Vitamin D represents a generic term for seco steroids (B-ring in steroid is open) with biologically active activity. Medically significant are:
- Ergosterol (provitamin) → vitamin D2 (ergocalciferol) – found in plant foods.
- 7-Dehydrocholesterol (provitamin) → vitamin D3 (cholecalciferol) – occurring in animal foods.
- Calcidiol (25-hydroxycholecalciferol, 25-OH-D3) – endogenous synthesis in liver.
- Calcitriol (1,25-dihydroxylcholecalciferol, 1,25-(OH)2-D3) – endogenous synthesis in kidney; hormonal active form
Structurally, like all steroids, vitamin D2 and D3 contain the typical ring system of cholesterol (A, B, C, D), with the B ring broken. Vitamin D amounts are expressed in units of weight:
- 1 International Unit (IU) is equivalent to 0.025 µg of vitamin D.
- 1 µg corresponds to 40 IU vitamin D
Synthesis
The starting substance for the endogenous synthesis of vitamin D3 in the skin is 7-dehydrocholesterol. This provitamin is found in the highest concentration in the stratum basale (basal layer) and stratum spinosum (prickle cell layer) of the skin and is derived from cholesterol in intestinal mucosa (intestinal mucosa) and liver by the action of a dehydrogenase (hydrogen-splitting enzyme). The latter, in turn, can be synthesized endogenously in intestinal mucosa (intestinal mucosa) and liver and ingested via food of animal origin. Under the influence of UV-B radiation with a wavelength between 280-315 nm with a maximum effect around 295 nm, in a first step a photochemical reaction leads to the splitting of the B-ring in the sterane skeleton, resulting in the conversion of 7-dehydrocholesterol into previtamin D3. In a second step, previtamin D3 is converted to vitamin D3 by a light-independent thermal isomerization (conversion of the molecule to another isomer) [2-4, 6, 11]. Vitamin D2 can be synthesized endogenously from ergosterol. Ergosterol originates from plant organisms and enters the human body through the consumption of plant foods. Analogous to endogenous vitamin D3 synthesis, vitamin D2 is synthesized from ergosterol in the skin under the influence of UV-B light by a photochemical reaction followed by light-independent thermoisomerization (conversion of the molecule to another isomer under the influence of heat). More than 50% of the daily vitamin D requirement is met from endogenous production.Hypervitaminosis is not possible by prolonged exposure to UV-B radiation, because above a previtamin D3 concentration of 10-15% of the original content of 7-dehydrocholesterol, both previtamin D3 and vitamin D3 are converted to inactive isomers. The rate of vitamin D synthesis depends on several factors, such as:
- Season
- Place of residence (latitude)
- Extent of air pollution, ozone pollution in industrial agglomerations.
- Stay outdoors
- Use of sunscreens with sun protection factor (> 5)
- Body covering for religious reasons
- Skin color and pigmentation
- Skin diseases, burns
- Age
Resorption
Like all fat-soluble vitamins, vitamin D is absorbed (taken up) in the upper small intestine as part of fat digestion, i.e., the presence of dietary fats as transporters of lipophilic (fat-soluble) molecules and bile acids to solubilize (increase solubility) and form micelles (form transport globules that make fat-soluble substances transportable in aqueous solution) is necessary for optimal intestinal absorption (uptake via the intestine). Dietary vitamin D enters the small intestine and is absorbed as a component of mixed micelles into enterocytes (cells of the small intestinal epithelium) via passive diffusion. Absorption is highly dependent on the type and amount of lipids supplied at the same time. Intracellularly (within the cell), incorporation (uptake) of vitamin D occurs into chylomicrons (lipid-rich lipoproteins), which transport vitamin D via the lymph into the peripheral circulation. With intact liver/gallbladder, pancreas (pancreatic), and small intestine function, as well as adequate intake of dietary fats, approximately 80% of alimentary (dietary) vitamin D is absorbed.
