Vitamins D: Relationship between Structure and Biological Activity

The most active metabolite of vitamin D is 1α,25-dihydroxyvitamin D3, which is a central regulator of mineral homeostasis: excessive administration leads to hypercalcemia. Additionally, 1α,25-dihydroxyvitamin D3 is important to decision-making by cells, driving many cell types to growth arrest, differentiate and undergo apoptosis. 1α,25-Dihydroxyvitamin D3 regulates gene transcription by binding to a single known receptor, the vitamin D receptor. Rapid intracellular signals are also elicited in vitro by 1α,25-dihydroxyvitamin D3 that are independent of transcription. There are many aspects of the multiple actions of 1α,25-dihydroxyvitamin D3 that we do not fully understand. These include how a single receptor and provoked rapid events relate to the different actions of 1α,25-dihydroxyvitamin D3, its calcemic action per se, and whether a large number of genes are activated directly, via the vitamin D receptor, or indirectly. A strategy to resolving these issues has been to generate synthetic analogues of 1α,25-dihydroxyvitamin D3: Some of these separate the anti-proliferative and calcemic actions of the parent hormone. Crystallography is important to understanding how differences between 1α,25-dihydroxyvitamin D3- and analogue-provoked structural changes to the vitamin D receptor may underlie their different activity profiles. Current crystallographic resolution has not revealed such information. Studies of our new analogues have revealed the importance of the A-ring adopting the chair β-conformation upon interaction with the vitamin D receptor to receptor-affinity and biological activity. Vitamin D analogues are useful probes to providing a better understanding of the physiology of vitamin D.

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Epimers of Vitamin D: A Review

International Journal of Molecular Sciences ◽

10.3390/ijms21020470 ◽

2020 ◽

Vol 21 (2) ◽

pp. 470 ◽

Cited By ~ 7

Author(s):

Bashar Al-Zohily ◽

Asma Al-Menhali ◽

Salah Gariballa ◽

Afrozul Haq ◽

Iltaf Shah

Keyword(s):

Vitamin D ◽

Biological Activity ◽

Hydroxyl Group ◽

Vitamin D Metabolites ◽

Dihydroxyvitamin D3 ◽

In Vivo Models ◽

Vitamin D Receptors ◽

Potential Factors

In this review, we discuss the sources, formation, metabolism, function, biological activity, and potency of C3-epimers (epimers of vitamin D). We also determine the role of epimerase in vitamin D-binding protein (DBP) and vitamin D receptors (VDR) according to different subcellular localizations. The importance of C3 epimerization and the metabolic pathway of vitamin D at the hydroxyl group have recently been recognized. Here, the hydroxyl group at the C3 position is orientated differently from the alpha to beta orientation in space. However, the details of this epimerization pathway are not yet clearly understood. Even the gene encoding for the enzyme involved in epimerization has not yet been identified. Many published research articles have illustrated the biological activity of C3 epimeric metabolites using an in vitro model, but the studies on in vivo models are substantially inadequate. The metabolic stability of 3-epi-1α,25(OH)2D3 has been demonstrated to be higher than its primary metabolites. 3-epi-1 alpha, 25 dihydroxyvitamin D3 (3-epi-1α,25(OH)2D3) is thought to have fewer calcemic effects than non-epimeric forms of vitamin D. Some researchers have observed a larger proportion of total vitamin D as C3-epimers in infants than in adults. Insufficient levels of vitamin D were found in mothers and their newborns when the epimers were not included in the measurement of vitamin D. Oral supplementation of vitamin D has also been found to potentially cause increased production of epimers in mice but not humans. Moreover, routine vitamin D blood tests for healthy adults will not be significantly affected by epimeric interference using LC–MS/MS assays. Recent genetic models also show that the genetic determinants and the potential factors of C3-epimers differ from those of non-C3-epimers.Most commercial immunoassays techniques can lead to inaccurate vitamin D results due to epimeric interference, especially in infants and pregnant women. It is also known that the LC–MS/MS technique can chromatographically separate epimeric and isobaric interference and detect vitamin D metabolites sensitively and accurately. Unfortunately, many labs around the world do not take into account the interference caused by epimers. In this review, various methods and techniques for the analysis of C3-epimers are also discussed. The authors believe that C3-epimers may have an important role to play in clinical research, and further research is warranted.

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Dendritic cell modulation by 1 ,25 dihydroxyvitamin D3 and its analogs: A vitamin D receptor-dependent pathway that promotes a persistent state of immaturity in vitro and in vivo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.121172198 ◽

2001 ◽

Vol 98 (12) ◽

pp. 6800-6805 ◽

Cited By ~ 415

Author(s):

M. D. Griffin ◽

W. Lutz ◽

V. A. Phan ◽

L. A. Bachman ◽

D. J. McKean ◽

...

