Vitamin D

BY
Dr. Samy Ali Hussein Aziza
Professor of Biochemistry and
Clinical Biochemistry
Faculty of Veterinary Medicine,
Moshtohor, Benha University,
Egypt.
E-Mail: [email protected]
 Vitamin D
Synonyms:
Anti-rachitic factor
 VITAMIN D
The D vitamins are a group of sterols that have a
hormone-like function.
 The active molecule, 1,25-dihydroxy cholecaliferol(1,25
diOH D3)binds to intracellular receptor proteins.
 The (1,25 diOH D3)-receptor complex interacts with
DNA in the nucleus of target cells in a manner similar to
that of vitamin A, and either selectively stimulates gene
expression, or specifically represses gene transcription.
 The most prominent actions of (1,25 diOH D3) are to
regulate the plasma levels of calcium and phosphorus.
 Vitamin D
•Vitamin D is a steroid hormone that functions to
regulate specific gene expression following
interaction with its intracellular receptor.
• The biologically active form of the hormone is
1,25-dihydroxy vitamin D3 (1,25-(OH)2D3), also
termed (calcitriol).
• Calcitriol functions primarily to regulate calcium
and phosphorous homeostasis.
 Distribution of vitamin D
1. Diet:
 Ergocalciferol (vitamin D2),found in plants,
and cholecalciferol (vitamin D3),found in
animal tissues, are sources of preformed
vitamin D activity .
 Ergocalciferol and cholecalciferol differ
chemically only in the presence of an additional
double bond and methyl group in the plant
sterol.
2. Endogenous vitamin precursor:
• 7-dehydrocholesterol ,an intermediate
in cholesterol synthesis, is converted to
cholecalciferol in the dermis and
epidermis of humans exposed to
sunlight. Preformed vitamin D is a
dietary requirement only in individuals
with limited exposure to sunlight.
 Form of Vitamin D
Two forms:
Ergocalciferol (vitamin D2) , found in plants
Cholecalciferol ( vitamin D3)in animals &their products

Synthesis in the body from cholesterol– not enough

• Cholecalciferol is synthesised by the body in the skin by the
action of light. Uv light
Cholesterol to 7 dehydrocholesterol Cholecalciferol
Formed by the opening of steroid nucleus

• Cholecalciferol is also known as “sunshine vitamin”

• Vitamin D3 is to be converted to 1, 25 dihydroxy D3 in order

to exert its biological activity
Ergosterol
Vitamin D2
7-Dehydrocholesterol
Vitamin D3
 Vitamin D Is Synthesized in the Skin
• 7-Dehydrocholesterol (an
intermediate in the synthesis of
cholesterol that accumulates in the
skin) undergoes a nonenzymic
reaction on exposure to ultraviolet
light, yielding previtamin D.
• This previtamin D undergoes a further
reaction to form cholecalciferol, which
is absorbed into the bloodstream.
The synthesis of vitamin D in the skin
 Vitamin D Is Metabolized to the Active Metabolite,
Calcitriol, in Liver & Kidney
• Cholecalciferol, either synthesized in the skin or
from food, undergoes two hydroxylations to yield
the active metabolite, 1,25-dihydroxyvitamin D or
calcitriol.
• Ergocalciferol from foods undergoes similar
hydroxylation to yield ercalcitriol.
• In the liver, cholecalciferol is hydroxylated to form
the 25-hydroxy-derivative, calcidiol.
• This is released into the circulation bound to a
vitamin D binding globulin, which is the main
storage form of the vitamin.
• In the kidney, calcidiol undergoes either 1-
hydroxylation to yield the active metabolite
1,25-dihydroxy-vitamin D (calcitriol), or 24-
hydroxylation to yield a probably inactive
metabolite, 24,25-dihydroxyvitamin D (24-
hydroxycalcidiol).
Chemistry of Vitamin D
• Metabolism of vitamin D
 FORMATION & ACTIVATION OF VITAMIN D3

7-Dehydrocholesterol
uv
Skin
rays 25 hydroxylase (liver)

Cholecalciferol 25 hydroxy cholecalciferol

1 hydroxylase
kidney

1,25 Dihydroxycholecalciferol
(Calcitriol)
Active form of Cholecalciferol
 Metabolism of vitamin D
1. Formation of 1,25-dihydroxy
cholecaliferol(1,25 diOH D3):
 -Vitamins D2 and D3 are not
biologically active, but are converted in
vivo to the active form of the D vitamin
by two sequential hydroxylation
reactions.
 - The first hydroxylation occurs at the
25-position, and is catalyzed by a
specific hydroxylase in the liver.
1. The product of the reaction, 25-
hydroxycholecalciferol, is the
predominant form of vitamin D in the
plasma and the major storage form of
the vitamin.
2. 25-hydroxycholecalciferol is further
hydroxylated at the one position by a
specific 25-hydroxycholecalciferol 1 -
hydroxylase found primarily in the
kidney, resulting in the formation of
1,25-dihydroxycholecalciferol.
2. Regulation of 25- hydroxycholecalciferol 1-hydroxylase:
1,25-dihydroxy cholecaliferol(1,25
diOH D3)is the most potent vitamin D
metabolite.
 Its formation is tightly regulated by the level of
plasma phosphate and calcium ions .
 25-hydroxycholecalciferol 1 -hydroxylase
activity is increased directly by low plasma phosphate
or indirectly by low plasma calcium, which triggers
the release of parathyroid hormone (PTH).
 Hypocalcemia caused by insufficient dietary calcium
thus results in elevated levels of plasma 1,25 diOH
D3.
 1 -hydroxylase activity is also decreased by excess
1,25 diOH D3 the product of the reaction.
Metabolism of Vitamin D
 Vitamin D Metabolism Is Both Regulated by and
Regulates Calcium Homeostasis

The principal function of vitamin D is to

maintain the plasma calcium concentration.
Calcitriol achieves this in three ways:

1.It increases intestinal absorption of calcium.

