METABOLISME

VITAMIN A & D
Ayu Rahadiyanti
 Nutrition in Your
Life
Realizing that vitamin A from vegetables participates in vision,
Mom encourages her children to “eat your carrots” because
“they’re good for your eyes”. Dad takes his children outside to
“enjoy the fresh air and sunshine” because they need the vitamin
D that is made with the help of the sun. Physician recommends
that a patient use vitamin E to slow the progression of heart
disease. Another Physician gives a newborn a dose of vitamin K to
protect against life-threatening blood loss. These common daily
occurences highlight some of the heroic work of the fat-soluble
vitamins.
RETINOIDS
Dietary Sources
• All natural sources of vitamin A in diet are derived
from provitamin A carotenoids.
• Vegetables and fruits provide the main dietary
sources of vitamin A in the form beta carotene and
other provitamin A.
• The richest sources of the retinoids are foods derived
from animals—liver, fish liver oils, milk and milk
products, butter, and eggs.
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• Vitamin A in animal foods occurs as retinyl esters of fatty
acids in association with membrane-bound cellular lipid
and fat-containing storage cells.
• Provitamin A carotenoids in foods of vegetable origin are
also associated with cellular lipids but are embedded in
complex cellular structures such as the
cellulose-containing matrix of chloroplasts or the
pigment-containing portion of chromoplasts.
• Normal digestive processes free vitamin A and
carotenoids from food matrices, which is a more efficient
process from animal than from vegetable tissues.
Absorption &
Metabolism

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Conversion of Vitamin A
Compounds
Function
Metabolism

Haematopoiesis

Bone development

Pattern formation during embryogenesis

The maintenance of differentiated epithelia

Immunocompetence
Vitamin A’s Role in
Vision
All-trans-Retinol
Why is vitamin A needed for night vision to occur?
• Vitamin A (all-trans-retinol) is a precursor to the formation of the photopigment
rhodopsin, which is located in the rods. In order for rhodopsin to be formed, vitamin
A must be converted to 11-cis-retinal. This can occur in one of two ways. Vitamin A
(all-trans-retinol) can be converted to 11-cis-retinol by isomerase. This
11-cis-retinol can then be converted to 11-cis-retinal. Alternatively, vitamin A
(all-trans-retinol) can be converted to all-trans-retinal which can then be converted to
11-cis-retinal.
• Now that 11-cis-retinal has been formed by either method, it can combine with
scotopsin to form the rhodopsin. As rhodopsin absorbs light in the rods, a
conformational change occurs in 11-cis-retinal to become all-trans-retinal. A
conformational change also occurs in the opsin fragment to form metarhodopsin II,
which is the activated form of rhodopsin. The metarhodopsin II then stimulates
transducin, a G-coupled protein found on the surface of the disk within the outer
membrane in the rod cell. This activation of transducin causes an activation in cGMP
phosphodiesterase, which will remove the cGMP mediated activation of cGMP-gated
channels that are letting Na+ ions leak into the rod cytoplasm resulting in a
hyperpolarization of that rod cell. Thus, in the presence of light, the blockage of
Na+ movement into the rod cell will result in a hyperpolarization of that rod cell
which then allows messages about light being seen during night vision to be sent to
the brain for final interpretation.
Vit A in Hematopoiesis
• Retinol is transformed by the cells into
RA by alcohol and ADHs and RALDHs
respectively. RA is transported by CRABP
and it can be degraded by CYP26 or
translocated to the nucleus, where it
binds and activates nuclear RARs and
RXRs, displacing co-repressors and
recruiting coactivators of the
transcription of target genes.
• In this way, RA regulates the
developmental hematopoiesis,
modulates lympho and granulopoiesis
and contributes to the homeostasis of
the hematopoietic stem cells. VDR can
also dimerize with RXRs and modulate
the immune response.
 Vit A Bone Development

