, the animal form of vitamin A
, is a fat-soluble vitamin important in
growth. It is also a diterpenoid
is among the most usable forms of vitamin A, which also include
(aldehyde form), Retinoic acid
(acid form) and retinyl ester
(ester form). These chemical compounds are collectively known as
, and all possess the biological
activity of all-trans retinol as a common feature in their
structure. Structurally, retinoids possess a β-ionone ring and a
polyunsaturated side chain, with either an alcohol, aldehyde, a
carboxylic acid group or an ester group. The side chain is composed
of four isoprenoid units, with a series of conjugated double bonds
which may exist in trans or cis configuration.
Retinol is produced from the hydrolysis of retinyl esters and
retinal. Commercial production typically requires retinal synthesis
through reduction of a pentadiene derivative and subsequent
acidification/hydrolysis of the resulting isomer to produce
retinol. When prepared as a dietary supplement, retinol is
stabilized as retinyl acetate or palmitate.
Retinol is ingested in a precursor form; animal sources (liver
, whereas plants
) contain pro-vitamin A carotenoids
of retinyl esters results in retinol, while pro-vitamin A
carotenoids can be cleaved to produce retinal
. Retinal, also known as retinaldehyde, can
be reversibly reduced to produce retinol or it can be irreversibly
oxidized to produce retinoic acid. The best described active
retinoid metabolites are 11-cis
-retinal and the all-trans
and 9-cis-isomers of retinoic acid.
Elmer McCollum, a biochemist at the University of
Wisconsin–Madison, and colleague Marguerite Davis identified a fat-soluble
nutrient in butterfat and cod liver oil. Their work confirmed
that of Thomas Osborne
and Lafayette Mendel, at Yale, which suggested a fat-soluble nutrient in
butterfat, also in 1913.
Vitamin A was first synthesized in
1947 by two Dutch chemists, David
Adriaan van Dorp
and Jozef Ferdinand Arens.
Although the Vitamin A was not identified until the 20th century,
written observations of conditions created by deficiency of this
nutrient appeared much earlier in history. Sommer (2008) classified
historical accounts related to Vitamin A and/or manifestations of
deficiency as follows: "Ancient" accounts; 18th- to 19th-century
clinical descriptions (and their purported etiologic associations);
early 20th-century laboratory animal experiments, and clinical and
epidiomologic observations that identified the existence of this
unique nutrient and manifestations of its deficiency.
Chemical structure and function
Many different geometric isomers of retinol, retinal and retinoic
acid are possible as a result of either a trans
configuration of four of the five double
found in the polyene
isomers are less stable and can readily convert to the
configuration (as seen in the structure of
-retinol shown here). Nevertheless, some
isomers are found naturally and carry out essential
functions. For example, the 11-cis
-retinal isomer is the
, the vertebrate photoreceptor
molecule. Rhodopsin is comprised
of the 11-cis-retinal covalently linked via a Schiff base
to the opsin
protein (either rod opsin or blue, red or green cone opsins). The
process of vision relies on the light-induced isomerisation of the
chromophore from 11-cis
a change of the conformation and activation of the photoreceptor
molecule. One of the earliest signs of vitamin A deficiency is
night-blindness followed by decreased visual acuity.
won the 1967 Nobel Prize in Physiology
for his work with retina
pigments (also called visual pigments), which led to the
understanding of the role of vitamin A in vision.
Many of the non-visual functions of vitamin A are mediated by
retinoic acid, which regulates gene expression by activating
intracellular retinoic acid
. The non-visual functions of vitamin A are essential
in the immunological function, reproduction and embryonic
development of vertebrates as evidenced by the impaired growth,
susceptibility to infection and birth defects observed in
populations receiving suboptimal vitamin A in their diet.
Role in embryology
Retinoic acid via the retinoic acid receptor influences the process
of cell differentiation, hence, the growth and development of
embryos. During development there is a concentration gradient of
retinoic acid along the anterior-posterior (head-tail) axis. Cells
in the embryo respond differently to retinoic acid depending on the
amount present. For example, in vertebrates the hindbrain
transiently forms eight rhombomers and each rhombomere has a
specific pattern of genes being expressed. If retinoic acid is not
present the last four rhombomeres do not develop. Instead
rhombomeres 1-4 grow to cover the same amount of space as all eight
would normally occupy. Retinoic acid has its effects by turning on
a differential pattern of Hox genes which encode different
homeodomain transcription factors which in turn can turn on cell
type specific genes. Deletion of the Hox-1 gene from rhombomere 4
makes the neurons growing in that region behave like neurons from
rhombomere 2. The retina is also patterned by retinoic acid, with a
concentration gradient that is high on the ventral side of the
retina and low on the dorsal side.