2.It reduces excretion of calcium (by
stimulating resorption in the distal renal
tubules).
3.It mobilizes bone mineral.
• Also calcitriol is involved in:
 insulin secretion.
 synthesis and secretion of parathyroid and
thyroid hormones.
 inhibition of production of interleukin by activated
T-lymphocytes and of immunoglobulin by
activated B-lymphocytes, differentiation of
monocyte precursor cells, and modulation of cell
proliferation.
 it acts like a steroid hormone, binding to nuclear
receptors and enhancing gene expression.
 it also has rapid effects on calcium transporters
in the intestinal mucosa.
 Function of vitamin D
• The overall function of 1,25-diOH D3 is
to maintain adequate plasma levels of
calcium.
• It performs this function by:
1. Increasing uptake of calcium by the
intestine.
2. Minimizing loss of calcium by the
kidney.
3. Stimulating resorption of bone when
necessary.
1. Effect of vitamin D on the intestine:
1,25 diOH D3stimulates intestinal absorption
of calcium and phosphate.
1,25 diOH D3enters the intestinal cell and
binds to a cytosolic receptor.
The 1,25 diOH D3-receptor complex then
moves to the nucleus where it selectively
interacts with the cellular DNA. As a result,
calcium uptake is enhanced by an increased
synthesis of a specific calcium-binding protein.
 Thus, the mechanism of action of 1,25 diOH
D3 is typical of steroid hormones .
2. Effect of vitamin D on bone:
1,25 diOH D3 stimulates the
mobilization of calcium and phosphate
from bone by a process that requires
protein synthesis and the presence of PTH.
The result is an increase in plasma calcium
and phosphate. Thus, bone is an important
reservoir of calcium that can be mobilized
to maintain plasma levels.
 Functions of Vitamin D (Calciferol )

• Maintenance of calcium balance.

• Enhances intestinal absorption of
Ca2+.
• Mobilizes bone mineral.
• Regulation of gene expression
and cell differentiation.
 Sources and requirement of vitamin D

• Vitamin D occurs naturally in fatty fish,

liver, and egg yolk.
• The RDA for adults is 5μg cholecalciferol,
or 200 international units (IU) of vitamin D.
RECOMMENDED DAILY ALLOWANCE FOR
VITAMIN D

Infants & Children 10 microgram (400 IU)

Adults 7.5 microgram
Pregnancy +5 microgram (200 IU)
Lactation +5 microgram

1 IU = 0.025 microgram of cholecalciferol

 Clinical indications of Vitamin D
1. Nutritionalrickets:
 Vitamin D deficiency causes a net
demineralization of bone, resulting in rickets
in children and osteomalacia in adults .
 Rickets is characterized by the continued
formation of the collagen matrix of bone, but
incomplete mineralization, resulting in soft,
pliable bones.
In osteomalacia, demineralization of
preexisting bones increases their susceptibility
to fracture.
2. Renal rickets (renal osteodystrophy):
 This disorder results from chronic
renal failure and, thus, the decreased
ability to form the active form of the
vitamin.
 1,25 diOH cholecalciferol(calcitriol)
administration is effective replacement
therapy.
3. Hypoparathyroidism:
Lack of parathyroid hormone
causes hypocalcemia and
hyperphosphatemia.
 These patients may be treated
with any form of vitamin D,
together with parathyroid hormone.
 Deficiency disease of Vitamin D
Rickets = poor mineralization of bone.
Osteomalacia = bone demineralization
 Renal rickets (renal osteodystrophy).
Hypoparathyroidism.
 Vitamin D Deficiency Affects Children &
Adults
• The main symptom of vitamin D deficiency in
children is rickets and in adults is osteomalacia.
• Rickets is characterized improper mineralization
during the development of the bones resulting in
soft bones.
• Osteomalacia is characterized by
demineralization of previously formed bone
leading to increased softness and susceptibility to
fracture.
 Toxicity of vitamin D
High doses of Vitamin D (100,000 IU for
weeks or months) can cause loss of
appetite, nausea, thirst, and stupor.
Enhanced calcium absorption and bone
resorption results in hypercalcemia,
which can lead to deposition of calcium
in many organs, particularly the arteries
and kidneys.
Vitamin D Is Toxic in Excess:
• Some infants are sensitive to
intakes of vitamin D as low as 50
µg/day, resulting in an elevated
plasma concentration of calcium.
This can lead to contraction of
blood vessels, high blood
pressure, and calcinosis—the
calcification of soft tissues.
Although excess dietary vitamin D is
toxic, excessive exposure to sunlight
does not lead to vitamin D
poisoning, because there is a limited
capacity to form the precursor, 7-
dehydrocholesterol, and prolonged
exposure of previtamin D to sunlight
leads to formation of inactive
compounds.
 VITAMIN D AS A HORMONE
 Can be synthesised in the body
 Produced in the inactive form, which needs to
be activated

 Has definite target organs – intestine, bone and

kidney

 Formation of active vitamin D3 is subjected to

feedback control

 Active form maintains calcium homeostasis along

with two other hormones, PTH and calcitonin
References:
1. Lippincott’s review of biochemistry, 3rd
edition.
1. Biochemistry Stryer 5th edition.
2. Harper,s Biochemistry 28 edition.