Vitamin D absorption, transport and metabolism

Domina Petric, MD
Vitamin D absorption,
transport and metabolism

Enteric absorption of vitamin D
I.
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Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
2

• Vitamin D is absorbed from the small intestine by
nonsaturable passive diffusion that is dependent
on micellar solubilization and the presence of bile
salts.
• The fastest absorption appears to be in the upper
portions of the small intestine: the duodenum and
jejunum.
• Owing to the longer transit time of food in the distal
portion of the small intestine, the greatest amount
of vitamin D absorption probably occurs in ileum.
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•Vitamin D enters the lymphatic
circulation predominantly (about 90% of
the total amount absorbed) in
association with chylomicra, with most
of the balance being associated
with the α-globulin fraction.
•The efficiency of this absorption process
for vitamin D appears to be about 50%.
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Transport of vitamin D
II.
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Transfer from chylomicra to a plasma
• Almost all absorbed vitamin D is retained in non
esterified form, which is associated with the surface of
chylomicrons (lipoprotein particles).
• A portion of the vitamin D can be transferred
from chylomicra to a binding protein in the plasma,
either directly or during the process of chylomicron
degradation.
• Vitamin D that is not transferred in the plasma is taken
up with chylomicron remnants by the liver, where it is
transferred to the same binding protein and released to
the plasma.
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Vitamin D binding protein
Vitamin D-binding protein (DBP) is a glycosylated,
cysteine rich, α-globulin of 55 kDa and 458 amino
acids.
It binds vitamins D2 or D3 and their metabolites
stoichiometrically, with ligand-binding dependent
on the cis-triene structure and C3-hydroxyl grouping.
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DBP is depressed in patients with hepatic
disease.
It is increased during estrogen therapy or
pregnancy.
It does not appear to cross the placenta.
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• DBP mobilizes the vitamin produced
endogenously in the skin.
• The efficiency of endogenously produced vitamin
D3 is greater than that given orally: the former
enters the circulation strictly via DBP, whereas
orally given enters as complexes of DBP as well
as chylomicra.
• DBP protein has also been found on the surfaces
of lymphocytes and macrophages.
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Tissue distribution
• Vitamin D is not stored by the liver.
• It reaches the liver within a few hours after
being absorbed across the gut or synthesized
in the skin.
• From the liver it is distributed relatively
evenly among the various tissues, where it
resides in hydrophobic compartments.
• Fatty tissues such as adipose show slightly
greater concentrations.
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Tissue distribution
• About half of the total vitamin D in the tissues
occurs as the parent vitamin D3 species, with
the next most abundant form, 25-OH-D3 (20%).
• In the plasma, 25-OH-D3 predominates by
several fold.
• Tissues including those of the kidneys, liver,
lungs, aorta and heart also tend to
accumulate 25-OH-D3.
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Vitamin D receptors
Vitamin D receptors (VDRs) have been
identified in more than 30 different cell types.
These include cells closely related to the
maintenance of calcium homeostasis as well as
immune, endocrine, hematopoetic, skin and
tumor cells.
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Vitamin D receptors
Organ system Cell type
Bone Osteoblasts
Alimentary tract Epithelial cells, enterocytes, colonocytes,
stomach
Liver Hepatocytes
Kidney Epithelial (proximal and distal) cells
Heart Atrial myoendrocrine cells, heart muscle cells
Skeletal, smooth muscle Myocytes
Cartilage Chondrocytes
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Vitamin D receptors
Organ system Cell type
Hematolymphopoetic Activated T and B cells, macrophages, monocytes, spleen,
thymus reticular cells and lymphocytes, lymph nodes,
tonsillary dendritic cells
Reproductive Amnion, chorioallantoic membrane, epididymus,
mammary gland alveolar and ductal cells, ovary, oviduct,
placenta, testis Sertoli and Leydig cells, uterus, yolk sac