Transport and distribution in the body
During transport to the liver, chylomicrons are degraded to chylomicron remnants (low-fat chylomicron remnant particles) and absorbed vitamin D is transferred to a specific vitamin D-binding protein (DBP). Vitamin D synthesized in the skin is released into the bloodstream and also transported to the liver bound to DBP.DBP binds with both vitamin D2 and vitamin D3, as well as with hydroxylated (OH group-containing) vitamin D. The DBP binds with vitamin D2 and vitamin D3. The serum concentration of DBP is about 20-fold higher than that of the above ligands (binding partners). It is assumed that under normal conditions only between 3-5% of the binding capacity of DBP is saturated. Vitamin D3 is stored predominantly in fat and muscle with a long biological half-life.
Biotransformation
In the liver and kidney, vitamin D3 is converted to calcitriol (1,25-dihydroxylcholecalciferol, 1,25-(OH)2-D3), the metabolically active vitamin D hormone, by twofold hydroxylation (insertion of OH groups). The first hydroxylation reaction occurs in the mitochondria (“energy power plants”) or microsomes (small membrane-limited vesicles) of the liver, and to a lesser extent in the kidney and intestine, by means of 25-hydroxylase (an enzyme), which converts vitamin D3 to 25-hydroxycholecalciferol (25-OH-D3, calcidiol). 1-alpha-hydroxylase mediates the second hydroxylation step in the mitochondria of the proximal renal tubule (renal tubules). This enyzm converts 25-OH-D3 bound to DBP from the liver to the kidney by insertion of another OH group into the biologically active 1,25-(OH)2-D3, which exerts its hormonal effects at target organs, including the small intestine, bone, kidney, and parathyroid gland. Low activities of 1-alpha-hydroxylase are also found in other tissues with vitamin D receptors that have autocrine (released hormones act on the secreting cell itself) or paracrine functions (released hormones act on cells in the immediate environment), such as colon, prostate, breast, and immune system [2-4, 6, 7, 10, 11]. In an alternative hydroxylation step, 25-OH-D3 can be converted to 24,25-(OH)2-D3 in the mitochondria of the proximal renal tubule by the action of 24-hydroxylase. Until now, this hydroxylation reaction was considered a degradation step with the generation of ineffective metabolites (intermediates). However, 24,25-dihydroxylcholecalciferol is now thought to have functions in bone metabolism [2-4, 10, 11]. 25-OH-D3 is the predominant vitamin D metabolite circulating in plasma and represents the best indicator of vitamin D3 supply status. The concentration of circulating 1,25-(OH)2-D3 is finely regulated by plasma levels of parathyroid hormone (PTH) and vitamin D and calcium levels, respectively. Hypercalcemia (calcium excess) and elevated vitamin D levels promote 24-hydroxylase activity, while inhibiting 1-alpha-hydroxylase activity. In contrast, hypocalcemia (calcium deficiency) and hypophosphatemia (phosphate deficiency) lead to an increase in 1-alpha-hydroxylase activity via stimulation of PTH production [1-3, 6, 7, 10].
Equivalence of vitamin D2 and vitamin D3
The previously established view of equivalence and interchangeability of vitamin D2 and vitamin D3 has been refuted by recent pharmacokinetic studies. In their work, Trang et al. found a 1.7-fold higher serum concentration of 25-OH-D3 in the vitamin D3-supplemented group of subjects after 2 weeks of taking 4,000 IU of vitamin D2 and vitamin D3, respectively.Mastaglia et al. concluded that in postmenopausal, osteoporotic women in a three-month intervention, much higher oral doses of vitamin D2 are required compared with the usual recommended daily vitamin D3 dose of 800 IU to achieve adequate serum levels of 25-OH-D3. In addition, vitamin D2 metabolites are thought to have lower binding to plasmatic vitamin D-binding protein, nonphysiologic metabolism, and shorter half-life compared with vitamin D3.Because of the discrepancy between the two forms of vitamin D at the molar level, vitamin D 2 cannot be recommended for supplementation or food fortification.
Excretion
Vitamin D and its metabolites are excreted predominantly via bile and only to a small extent renally.