• Vit A participates in the

dismantling part. With the help
vit A, these bone-dismantling
cells destroy selected sites in
bone, removing the parts that
are not needed. After complete,
the bone dismantling cells die,
leaving excavation site to be
rebuilt by the bone-bulding
cells.
 Vit A in Pattern Formation during Embryogenesis
• Retinol binds to spesific
intracellular receptor
• Retinol receptor complex
binds to DNA and
regulates the expression
of genes required for
reproductive function
• In men retinol
participates in sperm
development, in women
vit A supports normal
fetal development during
pregnancy.
Vit A in Maintenance of Differentiated Cell
• Vitamin A promotes
differentiation of epithelial cells
and goblet cells, one celled
glands that synthesize and
secrete mucus.
• Mucus coats and protects the
epithelial cells from invasive
microorganisms and other
potentially damaging
substances, such as gastric
juices.
• The active form of vit A involved in growth and differentiation
is retinoic acid.
• Retinoic acid binds to spesific cellular retinoic acid binding
protein (receptor).
• Retinoic acid receptor complex binds to DNA and regulate the
expression of genes required for growth and differentiation.
• All trans retinoic acid induces apoptosis (programmed cell
death) of cancer cells.
Maintenance of epithelial integrity and
glycoprotein synthesis
• Retinol is involved in the maintenance of epithelial integrity and
glycoprotein synthesis.
• Retinol prevents the excess keratin synthesis.
• Retinyl phosphate formed from retinol is required for glycoprotein
synthesis.
• Glycosyl retinyl phosphate acts as donor of CH for synthesis of
glycoproteins and GAGs.
• Collagen breakdown : retinoic acid inhibits the enzyme
collagenase and thus prevents the breakdown of collagen
• The antioxidant effect of β-carotene is due to the stabilization
of peroxide free radicals within the conjugated alkyl structure
of β-carotene.
• The antioxidant properties of β-carotene is partly responsible
for its anti cancer activity, protective effect against CHD, and
prevention of cataract formation.
Vitamin A in Immunocompetence
• Vitamin A deficiency is strongly associated with depressed
immunity.
• Retinoic acid was shown to stimulate, and retinaldehyde to
inhibit, the activity of protein kinase C derived from T cells.
• Retinol is essential for proliferation of activated human B cells.
• Retinoic acid increased the proliferation of
granulocyte/macrophage precursor cells.
 Unit of Expression Vitamin A
1 RE = 1 µg retinol Diet contained 150 µg retinol, 1550 µg
1 RE = 12 µg β-carotene β-carotene, and 1200 µg other provitamin A
1 RE = 24 µg other provitamin A carotenoids, the vitamin A equivalency of
1 IU = 0,3 µg retinol the diet would be:
1 IU = 0,6 µg β-carotene 150 µg + (1550 µg / 12) + (1200 µg / 24) =
329,16 µg retinol equivalency.
Nutritional factors that influence vit A status

• Adequate amounts of dietary fat is essential in forming

Fat micelles and providing a lipid vehicle for vit A absorption
and transport.

deficiency • Absorption of retinol and carotenoids is markedly lower

than normal when diets contain very little fat (< 5 g/day).

Protein • The lack of dietary protein leads to an impairment of all

stages of vit A metabolism due to a depressed synthesis of

deficiency enzymes, RBP, and receptors.

 • Zn deficiency reduces the enzymatic oxydation
Zn of retinol to retinaldehyde in the retina.
• Zn dependent enzymes are involved in the
deficiency synthesis of proteins, including RBP and
receptors.

