Recent Advances in Vitamin D Biology: Something New under the Sun

Clinical Implications•Alternative pathways of vitamin D, lumisterol, and tachysterol activation were discovered.•Discovered secosteroidal hydroxyderivatives are biologically active in vitro and in vivo.•They can act on six nuclear receptors, alternatives to the vitamin D receptor.Robert C. TuckeyView Large Image Figure ViewerDownload Hi-res image Download (PPT) •Alternative pathways of vitamin D, lumisterol, and tachysterol activation were discovered.•Discovered secosteroidal hydroxyderivatives are biologically active in vitro and in vivo.•They can act on six nuclear receptors, alternatives to the vitamin D receptor. Enormous progress has been made over the last two decades in defining the biological roles of vitamin D. This progress is best illustrated in the newest edition of the comprehensive book on vitamin D to be available on October 1, 2023 (Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar). Although most chapters report linear progress in different fields of vitamin D biology, two chapters on “Photobiology of Vitamin D” and on “Alternative Pathways for Vitamin D Metabolism” review recent data that provide mechanistic explanations for the diverse and sometimes contradictory actions of vitamin D. They also emphasize that UVB-induced vitamin D signaling can be different from that observed after oral vitamin D delivery. These considerations are briefly discussed below. Vitamin D (vitamin D3 [D3] and vitamin D2) is a secosteroid present in living organisms on earth for at least 500 million years. D3 is a product of the photochemical transformation of 7-dehydrocholesterol (7DHC) after it absorbs UVB energy (optimal peak at 295 nm), resulting in the opening of its B ring to generate pre-D3. Pre-D3 is thermodynamically unstable and subsequently undergoes a thermal isomerization to D3 (reviewed in Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholarand Wacker and Holick, 2013Wacker M. Holick M.F. Sunlight and vitamin D: a global perspective for health.Dermatoendocrinol. 2013; 5: 51-108Crossref PubMed Scopus (703) Google Scholar). Exposure of pre-D3 to higher doses of UVB leads to the formation of lumisterol and tachysterol (Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar; Wacker and Holick, 2013Wacker M. Holick M.F. Sunlight and vitamin D: a global perspective for health.Dermatoendocrinol. 2013; 5: 51-108Crossref PubMed Scopus (703) Google Scholar). The presence of singlet oxygen, photosensitizers, and longer UVR wavelength can lead to their further isomerization and degradation with production of 5,6-trans-vitamin D3, suprasterols, isotachysterols, and cholesta-5,7,9(11)-triene (reviewed in Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar and Wacker and Holick, 2013Wacker M. Holick M.F. Sunlight and vitamin D: a global perspective for health.Dermatoendocrinol. 2013; 5: 51-108Crossref PubMed Scopus (703) Google Scholar). For decades, only D3 was considered a prohormone, with lumisterol, tachysterol, and other derivatives considered as only biologically inert compounds or products of degradation (Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar; Wacker and Holick, 2013Wacker M. Holick M.F. Sunlight and vitamin D: a global perspective for health.Dermatoendocrinol. 2013; 5: 51-108Crossref PubMed Scopus (703) Google Scholar). To be biologically active, D3 must be activated by sequential hydroxylations mediated by cytochrome P450 (CYP) enzymes (Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar; Slominski et al., 2021Slominski R.M. Raman C. Elmets C. Jetten A.M. Slominski A.T. Tuckey R.C. The significance of CYP11A1 expression in skin physiology and pathology.Mol Cell Endocrinol. 2021; 530111238Crossref PubMed Scopus (44) Google Scholar; Wacker and Holick, 2013Wacker M. Holick M.F. Sunlight and vitamin D: a global perspective for health.Dermatoendocrinol. 2013; 5: 51-108Crossref PubMed Scopus (703) Google Scholar). It is well-known that this involves hydroxylation at C25 by CYP2R1 or CYP27A1 producing 25-hydroxyvitamin D3 (25(OH)D3), followed by hydroxylation at C1α by CYP27B1 to produce biologically active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). This route of activation is defined as the canonical pathway. The 1,25(OH)2D3 is inactivated by CYP24A1 (Bouillon et al., 2019Bouillon R. Marcocci C. Carmeliet G. Bikle D. White J.H. Dawson-Hughes B. et al.Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions.Endocr Rev. 2019; 40: 1109-1151Crossref PubMed Scopus (523) Google Scholar; Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar). The alternative (noncanonical) pathways of vitamin D activation are initiated by the rate-limiting enzyme of steroidogenesis, CYP11A1. Its products can be modified by CYP27A1, CYP27B1, CYP24A1, CYP2R1, and/or CYP3A4, as described recently (Slominski et al., 2015Slominski A.T. Li W. Kim T.K. Semak I. Wang J. Zjawiony J.K. et al.Novel activities of CYP11A1 and their potential physiological significance.J Steroid Biochem Mol Biol. 2015; 151: 25-37Crossref PubMed Scopus (217) Google Scholar; Tuckey et al., 2019Tuckey R.C. Cheng C.Y.S. Slominski A.T. The serum vitamin D metabolome: what we know and what is still to discover.J Steroid Biochem Mol Biol. 2019; 186: 4-21Crossref PubMed Scopus (127) Google Scholar). Importantly, this noncanonical pathway requires unmodified D3 because CYP11A1 does not exert any catalytic activity on 25(OH)D3 (Slominski et al., 2015Slominski A.T. Li W. Kim T.K. Semak I. Wang J. Zjawiony J.K. et al.Novel activities of CYP11A1 and their potential physiological significance.J Steroid Biochem Mol Biol. 2015; 151: 25-37Crossref PubMed Scopus (217) Google Scholar). Furthermore, it was found that lumisterol and tachysterol and their precursors were activated by CYP11A1 and CYP27A1 (Slominski et al., 2022bSlominski A.T. Kim T.K. Slominski R.M. Song Y. Janjetovic Z. Podgorska E. et al.Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors.FASEB J. 2022; 36e22451Crossref PubMed Scopus (18) Google Scholar, Slominski et al., 2021Slominski R.M. Raman C. Elmets C. Jetten A.M. Slominski A.T. Tuckey R.C. The significance of CYP11A1 expression in skin physiology and pathology.Mol Cell Endocrinol. 2021; 530111238Crossref PubMed Scopus (44) Google Scholar; Tuckey et al., 2019Tuckey R.C. Cheng C.Y.S. Slominski A.T. The serum vitamin D metabolome: what we know and what is still to discover.J Steroid Biochem Mol Biol. 2019; 186: 4-21Crossref PubMed Scopus (127) Google Scholar). These pathways operate in vivo with observable accumulation of the metabolites in the human body (Jenkinson et al., 2021Jenkinson C. Desai R. Slominski A.T. Tuckey R.C. Hewison M. Handelsman D.J. Simultaneous measurement of 13 circulating vitamin D3 and D2 mono and dihydroxy metabolites using liquid chromatography mass spectrometry.Clin Chem Lab Med. 2021; 59: 1642-1652Crossref PubMed Scopus (19) Google Scholar; Slominski et al., 2022bSlominski A.T. Kim T.K. Slominski R.M. Song Y. Janjetovic Z. Podgorska E. et al.Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors.FASEB J. 2022; 36e22451Crossref PubMed Scopus (18) Google Scholar, Slominski et al., 2021Slominski R.M. Raman C. Elmets C. Jetten A.M. Slominski A.T. Tuckey R.C. The significance of CYP11A1 expression in skin physiology and pathology.Mol Cell Endocrinol. 2021; 530111238Crossref PubMed Scopus (44) Google Scholar; Tuckey et al., 2019Tuckey R.C. Cheng C.Y.S. Slominski A.T. The serum vitamin D metabolome: what we know and what is still to discover.J Steroid Biochem Mol Biol. 2019; 186: 4-21Crossref PubMed Scopus (127) Google Scholar). In the skin, these pathways and the generation of different secosteroidal products are dependent on the action of UVB (Figure 1). Besides 7DHC, there are other 5,7-dienes that UVB could potentially act on, producing metabolites on which CYP11A1 could hydroxylate, as discussed previously (Slominski et al., 2015Slominski A.T. Li W. Kim T.K. Semak I. Wang J. Zjawiony J.K. et al.Novel activities of CYP11A1 and their potential physiological significance.J Steroid Biochem Mol Biol. 2015; 151: 25-37Crossref PubMed Scopus (217) Google Scholar). The resulting large number of products with further modifications by cutaneous enzymes (Slominski et al., 2022bSlominski A.T. Kim T.K. Slominski R.M. Song Y. Janjetovic Z. Podgorska E. et al.Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors.FASEB J. 2022; 36e22451Crossref PubMed Scopus (18) Google Scholar, Slominski et al., 2020Slominski A.T. Chaiprasongsuk A. Janjetovic Z. Kim T.K. Stefan J. Slominski R.M. et al.Photoprotective properties of vitamin D and lumisterol hydroxyderivatives.Cell Biochem Biophys. 2020; 78: 165-180Crossref PubMed Scopus (99) Google Scholar) may explain a variety of local and systemic homeostatic effects of UVB, which are not assigned to 1,25(OH)2D3. The route of vitamin D delivery is important (Slominski et al., 2021Slominski R.M. Raman C. Elmets C. Jetten A.M. Slominski A.T. Tuckey R.C. The significance of CYP11A1 expression in skin physiology and pathology.Mol Cell Endocrinol. 