Fat soluble vitamin :Vitamin A

FAT SOLUBLE
VITAMINS-VITAMIN:A
DR.KOPPUKONDA RAVI BABU B.Sc., MBBS ; MD
BIOCHEMISTRY
ASSISTANT PROFESSOR

Vitamin A
Vitamin A serves an important role in vision, is required for
gene expression, embryonic development, for immune and
reproductive functions, and is an antioxidant.

VITAMIN –A : Chemistry
Vitamin A is the nutritional term for the group of
compounds with a 20-carbon structure containing a methyl-
substituted cyclohexenyl ring (β-ionone ring) and an
isoprenoid side chain .
 with a hydroxyl group (retinol), an aldehyde group (retinal),
a carboxylic acid group (retinoic acid), or an ester group
(retinyl ester) at the terminal C15.

Fig.Vitaminic Forms of A1, A2, and β-Carotene.

Fig. β-Carotene and the major vitamin A vitamers. Asterisk shows the site of
symmetrical cleavage of β-carotene by carotene dioxygenase, to yield retinaldehyde.

Retinol, the principal vitamin A vitamer, can be oxidized
reversibly to retinal—which shares all the biological activity
of retinol—or further oxidized to retinoic acid, which shows
some of its biological activity.
 The principal storage forms of vitamin A are retinyl esters,
particularly palmitate.
 The term retinoids refers to retinol, its metabolites, and
synthetic analogs with similar structure.
Some dietary carotenoids (C40
polyisoprenoid compounds) are included in the vitamin A
family and are classified as provitamin A because they are
cleaved biologically to yield retinol.

β-carotene, α-carotene, and β-cryptoxanthin.
Vitamin A compounds are yellowish oils or low-melting-
point solids (depending on isomeric purity) that are
practically insoluble in water but are soluble in organic
solvents and mineral oil.

Vitamin A is sensitive to O2 and to ultraviolet light, which
induces a greenish fluorescence with an absorbance peak at
325 nm.
Provitamin A, β-carotene.
This compound is an orange-to-purple, water-insoluble solid
that is oxidized in air to inactive products.
The other carotenes, cryptoxanthin and β-apocarotenals,
are asymmetric with only one β-ionone ring and yield less
vitamin A activity.

VITAMIN-A : Dietary Sources
animal-derived foods, such as liver, offal, and fish oils.
Other sources are full cream milk, butter, and fortified
margarines.
The provitamin A carotenoids are obtained from yellow to
orange fruits and vegetables, and from green leafy
vegetables.
Good sources are pumpkin, carrots, tomatoes, apricots,
grapefruit, lettuce, and most green vegetables.
25% -carotenoids and approximately 75%-preformed
retinol.

VITAMIN –A :Absorption, Transport, Metabolism, and
Excretion
Preformed vitamin A, most often in the form of retinyl
esters or carotenoids, is subject to emulsification and mixed
micelle formation by the action of bile salts before they are
transported into the intestinal cell.
The retinyl esters are moved across the mucosal membrane
and hydrolyzed to retinol within the cell to be then re-
esterified by cellular RBP II
 And packaged into chylomicrons, which then enter the
mesenteric lymphatic system and pass into the systemic
circulation.
A small amount of the ingested retinoid is converted into
retinoic acid in the intestinal cell.
The efficiency of absorption of preformed vitamin A is high

Absorption, Transport, Metabolism, and Excretion continue….
Carotenoids, also in micellar form, are absorbed into the
duodenal mucosal cells by passive diffusion.
 The efficiency of absorption of carotenoids is much lower
than that for vitamin A (9% and 22%),and is subject to more
variables, including the carotenoid type, the amount in the
meal, matrix properties, nutrient status, and genetic factors.
Once inside the mucosal cell, β-carotene is principally
converted to retinal by the enzyme β-carotene-15,15′-
dioxygenase.
 Retinal is converted by retinal reductase to retinol and
esterified.
Betacarotene can also be cleaved eccentrically to β-
apocarotenals.

