Vitamin D is associated with 6 genes, 7 receptors, and a new book - Oct 2023

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

J of Investigative Dermatology October 04, 2023 DOI:https://doi.org/10.1016/j.jid.2023.07.003
Andrzej T. Slominski, Robert C. Tuckey, Anton M. Jetten. Michael F. Holick

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.

• Figure 1. UVB-dependent pathways of secosteroidal activation(s). Vitamin D3, lumisterol, tachysterol, and 7DHC are substrates for CYP11A1 activity that by itself or in cooperation with other CYP enzymes produces the corresponding hydroxyderivatives. In the case of lumisterol and 7HDC, the side chain can be cleaved by CYP11A1 to produce 7DHP or pL, which can be further metabolized by steroidogenic enzymes. Production of tachysterol derivatives is also presented. Image was taken from Slominski et al. (2020) with permission from the publisher. ES denotes steroidogenic enzymes. 7DHC, 7-dehydrocholesterol; 7DHP, 7-dehydropregnenolone; CYP, cytochrome P450; D3, vitamin D3; L3, lumisterol3; pL, pregna-lumisterol; pre-D3, previtamin D3; T3, tachysterol3.

INTRODUCTION

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., 2023). 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.

PHOTOSYNTHESIS OF VITAMIN D

Vitamin D (vitamin D3 [D3] and vitamin D2) is a secos- teroid 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. [2023]and Wacker and Holick [2013]). Exposure of pre-D3 to higher doses of UVB leads to the formation of lumisterol and tachysterol (Hewison et al., 2023; Wacker and Holick, 2013). 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. [2023] and Wacker and Holick [2013]). 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., 2023; Wacker and Holick, 2013).

ACTIVATION OF D3

To be biologically active, D3 must be activated by sequential hydroxylations mediated by cytochrome P450 (CYP) en­zymes (Hewison et al., 2023; Slominski et al., 2021; Wacker and Holick, 2013). 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 C1a 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., 2019; Hewison et al., 2023).

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., 2015; Tuckey et al., 2019). Importantly, this noncanonical pathway requires unmodified D3 because CYP11A1 does not exert any cat­alytic activity on 25(OH)D3 (Slominski et al., 2015). Furthermore, it was found that lumisterol and tachysterol and their precursors were activated by CYP11A1 and CYP27A1 (Slominski et al., 2022b, 2021; Tuckey et al., 2019). These pathways operate in vivo with observable accumulation of the metabolites in the human body (Jenkinson et al., 2021; Slominski et al., 2022b, 2021; Tuckey et al., 2019).

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., 2015). The resulting large number of products with further modifi­cations by cutaneous enzymes (Slominski et al., 2022b, 2020) 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., 2021) 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., 2021). This challenges the strict reliance on 25(OH)D3 as the sole reflection of D3 load.

BIOLOGICAL ACTIVITY AND MECHANISMS OF ACTION

The metabolites mentioned earlier produced by noncanoni- cal 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., 2023).

These metabolites can act on the

• vitamin D receptor (VDR) and on alternative receptors, including
• the retinoid-related orphan receptors a and g,
• aryl hydrocarbon receptor,
• liver X receptor, and
• peroxisome proliferator—activated receptor g (Slominski et al., 2022b, 2020).

They inhibit NF-kb activity and the hedgehog and WNT/b-catenin pathways (Slominski et al., 2022a). 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., 2020), or act in a receptor-independent fashion for antiviral effects (Qayyum et al., 2022).
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.

CONCLUSIONS

The recent advances in alternative pathways of vitamin D activation and alternative nuclear receptors for D3 hydrox-yderivatives offer an explanation for the observed pleio- tropic 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.

In summary, the characterization of alternative signaling pathways by D3 and related molecules offers a new perspective that vitamin D, its photoproducts, and metabo­lites have a multitude of biologic functions independent of calcium and bone metabolism that requires further investi­gation. These new findings also show that UVB can generate a myriad of molecules that could eventually regulate local and global homeostasis.