Skin Epidermis, fibroblasts, hair follicles, keratinocytes,
melanocytes, sebaceous glands
Nervous Brain (hippocampus, cerebellar Purkinje and granule cells,
bed nucleus, stria terminalis, amygdala central nucleus),
sensory ganglia, spinal cord
Other endocrine Adrenal medulla and cortex, pancreatic b cells, pituitary,
thyroid follicles and C cells, parathyroid gland
Other Bladder, choroid plexus, lung, endothelial cells, parotid
gland
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Metabolism of vitamin D
III.
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Metabolic activation of vitamin D
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25-hydroxylation
• Most of the vitamin D taken up by the liver from
either DBP or lipoproteins is converted by
hydroxylation of side-chain carbon C-25 to yield
25-OH-D3 (calcidiol).
• Enzyme is vitamin D 25-hydroxylase.
• Calcidiol is the major circulating form of the vitamin.
• 25-hydroxyvitamin D3 is not retained within the cell,
but is released to the plasma where it accumulates
by binding with DBP.
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25-hydroxylation
The circulating level of
25-OH-D3, normally
10–40 ng/ml (25–125 nM),
is a good indicator of
vitamin D status.
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1-hydroxylation
• The initial hydroxylation product of vitamin D
(25-OH-D3) is further hydroxylated at the C-1
position of the A ring to yield 1,25-(OH)2-D3.
• This hydroxylation is catalyzed by 25-OH-vitamin
D 1-hydroxylase.
• This activity is located primarily in renal cortical
mitochondria, but also in mitchondrial and
microsmal fractions of at least some extrarenal
tissues: bone cells, liver, placenta.
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1-hydroxylation
The 1-hydroxylase uses NADPH2 as
the electron donor and has three
constituent proteins:
•ferridoxin reductase
•ferridoxin
•cytochrome P-450
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Catabolism of vitamin D
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24-hydroxylation
• Hydroxylation at the C-24 of the side chain can occur
to both 25-OH-D3 or 1,25-(OH)2-D3 to produce the
di- and tri-hydroxy metabolites 24,25-(OH)2-D3
(calcidiol) and 1,24,25-(OH)3-D3 (calcitroic acid or
calcitriol).
• The 24-hydroxylase has a 10-fold greater affinity for
1,25-(OH)2-D3 than for 25-OH-D3.
• The greatest activity of the 24-hydroxylase is found
in renal mitochondria.
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24-hydroxylation
• 24-hydroxylase is a cytochrome P-450-
dependent enzyme requiring NADPH.
• It is inhibited by hypercalcemia and
hyperphosphatemia.
• Both calcitriol and 24,25-(OH)2-D3 appear to
be produced under conditions of vitamin D
adequacy and normal calcium homeostasis.
• Calcitriol is a major biliary metabolite of the
vitamin.
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Regulation of vitamin D metabolism
IV.
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Regulation of vitamin D metabolism
The dominant renal synthesis of
1,25-(OH)2-D3 is effected by the
responses of parathyroiod
hormone (PTH) and calcitonin
(CT) to serum levels of Ca2+ and
phosphate.
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Renal synthesis of 1,25-(OH)2-D3 is
increased when:
Serum Ca2+ is low, the Ca
receptor mediated stimulation
of the parathyroid to produce
PTH, stimulates an increase in
the renal 1-hydroxylase activity.
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increased when:
Serum phosphate is low (in the
presence of normal serum Ca2+),
an unknown mechanism that
appears to involve a pituitary
gland hormone increases the
1-hydroxylase.
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increased when:
Serum levels of both Ca2+
and phosphate are low,
both mechanisms result in
the superstimulation of the
1-hydroxylase.
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Renal 1-hydroxylase
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Production of D3 in macrophages
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Catabolism
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1,25-(OH)2-D3
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• Combs GF. The Vitamins. Fundamental Aspects in
Nutrition and Health. Elsevier Inc. 2008.
Literature
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33

Vitamin D absorption, transport and metabolism

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