• Vit E is necessary for optimal utilization of

vitamin A. More vitamin A is stored in the liver
Vit E when the diet contains vitamin E than when
the diet is deficient in vitamin E.
• Most of the body’s vitamin A reserve remains in the
liver, carotenoids are also deposited elsewhere in fatty
tissues throughout the body.
• Dietary restriction in energy, proteins, and some
micronutrients can limit hepatic synthesis of proteins
specific to mobilization and transport of vitamin A.
• Altered kidney functions or fever associated with
infections (e.g. respiratory infections or diarrhoea) can
increase urinary vitamin A loss.
 Deficiency Vit A
• Tanda awal kurangnya kepekaan thd sinar
hijau yg diikuti dg gangguan beradaptasi thd
cahaya temaram, dan diikuti buta senja.
• Xeroftalmia : keratomalasia kornea dan
kebutaan
• Defisiensi ringan 🡪 memperlemah sistem
imun, rentan infeksi
 Toxicity Vit
A
• Kapasitas tubuh untuk memetabolisme vit A
terbatas, asupan berlebihan dpt menyebabkan
penimbunan yg melebihi protein pengikat shg vit
A dlm bentuk tdk terikat dpt merusak jaringan.
• Gejala toksisitas : nyeri kepala, mual, ataksia,
anoreksia (berkaitan dg peningkatan cairan
serebrospinal), hepatomegali disertai
hiperlipidemia, homeostasis Ca (penebalan
tulang panjang, hiperkalsemia, kalsifikasi
jar.lunak), kulit (kering, deskuamasi, alopesia).
• Vitamin D differs from the other nutrients
because the body can synthesize it, with the
help of sunlight, from a precursor that the
body makes from cholesterol.
• Also known as calciferol, vitamin D comes in
two major forms. Vit D2 derives primarily
from plant foods in the diet. Vitamin D3
derives from animal foods in the diet and
from synthesis in the skin.
These two forms of vitamin D
are similar and both must be
activated before they can
fully function.
Factors Affecting Vitamin D
Synthesis
Sources Vit D

1 IU = 0,025 µg vitamin D
 Vit D in Bone Growth

• Vit D is a member of a large and cooperative bone-making and

maintenance team composed of nutrients and other
compounds, including vitamins A and K; the hormones
parathyroid hormone and calcitonin; the protein collagen; and
the minerals (Ca, P, Mg, F). Vit D’s special role in bone health is
to assist in the absorption of calcium and phosphorus, thus
helping to maintain blood concentrations of these minerals.
• The bones grow denser and stronger as they absorb and deposit
these minerals. Adequate nutrition and regular exercise are
essential to achieving peak bone mass before age 30.
Vitamin D raises blood concentrations of bone minerals in 3 ways :

When the diet is sufficient, vitamin D enhances mineral

absorption from the GI tract.

When the diet is insufficient, vitamin D provides the

needed minerals from other sources: reabsorption by the
kidneys and mobilization from the bones into the blood.

The vitamin may work alone, as it does in the GI tract, or

in combination with parathyroid hormone, as it does in
the bones and kidneys.
The photoproduction and metabolism of vitamin D and the various
biologic effects of 1,25(OH)2D on calcium, phosphorus, and bone
metabolism. Vitamin D is either produced in the skin by exposure to
UVB radiation or is ingested in the diet. Vitamin D (D represents
vitamin D2 or vit D3) is converted by the vitamin D-25-hydroxylase
(25-OHase) in the liver to 25(OH)D. 25(OH)D is converted in the
kidneys by 1-OHase to 1,25(OH)2D. Once formed, 1,25(OH) 2D
enhances intestinal calcium and phosphorus absorption and
stimulates the expression of RANKL on the osteoblast to interact with
its receptor RANK on preosteoclasts to induce mature osteoclastic
activity, which releases calcium and phosporus (HPO42-). In addition,
1,25(OH) 2D inhibits the renal 1-OHase and stimulates the expression
of the renal 25(OH)D-24-hydroxylase (24-OHase). The induction of the
24-OHase results in the destruction of 1,25(OH) 2D into a
water-soluble inactive metabolite calcitroic acid.
 Vitamin D in Gene Expression