11 REFERENCES, includes a new book

• Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocr Rev 2019;40:1109—51.
• Hewison M, Bouillon R, Giovannucci E, Goltzman D, Meyer B, Welsh J. Feldman and Pike's vitamin D. Cambridge, MA: Academic Press; 2023.
  5th edition is in 2 volumes, each costs $187
  Volume II: Health, Disease and Therapy authoritatively covers the evidence for new roles of vitamin D, ranging from organ transplantation to cancer, diabetes, inflammatory bowel disease, multiple sclerosis, and renal disease. The coverage is appropriately broad, drawing on aspects of internal medicine, pediatrics, nutrition, orthopedics, oncology, neurology, obstetrics and gynecology, and immunology, as well as, new areas for vitamin D including liver metabolism, veterinary medicine and ICU care – including COVID-19. Clinical researchers will gain a strong understanding of the molecular basis for a particular disease and better understand future directions for research in this still-growing field.
• Jenkinson C, Desai R, Slominski AT, Tuckey RC, Hewison M, Handelsman DJ. 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—52.
• Qayyum S, Slominski RM, Raman C, Slominski AT. Novel CYP11A1-derived vitamin D and lumisterol biometabolites for the management of COVID- 19. Nutrients 2022;14:4779.
• Slominski AT, BroZyna AA, Kim TK, Elsayed MM, Janjetovic Z, Qayyum S, et al. CYP11A1-derived vitamin D hydroxyderivatives as candidates for therapy of basal and squamous cell carcinomas. Int J Oncol 2022a;61:96.
• Slominski AT, Chaiprasongsuk A, Janjetovic Z, Kim TK, Stefan J, Slominski RM, etal. Photoprotective properties of vitamin D and lumisterol hydroxyderivatives. Cell Biochem Biophys 2020;78:165—80.
• Slominski AT, Kim TK, Slominski RM, Song Y, Janjetovic Z, Podgorska E, et al. Metabolic activation of tachysterol3 to biologically active hydroxyderivatives that act on VDR, AhR, LXRs, and PPARg receptors. FASEB J 2022b;36:e22451.
• Slominski AT, Li W, Kim TK, Semak I, Wang J, Zjawiony JK, et al. Novel activities of CYP11A1 and their potential physiological significance. J Steroid Biochem Mol Biol 2015;151:25—37.
• Slominski RM, Raman C, Elmets C, Jetten AM, Slominski AT, Tuckey RC. The significance of CYP11A1 expression in skin physiology and pathology. Mol Cell Endocrinol 2021;530:11 1238.
• Tuckey RC, Cheng CYS, Slominski AT. The serum vitamin D metabolome: what we know and what is still to discover. J Steroid Biochem Mol Biol 2019;186:4—21.
• Wacker M, Holick MF. Sunlight and vitamin D: a global perspective for health. Dermatoendocrinol 2013;5:51 —108.

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Vitamin D Life – Genetics category contains

332 articles in the Genetics category

see also

• Vitamin D Receptor has 512 items
• Vitamin D Binding Protein = GC has 176 items
• CYP27B1 has 60 items
• CYP24A1 in title of 34+ items
• CYP2R1 25+ items
• Calcidiol has 46 items
• Calcitriol has 56 items
• Topical Vitamin D
• Nanoemulsion Vitamin D may be a substantially better form
• 1289 genes changed with higher doses of Vitamin D - RCT Dec 2019
• CYP3A4 (7 as of Dec 2022)
• Getting Vitamin D into your body
• 

Vitamin D blood test misses a lot

• Vitamin D from coming from tissues (vs blood) was speculated to be 50% in 2014, and by 2017 was speculated to be 90%
• Note: Good blood test results (> 40 ng) does not mean that a good amount of Vitamin D actually gets to cells
• A Vitamin D test in cells rather than blood was feasible (2017 personal communication)   Commercially available 2019
  • However, test results would vary in each tissue due to multiple genes
• Good clues that Vitamin D is being restricted from getting to the cells
  1) A vitamin D-related health problem runs in the family

    especially if it is one of 51+ diseases related to Vitamin D Receptor

+2) Slightly increasing Vitamin D shows benefits (even if conventional Vitamin D test shows an increase)+3) DNA and VDR tests - 120 to 200 dollars $100 to $250+4) PTH bottoms out ( shows that parathyroid cells are getting Vitamin d)

   Genes are good, have enough Magnesium, etc.

+4) Back Pain

   probably want at least 2 clues before taking adding vitamin D, Omega-3, Magnesium, Resveratrol, etc

• The founder of Vitamin D Life took action with clues #3&4