Keyword(s):

Vitamin D ◽

Dendritic Cell ◽

Vitamin D Receptor ◽

Dihydroxyvitamin D3 ◽

Dependent Pathway

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VITAMIN D RECEPTOR EXPRESSION AND 1.25-DIHYDROXYVITAMIN D3 RESPONSIVENESS IN OSTEOBLAST-LIKE CELLS IN VITRO

Vitamin D ◽

10.1515/9783110850345-186 ◽

1991 ◽

pp. 563-564

Keyword(s):

Vitamin D ◽

Vitamin D Receptor ◽

Receptor Expression ◽

Dihydroxyvitamin D3

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The vitamin D receptor in cancer

Proceedings of The Nutrition Society ◽

10.1017/s0029665108006964 ◽

2008 ◽

Vol 67 (2) ◽

pp. 115-127 ◽

Cited By ~ 80

Author(s):

James Thorne ◽

Moray J. Campbell

Keyword(s):

Vitamin D ◽

Cell Fate ◽

Vitamin D Receptor ◽

De Novo ◽

Lithocholic Acid ◽

Cell Types ◽

Cell Fate Decisions ◽

Wide Range

Over the last 25 years roles have been established for vitamin D receptor (VDR) in influencing cell proliferation and differentiation. For example, murine knock-out approaches have revealed a role for the VDR in controlling mammary gland growth and function. These actions appear widespread, as the enzymes responsible for 1α,25-dihydroxycholecalciferol generation and degradation, and the VDR itself, are all functionally present in a wide range of epithelial and haematopoietic cell types. These findings, combined with epidemiological and functional data, support the concept that local, autocrine and paracrine VDR signalling exerts control over cell-fate decisions in multiple cell types. Furthermore, the recent identification of bile acid lithocholic acid as a VDR ligand underscores the environmental sensing role for the VDR.In vitroandin vivodissection of VDR signalling in cancers (e.g. breast, prostate and colon) supports a role for targeting the VDR in either chemoprevention or chemotherapy settings. As with other potential therapeutics, it has become clear that cancer cells displayde novoand acquired genetic and epigenetic mechanisms of resistance to these actions. Consequently, a range of experimental and clinical options are being developed to bring about more targeted actions, overcome resistance and enhance the efficacy of VDR-centred therapeutics.

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Vitamin D-Binding Protein Influences Total Circulating Levels of 1,25-Dihydroxyvitamin D3 but Does Not Directly Modulate the Bioactive Levels of the Hormone in Vivo

Endocrinology ◽

10.1210/en.2008-0042 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3656-3667 ◽

Cited By ~ 98

Author(s):

Lee A. Zella ◽

Nirupama K. Shevde ◽

Bruce W. Hollis ◽

Nancy E. Cooke ◽

J. Wesley Pike

Keyword(s):

Vitamin D ◽

Biological Activity ◽

Binding Protein ◽

Biologically Active ◽

Vitamin D Binding Protein ◽

Wild Type ◽

Dihydroxyvitamin D3 ◽

Activation Profile

Mice deficient in the expression of vitamin D-binding protein (DBP) are normocalcemic despite undetectable levels of circulating 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We used this in vivo mouse model together with cells in culture to explore the impact of DBP on the biological activity of 1,25(OH)2D3. Modest changes in the basal expression of genes involved in 1,25(OH)2D3 metabolism and calcium homeostasis were observed in vivo; however, these changes seemed unlikely to explain the normal calcium balance seen in DBP-null mice. Further investigation revealed that despite the reduced blood levels of 1,25(OH)2D3 in these mice, tissue concentrations were equivalent to those measured in wild-type counterparts. Thus, the presence of DBP has limited impact on the extracellular pool of 1,25(OH)2D3 that is biologically active and that accumulates within target tissues. In cell culture, in contrast, the biological activity of 1,25(OH)2D3 is significantly impacted by DBP. Here, although DBP deficiency had no effect on the activation profile itself, the absence of DBP strongly reduced the concentration of exogenous 1,25(OH)2D3 necessary for transactivation. Surprisingly, analogous studies in wild-type and DBP-null mice, wherein we explored the activity of exogenous 1,25(OH)2D3, produced strikingly different results as compared with those in vitro. Here, the carrier protein had virtually no impact on the distribution, uptake, activation profile, or biological potency of the hormone. Collectively, these experiments suggest that whereas DBP is important to total circulating 1,25(OH)2D3 and sequesters extracellular levels of this hormone both in vivo and in vitro, the binding protein does not influence the hormone’s biologically active pool.

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