Absorption, Transport, Metabolism, and Excretion continue….
β-apocarotenals can be further degraded to retinal or
retinoic acid.
The newly synthesized retinyl esters, from both preformed
vitamin A and carotenoids, along with exogenous lipids and
nonhydrolyzed carotenoids, then pass with chylomicrons via
the lymphatic system to the liver,
 where uptake by parenchymal cells again involves
hydrolysis.

Absorption, Transport, Metabolism, and
Excretion continue….
In the liver, retinol is bound with and transthyretin
(thyroxine-binding prealbumin in a 1 : 1 : 1 complex of
sufficient size to prevent loss by glomerular filtration and is
returned to the circulation, or stored as esters within the
stellate cells.
Delivery of retinol to the tissue is controlled by the
availability of the vitamin A–protein complex in the
circulation, although this control mechanism can be
bypassed by large doses of retinol.

Retinoic acid from the intestinal mucosa is transported
bound to serum albumin via the portal vein.
 Retinoic acid cannot be significantly reduced to retinal, but
it is rapidly metabolized in tissue, such as liver, to yield more
polar catabolites (eg, 5,6-epoxyretinoic acid) and
conjugates, such as retinoyl β-glucuronide, which are
excreted.

A small amountof retinoic acid undergoes enterohepatic
circulation after intestinal hydrolysis of the glucuronide,
which is excreted in bile.

VITAMIN –A:Functions
Retinal in vision is considered the most important
physiological function of vitamin A.
 All-transretinol is the predominant circulating form of
vitamin A.
Cells of the retina isomerize this to the 11-cis alcohol that is
reversibly dehydrogenated to 11-cis retinal.
 This sterically hindered geometrical isomer of the aldehyde
combines as a lysyl-linked Schiff base with suitable proteins
(eg, opsin) to generate photosensitive pigments, such as
rhodopsin.

Illumination of such pigments causes photoisomerization
and the release of all-trans-retinal and the protein, a process
that couples the large conformational change with ion flux
and optic nerve transmission.
The all-trans-retinal is isomerized to the 11-cis isomer,
which combines with the liberated protein to reconstitute
the photo pigment in a visual cycle.
The pyridine nucleotide–dependent dehydrogenase
(reductase) can also reduce the all-trans-retinal to all-trans-
retinol.

role in reproduction, growth, embryonic development, and
immune function.
 Many of these functions are mediated through the binding
of retinoic acid to specific nuclear receptors that regulate
genomic expression.
 In normal growth, and in maintenance of the integrity of
epithelial cells, retinoic acid acts through the activation of
retinoic acid receptors and retinoid X receptors in the
nucleus to regulate various genes that encode for structural
proteins, enzymes, extracellula matrix proteins, RBPs, and
receptors.

Summary of kinetics and mechanism of action
of vitamin A

VITAMIN-A:Requirements and Reference Nutrient
Intakes
 Retinol activity equivalent (RAE) 1 RAE = 1 μg retinol, 12 μg
β-carotene, or 24 μg carotenoids.
 RDAs for vitamin A are the following:
 900 μg RAE for men 19 years and older;
 700 μg RAE for women 19 years and older,
with up to 770 μg RAE/day in pregnancy and up to 1300 μg
RAE/day in lactation;
300 to 900 μg RAE for children 1 to 18 years, dependent on
age and gender;
and an adequate intake (AI) of 400 μg RAE at 0 to 6 months
and 500 μg RAE from 7 to 12 months for infants.

VITAMIN – A : Intravenous Supply
TPN, is 1000 μg retinol.
 This is usually provided as retinol palmitate and may be
supplied with other fat-soluble vitamins in a mixture
dissolved in a fat emulsion for intravenous feeding, or may
be designed to be compatible with a mixture of all vitamins
suitable for addition to other water-soluble nutrients.