2021; 530111238Crossref PubMed Scopus (44) Google Scholar) because orally delivered D3 will be predominantly metabolized to 25(OH)D3 in the liver. Therefore, to initiate the noncanonical pathway of vitamin D activation, it must bypass the liver and be transported to organs expressing CYP11A1, including adrenals and other extra-adrenal tissues (Slominski et al., 2021Slominski R.M. Raman C. Elmets C. Jetten A.M. Slominski A.T. Tuckey R.C. The significance of CYP11A1 expression in skin physiology and pathology.Mol Cell Endocrinol. 2021; 530111238Crossref PubMed Scopus (44) Google Scholar). This challenges the strict reliance on 25(OH)D3 as the sole reflection of D3 load. The metabolites mentioned earlier produced by noncanonical vitamin D activation and activation of lumisterol and tachysterol are biologically active in ex vivo and in vivo experimental models and are nontoxic and noncalcemic at suprapharmacological doses (reviewed in Hewison et al., 2023Hewison M. Bouillon R. Giovannucci E. Goltzman D. Meyer B. Welsh J. Feldman and Pike’s vitamin D. Academic Press, Cambridge, MA2023Google Scholar). These metabolites can act on the vitamin D receptor (VDR) and on alternative receptors, including the retinoid-related orphan receptors α and γ, aryl hydrocarbon receptor, liver X receptor, and peroxisome proliferator–activated receptor γ (Slominski et al., 2022bSlominski A.T. Kim T.K. Slominski R.M. Song Y. Janjetovic Z. Podgorska E. et al.Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARγ receptors.FASEB J. 2022; 36e22451Crossref PubMed Scopus (18) Google Scholar, Slominski et al., 2020Slominski A.T. Chaiprasongsuk A. Janjetovic Z. Kim T.K. Stefan J. Slominski R.M. et al.Photoprotective properties of vitamin D and lumisterol hydroxyderivatives.Cell Biochem Biophys. 2020; 78: 165-180Crossref PubMed Scopus (99) Google Scholar). They inhibit NF-κβ activity and the hedgehog and WNT/β-catenin pathways (Slominski et al., 2022aSlominski A.T. Brożyna A.A. Kim T.K. Elsayed M.M. Janjetovic Z. Qayyum S. et al.CYP11A1-derived vitamin D hydroxyderivatives as candidates for therapy of basal and squamous cell carcinomas.Int J Oncol. 2022; 61: 96Crossref PubMed Scopus (11) Google Scholar). They induce the translocation of NRF2 and phosphorylated p53 from the cytoplasm to the nucleus, leading to the activation of downstream regulatory pathways (Slominski et al., 2020Slominski A.T. Chaiprasongsuk A. Janjetovic Z. Kim T.K. Stefan J. Slominski R.M. et al.Photoprotective properties of vitamin D and lumisterol hydroxyderivatives.Cell Biochem Biophys. 2020; 78: 165-180Crossref PubMed Scopus (99) Google Scholar), or act in a receptor-independent fashion for antiviral effects (Qayyum et al., 2022Qayyum S. Slominski R.M. Raman C. Slominski A.T. Novel CYP11A1-derived vitamin D and lumisterol biometabolites for the management of COVID-19.Nutrients. 2022; 14: 4779Crossref PubMed Scopus (10) Google Scholar). This challenges the narrow view that the biological effects of D3 are strictly dependent on activation of the VDR. Although we accept that 1,25(OH)2D3 has the highest affinity to the VDR, it can also act as a lower-affinity ligand on other nuclear receptors. Furthermore, other biologically active hydroxyderivatives of D3 show higher selectivity toward several other nuclear receptors. Thus, the position and number of hydroxyl groups on vitamin D define which nuclear receptor is activated. This opens a Pandora’s box of possibilities for medicinal chemistry, health sciences, and dermatology to investigate. The recent advances in alternative pathways of vitamin D activation and alternative nuclear receptors for D3 hydroxyderivatives offer an explanation for the observed pleiotropic effects of the D3 prohormone. They also challenge the current consensus conveyed by the majority of the literature that the main biologically relevant, phenotypic effects of D3 can be attributed solely to the activation of the VDR by 1,25(OH)2D3. Therefore, defining the biological and physiological effects of secosteroids that are independent of VDR interaction deserves further studies and challenges the conventional concept that the VDR is the sole nuclear receptor activated by the active forms of D3. Furthermore, lumisterol and tachysterol have been defined as prohormones because they can be activated by CYP enzymes to metabolites that exert biological activity through action on nuclear receptors. These possibilities are open for investigation by different laboratories because both biochemical and efficient chemical routes of synthesis of these metabolites have been established, as described in several publications.