Vitamin D metabolism, mechanism of action, and clinical applications

Bikle, Daniel D.

doi:10.1016/j.chembiol.2013.12.016

Cited by 1,933Vitamin D Research StudiesParathyroid Disorders and TreatmentsVitamin K Research Studies

Vitamin D metabolism, mechanism of action, and clinical applications

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Bikle, Daniel D.·2014·Chemistry & Biology

DOI 10.1016/j.chembiol.2013.12.016PMC PMC3968073

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Abstract

Vitamin D3 is made in the skin from 7-dehydrocholesterol under the influence of UV light. Vitamin D2 (ergocalciferol) is derived from the plant sterol ergosterol. Vitamin D is metabolized first to 25 hydroxyvitamin D (25OHD), then to the hormonal form 1,25-dihydroxyvitamin D (1,25(OH)2D). CYP2R1 is the most important 25-hydroxylase; CYP27B1 is the key 1-hydroxylase. Both 25OHD and 1,25(OH)2D are catabolized by CYP24A1. 1,25(OH)2D is the ligand for the vitamin D receptor (VDR), a transcription factor, binding to sites in the DNA called vitamin D response elements (VDREs). There are thousands of these binding sites regulating hundreds of genes in a cell-specific fashion. VDR-regulated transcription is dependent on comodulators, the profile of which is also cell specific. Analogs of 1,25(OH)2D are being developed to target specific diseases with minimal side effects. This review will examine these different aspects of vitamin D metabolism, mechanism of action, and clinical application.

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Vitamin D3 is modified through mitochondria in liver and kidney to assume its active form, 1,25 vitamin D.
“Vitamin D3 is modified through the mitochondria in the liver and kidney to assume its active form, 1,25 vitamin D (Bikle, 2014).”
From Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact (2020) · cites this paper as Bikle, 2014
The Summary and Conclusions and the 1α-hydroxylase section describe conversion of vitamin D to active 1,25(OH)2D, with the kidney the main source of its circulating form. The 25-hydroxylase section reports mitochondrial activity in the liver, but identifies the most important hepatic enzyme, CYP2R1, in the microsomal fraction. Thus the claim overstates that conversion proceeds through mitochondria in both organs. Page numbers were not supplied. (LLM, conf=0.87)
Experimental — accuracy not yet measured
Supplementation effects depend strongly on baseline vitamin D status, assay standardization, dose, formulation, adherence, and population context.
“supplementation effects depend strongly on baseline status, assay standardization, dose, formulation, adherence, and population context [1,2,3,4,5,6].”
From Vitamin D Supplementation, Total Testosterone, and Androgen Bioavailability Markers in Adult Men: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (2026) · cites this paper as [2]
In Vitamin D Production (page unavailable), Bikle reports that D2 and D3 supplementation produce different 25OHD levels unless D2 is given daily. Clinical Applications > The Skeleton (page unavailable) reports a dose-response relationship for fracture prevention. The paper also discusses differences in vitamin D measurement and clinical contexts, but these passages do not establish that supplementation effects depend strongly on baseline status, assay standardization, or adherence. (LLM, conf=0.86)
Experimental — accuracy not yet measured
3-Epi-1α,25(OH)2D3 generally has lower biological activity than 1α,25(OH)2D3.
“3-Epi-1α,25(OH)2D3 generally has reduced biological activity compared to 1α,25(OH)2D3 [14, 73–75] and is discussed further in Sections 2.1.3 and 3.6.”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [14]
Many other tissues express CYP27B1, which can modulate local 1α,25(OH)2D levels using plasma 25(OH)D as substrate.
“Many other tissues express CYP27B1 too which can modulate the local level of this hormone utilizing plasma 25(OH)D as substrate [10, 14, 51].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [14]
Serum 1α,25(OH)2D3 and 1α,25(OH)2D2 are produced in the kidney by CYP27B1 acting on circulating 25(OH)D.
“Serum 1α,25(OH)2D3 and 1α,25(OH)2D2 are produced in the kidney by the action of CYP27B1 on 25(OH)D obtained from the circulation [14].”
From The serum vitamin D metabolome: what we know and what is still to discover (2019) · cites this paper as [14]