VITAMIN A : Deficiency
Vitamin A deficiency primarily affects infants and children.
Risk factors include poverty, low birth weight, poor
sanitation, malnutrition, infection, and parasitism.
Because hepatic accumulation of vitamin A occurs during
the last trimester of pregnancy, preterm infants are
relatively vitamin A deficient at birth.

RDA of 400 μg RAE is sufficient.
 Infants with birth weights of less than 1500 g (those at <30
weeks’ gestation) have virtually no hepatic vitamin A stores
and are at risk of vitamin A deficiency.

 Various researchers have observed that:
(1) bronchopulmonary dysplasia is common in premature
infants;
Rx: intramuscula r injections of 630 μg RAE every 2 days.
(3) blood concentrations of vitamin A decline during TPN,
often reaching concentrations of 10 to 15 μg/dL (normal: 20
to 65 μg/dL) unless adequate supplements are given.
(4) vitamin A (retinol) delivered in TPN solutions may be
absorbed into the inner walls of plastic administration sets;
however, this loss can be minimized by using ethylene vinyl
acetate rather than polyvinyl chloride.

Fat malabsorption, particularly caused by celiac disease or
chronic pancreatitis, and protein-energy malnutrition
predispose to vitamin A deficiency.
Liver disease diminishes RBP synthesis, and ethanol abuse
leads to both hepatic injury and competition with retinol for
alcohol dehydrogenase, which is necessary for the oxidation
of retinol to retinal and retinoic acid.
Degenerative changes in the eyes and skin and poor dark
adaptation or night blindness (nyctalopia),followed by
degenerative changes in the retina.

Xerophthalmia occurs when the conjunctiva becomes dry
with small gray plaques with foamy surfaces (Bitot spots).
These lesions are reversible with vitamin A administration.
More serious effects of deficiency are known as
keratomalacia and cause ulceration and necrosis of the
cornea, which lead to perforation, prolapse,
endophthalmitis, and blindness.
skin changes include dryness, roughness, papular eruptions,
and follicular hyperkeratosis.
Atrophy of certain specialized epithelia, followed by
metaplastic hyperkeratinization.

VITAMIN – A : Toxicity
Ingestion of excess vitamin or as a side effect
of inappropriate therapy.
 Hypervitaminosis A occurs after liver storage
of retinol, and its esters exceeds 3000 μg/g
tissue, with ingestion of more than 30,000
μg/day for months or years,
 or if plasma vitamin A concentrations exceed
140 μg/ dL (4.9 μmol/L).
Older adults are more susceptible to vitamin
A toxicity at lower doses because exposure to
retinyl esters is longer because of delayed
postprandial clearance of lipoproteins.

 Acute toxicity present as abdominal pain, nausea, vomiting,
severe headaches, dizziness, sluggishness, and irritability,
followed within a few days by desquamation of the skin and
recovery.
Long-term toxicity :is characterized by Bone and joint pain,
hair loss, dryness and fissures of the lips, anorexia, benign
intracranial hypertension, weight loss, and hepatomegaly.

Threefold the RDA for several years resulted in classic
histological changes of hepatotoxicity .
Osteoporosis and hip fracture are associated with vitamin A
intakes that are only twice the RDA.
 Infants given excess vitamin A over months to years can
develop intracranial features, typically bulging fontanelle,
and skeletal abnormalities at doses of 5500 to 6750 μg/day.

High vitamin A intake in humans, acting via 13-cis-retinoic
acid, is teratogenic.
The critical period of susceptibility is the first trimester of
pregnancy, and primary abnormalities derive from the
cranial neural crest cells.

hypercalcemia, especially in chronic kidney disease.
Carotenemia -infants and children.
yellowing of the skin is observed, is benign because the
excess carotene is deposited rather than converted to
vitamin A.
There is a role for the measurement of β-carotene in the
differential diagnosis of specific cases of jaundice in
children.
impaired activity of the enzyme β-carotene-15,15′-
dioxygenase in children that leads to accumulation of β-
carotene, especially when consuming carotene-rich foods,
but it is a benign condition

Carotenemia
has also been linked to amenorrhea ?.
Increased concentrations have also been found in
hypothyroid patients, in whom conversion to vitamin A is
decreased, and in patients with hyperlipemia that is
associated with diabetes mellitus.