• Calcitriol functions primarily like

a steroid hormone. Its major
actions involve interaction with
cell membrane receptors and
nuclear VDR proteins to affect
gene transcription in a wide
variety of tissue.
• The VDR-calcitriol complex is
attached to the VDRE region,
transctiption for specific mRNAs
for spesific proteins is enhanced
or inhibited.
• Factors that contribute to vit D deficiency :
✔ Dark skin
✔ Breastfeeding without supplementation
✔ Lack of sunlight
✔ Not using fortified milk
• In Vit D deficiency, production of calbidin (protein that binds Ca
in intestinal cells) slow. Thus even when Ca in diet adequate, it
passes through GI tract unabsorbed, leaving the bones
undersupplied.
Sunbathing & Production Vit
D • Berjemur dpt meningkatkan produksi vitamin D3 5-6 kali.
• Berjemur yang diperpanjang 🡪 produksi pra D3 berhenti (karena
produk pra D3 terbatas)
• The pigments of dark skin provide some protection from the sun’s
damage, but they also reduce vitamin D synthesis. Dark-skinned
people require more sunlight exposure than light-skinned
people—perhaps as much as 4 to 6 times longer.
• Prolonged exposure to sunlight can, however, prematurely wrinkle
the skin and cause skin cancer. Sunscreens help reduce these risks,
but sunscreens with a SPF of 8 and higher can also reduce vitamin
D synthesis. Still, even with an SPF 15 to 30 sunscreen, sufficient
vitamin D synthesis can be obtained in 10 to 20 minutes of sun
exposure.
 Interaction Vit D, Ca, & Pb

• Keracunan Pb pada manusia terdapat tanda-tanda :

✔ Penurunan 1,25 di-OH D dan 25 –OH serum
✔ Rendahnya konsumsi Ca
✔ Peningkatan konsentrasi hormon PTH serum
• Aktivitas Pb memblok aktivitas stimuli vitamin D
terhadap pengambilan Ca oleh ginjal.
• Pemberian Vitamin D 🡪 meningkatkan akumulasi Pb
dalam darah, tulang, dan jaringan 🡪 vitamin D
merangsang pengambilan Pb.
Vit D & Metabolism Ca in
Pregnancy
• Selama periode Gestasi 25 – 30 minggu Ca ibu dipindahkan ke
fetus.
• Peningkatan penyerapan Ca oleh usus dan masa tulang
meningkat.
• Defisiensi Vitamin D tidak nyata menghambat pemindahan Ca ke
fetus.
• Peningkatan sirkulasi 1,25 di-OH D tidak ada hubungan dengan
peningkatan kadar paratiroid darah.
• Terdapat hormon lain (estrogen) dapat meningkatkan hidroksilasi
25-OH D atau faktor lain yang belum diketahui.
Deficiency Vit
D
• Rakitis 🡪 tulang anak kekurangan mineral akibat buruknya
penyerapan Ca. Masalah serupa timbul akibat defisiensi
pada pertumbuhan saat remaja.
• Osteomalasia 🡪 pd dewasa tjd demineralisasi tulang, tulang
mjd lunak, fleksibel, rapuh, dan berubah bentuk. Terutama
pd wanita karena jarang terpapar sinar matahari, sering tjd
setelah beberapa kali hamil.
Toxicity Vit
D
• Sebagian bayi peka thd asupan vit D 50 µg/hari shg tjd peningkatan
[Ca plasma]. Kondisi ini dpt menyebabkan kontraksi pemb darah,
peningkatan tekanan darah, dan kalsinosis (kalsifikasi jar.lunak).
• Pajanan berlebihan sinar matahari tdk bersifat toksik krn
terbatasnya kapasitas untuk membentuk prekuror vit D
(7-dehidrokolesterol) dan pajanan berkepanjangan pravit D oleh
sinar matahari menyebabkan terbentuknya senyawa inaktif.
• Kelebihan vit D meningkatkan konsentrasi Ca darah, yg
menyebabkan cenderung untuk mengendap di jaringan lunak
membentuk batu, terutama pd ginjal. Kalsifikasi jg dpt
mengeraskan pembuluh darah.
 REFERENSI

1. Rolfes SR, Pinna K, Whitney E. Understanding Normal

and Clinical Nutrition 8th ed. USA : Wadsworth. 2009.
2. WHO & FAO. Vitamin and Mineral Requirements in
Human Nutrition 2nd ed. 2004
3. Ball GFM. Vitamins Their Role in the Human Body. UK :
Blackwell Publishing. 2004
Always remember to take your Vitamins :
Take your Vitamin A for ACTION,
Vitamin B for BELIEF,
Vitamin C for CONFIDENCE,
Vitamin D for DISCIPLINE,
Vitamin E for ENTHUSIASM.
-Pablo-

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