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1 retracted

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Multifunctional Enhancers Regulate Mouse and Human Vitamin D Receptor Gene Transcription
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Alternative Splicing of Vitamin D-24-Hydroxylase
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Comparison of 6-s-cis- and 6-s-trans-Locked Analogs of 1α,25-Dihydroxyvitamin D3 Indicates That the 6-s-cis Conformation Is Preferred for Rapid Nongenomic Biological Responses and That Neither 6-s-cis- nor 6-s-trans-Locked Analogs Are Preferred for Genomic Biological Responses
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Genome-wide analysis of the VDR/RXR cistrome in osteoblast cells provides new mechanistic insight into the actions of the vitamin D hormone
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ANALOGS OF 1,25-DIHYDROXYVITAMIN D 3 AS DOSE-REDUCING AGENTS FOR CLASSICAL IMMUNOSUPPRESSANTS12
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Self-citation
1Alpha,25-dihydroxy-3-epi-vitamin D3, a natural metabolite of 1alpha,25-dihydroxyvitamin D3, is a potent suppressor of parathyroid hormone secretion.
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Sunlight Vitamin D and Skin Cancer
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Porcine Microsomal Vitamin D3 25-Hydroxylase (CYP2D25)
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The ionic control of 1,25-dihydroxyvitamin D3 production in isolated chick renal tubules.
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Self-citation
Parathyroid hormone regulates 25-hydroxyvitamin D 3 -24-hydroxylase mRNA by altering its stability
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2-Methylene-19-nor-(20S)-1,25-dihydroxyvitamin D3 Potently Stimulates Gene-specific DNA Binding of the Vitamin D Receptor in Osteoblasts
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The Role of the Vitamin D Receptor and ERp57 in Photoprotection by 1α,25-Dihydroxyvitamin D3
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The first genome-wide view of vitamin D receptor locations and their mechanistic implications.
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Regulation of 1,25-Dihydroxyvitamin D Production in Human Keratinocytes by Interferon-γ*
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Self-citation
Inhibition of prostate growth and inflammation by the vitamin D receptor agonist BXL-628 (elocalcitol)
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Inhibition of prostate cell growth by BXL-628, a calcitriol analogue selected for a phase II clinical trial in patients with benign prostate hyperplasia
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Sunlight Vitamin D and Skin Cancer
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In Vitro Stimulation of 25-Hydroxycholecalciferol lα- Hydroxylation by Parathyroid Hormone in Chick Kidney Slices: Evidence for a Role for Adenosine 3′,5′- Monophosphate *
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Self-citation
Tumor necrosis factor‐alpha induces vitamin D‐1‐hydroxylase activity in normal human alveolar macrophages
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Selective inhibition of vitamin D hydroxylases in human keratinocytes11Abbreviations: VD: vitamin D3; 25(OH)D3: 25-hydroxyvitamin D3; 3H-25(OH)D3: [26,27n-3H] 25-hydroxyvitamin D3; 1α,25(OH)2D3: 1α,25-dihydroxyvitamin D3; 1α,25(OH)2-3epi-D3: 1α,25-dihydroxyvitamin-3-epi-D3; 1α,24(R),25(OH)3D3: 1α,24(R),25-trihydroxyvitamin D3, 1α,25(OH)2-24oxo-D3: 1α,25-dihydroxy-24oxo-vitamin D3; 1α,23(S),25(OH)3-24oxo-D3: 1α,23(S),25-trihydroxy-24oxo-vitamin D3; calcitroic acid: 1α-hydroxy-23-carboxy-24,25,26,27-tetranorvitamin D3; CYP: cytochrome P450; 1α-hydroxylase: 25-hydroxyvitamin D3-1α-hydroxylase; 24-hydroxylase (CYP24), 1α,25-hydroxyvitamin D3-24-hydroxylase; PHK, primary human keratinocytes; KGM: keratinocyte growth medium; HPLC, high performance liquid chromatography; IC50: half-maximum inhibitor concentration; SD: standard deviation.
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Self-citation
The ionic control of 1,25-dihydroxyvitamin D3 synthesis in isolated chick renal mitochondria. The role of calcium as influenced by inorganic phosphate and hydrogen-ion.
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Extra Renal Synthesis of 1,25-dihydroxyvitamin D and its Health Implications
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Vitamin D and the heart
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Induction of the Vitamin D 24-Hydroxylase (CYP24) by 1,25-Dihydroxyvitamin D 3 Is Regulated by Parathyroid Hormone in UMR106 Osteoblastic Cells 1
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24-Hydroxylation of 1,25-dihydroxyergocalciferol. An unambiguous deactivation process.
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Regulation of the Porcine 1,25-Dihydroxyvitamin D3-24-Hydroxylase (CYP24) by 1,25-Dihydroxyvitamin D3 and Parathyroid Hormone in AOK-B50 Cells
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Single A326G mutation converts human CYP24A1 from 25-OH-D 3 -24-hydroxylase into -23-hydroxylase, generating 1α,25-(OH) 2 D 3 -26,23-lactone
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Tumor Necrosis Factor-α Regulation of 1,25-Dihydroxy vitamin D Production by Human Keratinocytes*
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Monocyte 1α-hydroxylase regulation: induction by inflammatory cytokines and suppression by dexamethasone and uremia toxin
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Metabolism of 1α,25-dihydroxyvitamin D3 and its C-3 epimer 1α,25-dihydroxy-3-epi-vitamin D3 in neonatal human keratinocytes