VITAMIN – A : LABORATORY ASSESSMENT
The plasma concentration of vitamin A- ( 20 μg/g liver ).
assessed by the measurement of retinol concentration.
Retinol circulates in plasma as a 1 : 1 : 1 complex with RBP
and transthyretin (TTR), forming a complex that prevents
glomerular filtration.
 The circulating concentration of RBP is determined by
dietary protein and Zn, which are necessary for RBP
synthesis.
Thus, protein malnutrition, liver disease, and Zn deficiency
resulting in RBP deficiency will lead to hypovitaminosis A .

Renal failure resulting in decreased excretion of RBP has
been reported to result in hypervitaminosis A.
Both RBP and TTR are negative acute-phase proteins; thus
inflammatory changes will result in transient falls in both
proteins and plasma retinol.
To distinguish inflammatory from nutritional causes of
reduced plasma retinol concentrations, it may be necessary
to measure CRP.

Early chemical methods that are rarely used include the
Carr-Price photometric method, which uses antimony
trichloride in chloroform as the reagent, and the later
Neeld-Pearson method, which uses trifluoroacetic acid to
produce a blue pigment with the conjugated double bonds
of vitamin A (and the carotenoids).
To improve specificity and sensitivity, later methods used
high-pressure liquid chromatography (HPLC) after solvent
extraction and other separation techniques, with
fluorometric or spectrophotometric

Both normal and reverse-phase HPLC have been used.
Reverse-phase HPLC is preferable for acid-sensitive
compounds (eg, 5,6-epoxyretinoic acid).
Photometric, electrochemical, and mass
spectrophotometric detectors have all been used.
 serum is deproteinized with ethanol that contains internal
standards, centrifuged, and extracted with hexane.
This is followed by evaporation to dryness, and the residue
is redissolved in tetrahydrofuran.

HPLC-mass spectrometry methods.
Recent advances : the use of supported liquid extraction
methodology for sample preparation using modified
diatomaceous earth (natural fossilized biominerals
containing high silica content) packed into columns or 96-
well plates.

VITAMIN – A :PREANALYTICAL VARIABLES
Plasma, serum, or whole blood specimens are all suitable
for retinol measurements.
Fasting samples are recommended, especially if a patient is
taking oral or parenteral vitamin A supplementation.
A sample should be taken at least 8 hours after
supplementation if fasting is not possible.
Vitamin A samples are light sensitive and should be
protected from light as much as possible by wrapping in foil.
 Vitamin A showed good stability in whole blood collected
into tubes containing lithium (Li) heparin for up to 48 hours
at room temperature and without light protection.
 Another study reported that vitamin A was stable for up to
72 hours in whole blood samples kept at 32°C and up to 14
days in serum stored at 11°C.

VITAMIN – A :Reference Intervals
20 to 40 μg/dL (0.70–1.40 μmol/L) for 1- to 6-year-old
children,
children,
adolescents,
And 30 to 80 μg/dL (1.05–2.80 μmol/L) for adults.
Values more than 30 μg/dL (1.05 μmol/L) are associated
with appreciable reserves in the liver and correlate well with
vitamin A intake.
Within the reference interval, values for men are generally
approximately 20% higher than those for women.

VITAMIN – A :Reference Intervals
By HPLC, with ultraviolet detection, the reference interval
for serum α-carotene is 14 to 60 μg/L (26–112 nmol/L),
β-carotene is 90 to 310 μg/L (167–577 nmol/L), lutein is 80
to 200 μg/L (140–352 nmol/L), and lycopene 100 to 300
μg/L (186–559 nmol/L).

Fat soluble vitamin :Vitamin A

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