Vitamin D2 (Ergocalciferol) | Supplementopedia

Overview

Vitamin D₂ (ergocalciferol) is a fat-soluble secosteroid derived from ergosterol, the fungal analogue of cholesterol.
In humans, it serves as a pro-hormone that, after hepatic and renal hydroxylation, becomes the active hormone 1,25-dihydroxy-vitamin D (calcitriol).
Calcitriol binds the vitamin D receptor (VDR) to regulate calcium-phosphate metabolism and influence numerous extra-skeletal processes.

Improved Serum 25-hydroxy-vitamin D Levels: Supports bone mineralization and reduces fracture risk in older adults.
Modest Muscle Strength Improvement: Reduces falls in frail populations.
Reduced Respiratory Infections: Especially in winter-time cohorts.
Immune Modulation: Decreases auto-immune activity in diseases such as multiple sclerosis.
Support for Cognitive Health: Observational studies link higher 25-OH-D levels to slower cognitive decline.
Aid in Glucose Regulation: Modest improvements in insulin sensitivity have been reported in vitamin-D-deficient individuals.
These benefits are dose-dependent and are most robust when baseline status is low.

Absorption: After oral ingestion, vitamin D₂ is absorbed with dietary fats via the intestinal lymphatics.
Hepatic Hydroxylation: In the liver, it is hydroxylated at carbon-25 forming 25-hydroxy-ergocalciferol (25-OH-D₂), the primary circulating biomarker.
Renal Hydroxylation: A second hydroxylation at carbon-1 in the kidney (or in immune cells) yields 1,25-dihydroxy-ergocalciferol (1,25-(OH)₂-D₂).
VDR Binding: This active metabolite binds the nuclear vitamin D receptor (VDR), a transcription factor that heterodimerizes with retinoid-X-receptor (RXR) and binds vitamin D response elements (VDREs) on DNA.
Gene Regulation: The resulting gene-regulatory cascade modulates calcium-binding proteins (e.g., calbindin), influences cytokine transcription (e.g., IL-10, suppresses IL-17), and regulates cell-cycle proteins.
Effects: Affects bone mineralization, immune tolerance, and cellular differentiation.
Regulation: The pathway is tightly regulated by parathyroid hormone, fibro-growth-factor-23, and renal 1-α-hydroxylase activity.

Typical Adult Supplementation: Ranges from 400 IU (10 µg) to 2,000 IU (50 µg) daily.
Effect: Reliably raises serum 25-OH-D by ~10–20 nmol/L over 8–12 weeks.
Deficiency Treatment: For individuals with proven deficiency (<30 nmol/L), higher therapeutic regimens of 5,000–10,000 IU (125–250 µg) daily for 6–8 weeks are frequently employed.
Maintenance Dose: Followed by a maintenance dose of 800–1,200 IU (20–30 µg).
Administration: Vitamin D₂ can be taken with any meal containing fat to enhance absorption; split dosing (morning and evening) improves steadiness of serum levels.
Special Populations: Elderly, malabsorption syndromes, or patients on anticonvulsants may require higher loading doses (e.g., 50,000 IU weekly for 8 weeks) under medical supervision.

General Tolerance: Vitamin D₂ is generally well-tolerated.
Primary Adverse Effect: Hypercalcemia when excessive doses (>10,000 IU/day) are taken chronically.
Symptoms of Hypercalcemia: Nausea, polyuria, and renal calcification.
Contraindications: Hyperparathyroidism, sarcoidosis, granulomatous disease, and severe renal impairment.
Drug Interactions:
- Thiazide diuretics and calcium supplements potentiate hypercalcemia.
- Glucocorticoids, anticonvulsants, and bariatric surgery can increase requirements.
Pregnancy and Lactation: Pregnant and lactating women should not exceed 4,000 IU/day unless prescribed.
Monitoring: Routine monitoring of serum calcium and 25-OH-D levels is recommended for long-term high-dose regimens.

Molecular Formula: C₂₈H₄₄O
IUPAC Name: (5Z,7E)-9,10-sec-cholesta-5,7,10-trien-3β-ol
Structure: Features a broken B-ring (secosteroid) with a double bond at C5-C6 (Z) and C7-C8 (E), and a conjugated diene (C10-C19) plus a hydroxyl group at C3 (β-orientation).
Lipophilicity: Highly lipophilic (log P ≈ 7.5).
Melting Point: Near 70 °C.
Solubility: Soluble in non-polar solvents (e.g., ethanol, olive oil).
Enzymatic Hydroxylation: The presence of a 3-β-hydroxyl group enables enzymatic hydroxylation to 25-OH-D₂ in the liver.
VDR Binding Affinity: The stereochemistry at C3 and the conjugated triene system are critical for VDR binding affinity.

Natural Production: Vitamin D₂ is naturally produced by UV-B irradiation of ergosterol in fungi and yeast (e.g., Saccharomyces cerevisiae, Candida spp.).
Commercial Extraction: Commercially extracted from irradiated mushroom (e.g., Agaricus bisporus).
Microbial Fermentation: Produced via microbial fermentation of Saccharomyces cultures.
Purification: Followed by purification through crystallization or high-performance liquid chromatography.
Synthetic Routes: Synthetic routes exist that chemically convert ergosterol into ergocalciferol using photochemical or chemical oxidation.
Quality Considerations:
- Verification of purity (>99 % by HPLC).
- Absence of UV-induced isomers (e.g., 5-cis-D₂).
- Accurate potency labeling.
Preferred Supplements: Good Manufacturing Practice (GMP)-certified supplements that use non-GMO, non-irradiated substrates are preferred for consistency and safety.