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Vitamin D and Skin Cancer
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Self-citation
ED-71, a new active vitamin D3, increases bone mineral density regardless of serum 25(OH)D levels in osteoporotic subjects
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Vitamin D Analogs
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Peroxisome targeting of porcine 17?-hydroxysteroid dehydrogenase type IV/D-specific multifunctional protein 2 is mediated by its C-terminal tripeptide AKI
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Vitamin D Analogs
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Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects
Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L., & Carmeliet, G. (2015) · Physiological Reviews · doi:10.1152/physrev.00014.2015 · Cited by 1,965 · see citing works
Exploring vitamin D metabolism and function in cancer
Jeon, S., & Shin, E. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0038-9 · Cited by 554 · see citing works
Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low‐ and middle‐income countries
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How UV Light Touches the Brain and Endocrine System Through Skin, and Why
Slominski, A. T., Zmijewski, M. A., Plonka, P. M., Szaflarski, J. P., & Paus, R. (2018) · Endocrinology · doi:10.1210/en.2017-03230 · Cited by 452 · see citing works
Vitamin D Toxicity–A Clinical Perspective
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Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact
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“Vitamin D3 is modified through the mitochondria in the liver and kidney to assume its active form, 1,25 vitamin D (Bikle, 2014).”
Recent trends in biocatalysis
Yi, D., Bayer, T., Badenhorst, C. P. S., Wu, S., Doerr, M., Höhne, M., & Bornscheuer, U. T. (2021) · Chemical Society Reviews · doi:10.1039/d0cs01575j · Cited by 387 · see citing works
A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm
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Vitamin D, infections and immunity
Ismailova, A., & White, J. H. (2021) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-021-09679-5 · Cited by 354 · see citing works
Physiological functions of Vitamin D in adipose tissue
Abbas, M. A. (2016) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2016.08.004 · Cited by 336 · see citing works
Vitamin D and cardiovascular health
de la Guía-Galipienso, F., Martínez‐Ferrán, M., Vallecillo, N., Lavie, C. J., Sanchis‐Gomar, F., & Pareja-Galeano, H. (2020) · Clinical Nutrition · doi:10.1016/j.clnu.2020.12.025 · Cited by 336 · see citing works
Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism
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PTH and Vitamin D
Khundmiri, S. J., Murray, R. D., & Lederer, E. D. (2016) · Comprehensive physiology · doi:10.1002/cphy.c140071 · Cited by 352 · see citing works
Analysis of vitamin D level among asymptomatic and critically ill COVID-19 patients and its correlation with inflammatory markers
Jain, A., Chaurasia, R., Sengar, N. S., Singh, M., Mahor, S., & Narain, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-77093-z · Cited by 295 · see citing works
Vitamin D and Cardiovascular Disease, with Emphasis on Hypertension, Atherosclerosis, and Heart Failure
Latic, N., & Erben, R. G. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186483 · Cited by 302 · see citing works
Influence of Vitamin D on Islet Autoimmunity and Beta-Cell Function in Type 1 Diabetes
Infante, M., Ricordi, C., Sanchez, J. E., Clare-Salzler, M. J., Padilla, N., Fuenmayor, V., Chavez, C., Alvarez, A., Baidal, D. A., Alejandro, R., et al. (2019) · Nutrients · doi:10.3390/nu11092185 · Cited by 275 · see citing works
Vitamin D Deficiency and Oral Health: A Comprehensive Review
Botelho, J., Machado, V., Proença, L., Delgado, A. S., & Mendes, J. J. (2020) · Nutrients · doi:10.3390/nu12051471 · Cited by 258 · see citing works
The serum vitamin D metabolome: what we know and what is still to discover
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Authors: Bikle, D. D.
Affiliations: San Francisco VA Medical Center (US)
Corresponding author: Bikle, Daniel D.
ORCID: Bikle, Daniel D.
Venue: Chemistry & Biology
Publisher: Elsevier BV
Published: 2014-03
Volume: 21
Issue: 3
Pages: 319-329
ISSN: 1074-5521 (ISSN-L)
DOI: 10.1016/j.chembiol.2013.12.016
PMC: PMC3968073
OpenAlex: W1976776496
Cited by: 1,933
References: 133
Citations by year: 2026: 148 · 2025: 189 · 2024: 196 · 2023: 272 · 2022: 219 · 2021: 211 · 2020: 228 · 2019: 142 · 2018: 135 · 2017: 84 · 2016: 60 · 2015: 37 · 2014: 10 · 2013: 1
FWCI: 9.02
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
Locations: Chemistry & Biology (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: U.S. Department of Defense
National Institutes of Health (AR050023)
National Cancer Institute (CA110338)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR038386, R01AR050023, P01AR039448)
National Center for Research Resources (P41RR001614)
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
Health Sciences › Nursing › Nutrition and Dietetics › Vitamin K Research Studies
Keywords: vitamin D metabolism, vitamin D3, vitamin D2, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, CYP2R1, CYP27B1, CYP24A1, vitamin D receptor, vitamin D response element, transcriptional regulation, vitamin D analogs, 7-dehydrocholesterol, ergosterol
MeSH terms: Cytochrome P-450 Enzyme System, DNA, Humans, Immune System, Metabolic Diseases, Neoplasms, Vitamin D, Receptors, Calcitriol, Response Elements

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Vitamin D metabolism, mechanism of action, and clinical applications

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