526-41. PMC: 3063966. DOI: 10.1152/ajpcell.00203.2010. View

Reichrath J, Saternus R, Vogt T . Endocrine actions of vitamin D in skin: Relevance for photocarcinogenesis of non-melanoma skin cancer, and beyond. Mol Cell Endocrinol. 2017; 453:96-102. DOI: 10.1016/j.mce.2017.05.001. View

Slominski A, Kim T, Hobrath J, Janjetovic Z, Oak A, Postlethwaite A . Characterization of a new pathway that activates lumisterol in vivo to biologically active hydroxylumisterols. Sci Rep. 2017; 7(1):11434. PMC: 5595834. DOI: 10.1038/s41598-017-10202-7. View

Tuckey R, Li W, Shehabi H, Janjetovic Z, Nguyen M, Kim T . Production of 22-hydroxy metabolites of vitamin d3 by cytochrome p450scc (CYP11A1) and analysis of their biological activities on skin cells. Drug Metab Dispos. 2011; 39(9):1577-88. PMC: 3164270. DOI: 10.1124/dmd.111.040071. View

10.

Brown Lobbins M, Slominski A, Hasty K, Zhang S, Miller D, Li W . Modulation by 17,20S(OH)pD of Fibrosis-Related Mediators in Dermal Fibroblast Lines from Healthy Donors and from Patients with Systemic Sclerosis. Int J Mol Sci. 2022; 23(1). PMC: 8745512. DOI: 10.3390/ijms23010367. View

11.

Muralidhar S, Filia A, Nsengimana J, Pozniak J, OShea S, Diaz J . Vitamin D-VDR Signaling Inhibits Wnt/β-Catenin-Mediated Melanoma Progression and Promotes Antitumor Immunity. Cancer Res. 2019; 79(23):5986-5998. DOI: 10.1158/0008-5472.CAN-18-3927. View

12.

Tang E, Li W, Janjetovic Z, Nguyen M, Wang Z, Slominski A . Purified mouse CYP27B1 can hydroxylate 20,23-dihydroxyvitamin D3, producing 1alpha,20,23-trihydroxyvitamin D3, which has altered biological activity. Drug Metab Dispos. 2010; 38(9):1553-9. PMC: 2939470. DOI: 10.1124/dmd.110.034389. View

13.

De Silva W, McCarthy B, Han J, Yang C, Holland A, Stern H . The Over-Irradiation Metabolite Derivative, 24-Hydroxylumister-ol, Reduces UV-Induced Damage in Skin. Metabolites. 2023; 13(7). PMC: 10383208. DOI: 10.3390/metabo13070775. View

14.

Wu D, Nealon G, Liu Y, Kim T, Slominski A, Tuckey R . Metabolism of Lumisterol by CYP27A1. J Steroid Biochem Mol Biol. 2023; 233:106370. DOI: 10.1016/j.jsbmb.2023.106370. View

15.

Li W, Chen J, Janjetovic Z, Kim T, Sweatman T, Lu Y . Chemical synthesis of 20S-hydroxyvitamin D3, which shows antiproliferative activity. Steroids. 2010; 75(12):926-35. PMC: 2937189. DOI: 10.1016/j.steroids.2010.05.021. View

16.

Slominski A, Zmijewski M, Zbytek B, Tobin D, Theoharides T, Rivier J . Key role of CRF in the skin stress response system. Endocr Rev. 2013; 34(6):827-84. PMC: 3857130. DOI: 10.1210/er.2012-1092. View

17.

Song Y, Slominski R, Qayyum S, Kim T, Janjetovic Z, Raman C . Molecular and structural basis of interactions of vitamin D3 hydroxyderivatives with aryl hydrocarbon receptor (AhR): An integrated experimental and computational study. Int J Biol Macromol. 2022; 209(Pt A):1111-1123. DOI: 10.1016/j.ijbiomac.2022.04.048. View

18.

Tait A, Hodge L, Allen W . Biosynthesis of 3 beta-hydroxy-5,7-pregnadien-20-one by the horse fetal gonad. FEBS Lett. 1983; 153(1):161-4. DOI: 10.1016/0014-5793(83)80139-2. View

19.

Postlethwaite A, Tuckey R, Kim T, Li W, Bhattacharya S, Myers L . 20-Hydroxyvitamin D3, a Secosteroid Produced in Humans, Is Anti-Inflammatory and Inhibits Murine Autoimmune Arthritis. Front Immunol. 2021; 12:678487. PMC: 8278399. DOI: 10.3389/fimmu.2021.678487. View

20.

Slominski A, Kim T, Li W, Postlethwaite A, Tieu E, Tang E . Detection of novel CYP11A1-derived secosteroids in the human epidermis and serum and pig adrenal gland. Sci Rep. 2015; 5:14875. PMC: 4597207. DOI: 10.1038/srep14875. View