Stem cell biology
Retinoic acid is an influential factor used in differentiation
of stem cells to
more committed fates, echoing retinoic acid's importance in natural
embryonic developmental pathways. It is thought to initiate
differentiation into a number of different cell lineages by
unsequestering certain sequences in the genome.
It has numerous applications in a plethora of stem cell
differentiation protocols; amongst these are the differentiation of
human embryonic stem cells
posterior foregut lineages and also to functional motor neurons
Vitamin A is required in the production of rhodopsin
, the visual
used in low light levels. This is why eating foods rich
in vitamin A is often said to allow an individual to see in the
Vitamin A is essential for the correct functioning of epithelial cells
. In Vitamin A deficiency,
replaced by keratin
producing cells, leading
adequate Vitamin A status. In severe Vitamin A deficiency, lack of
glycoproteins may lead to corneal ulcers or liquefaction.
Vitamin A is essential to maintain intact epithelial tissues
as a physical barrier
to infection; it is also involved in maintaining a number of immune
cell types from both the innate and acquired immune systems. These
include the lymphocytes
natural killer cells
), as well
as many myelocytes (neutrophils
, and myeloid dendritic cells
Formation of red blood cells (Haematopoiesis)
Vitamin A may be needed for normal haematopoiesis
; deficiency causes
abnormalities in iron
Vitamin A affects the production of human
All retinoid forms of vitamin A are used in cosmetic and medical
applications applied to the skin. Retinoic acid, termed Tretinoin
in clinical usage, is used in the
treatment of acne
and keratosis pilaris
in a topical cream. An
isomer of tretinoin, isotretinoin
also used orally (under the trade names Accutane
for severe or recalcitrant acne.
In cosmetics, vitamin A derivatives are used as anti-aging
chemicals- vitamin A is absorbed
through the skin and increases the rate of skin turnover, and gives
an increase in collagen
giving a more
Tretinoin, under the alternative name of all-trans retinoic
(ATRA), is used as chemotherapy for acute promyelocytic leukemia
subtype of acute myelogenous
. This is because cells of this subtype of leukemia are
sensitive to agonists of the retinoic acid receptors (RARs).
Units of measurement
When referring to dietary allowances or nutritional
science, retinol is usually measured
in international units
refers to biological activity and therefore is unique to each
individual compound, however 1 IU of retinol is equivalent to
approximately 0.3 micrograms (300 nanograms).
This vitamin plays an essential role in vision, particularly night
vision, normal bone and tooth development, reproduction, and the
health of skin and mucous membranes (the mucus-secreting layer that
lines body regions such as the respiratory tract). Vitamin A also
acts in the body as an antioxidant, a protective chemical that may
reduce the risk of certain cancers.
There are two sources of dietary vitamin A. Active forms, which are
immediately available to the body are obtained from animal
products. These are known as retinoids and include retinal and
retinol. Precursors, also known as provitamins, which must be
converted to active forms by the body, are obtained from fruits and
vegetables containing yellow, orange and dark green pigments, known
as carotenoids, the most well-known being beta-carotene. For this
reason, amounts of vitamin A are measured in Retinal Equivalents
(RE). One RE is equivalent to 0.001 mg of retinal, or
0.006 mg of beta-carotene, or 3.3 International Units of
In the intestine, vitamin A is protected from being chemically
changed by vitamin E. Vitamin A is fat-soluble and can be stored in
the body. Most of the vitamin A you eat is stored in the liver.
When required by a particular part of the body, the liver releases
some vitamin A, which is carried by the blood and delivered to the
target cells and tissues.
The Dietary Reference
(DRI) Recommended Daily Amount (RDA) for Vitamin A for a
25-year old male is 900 micrograms/day, or 3000 IU.
The ratio of conversion of β-carotene to vitamin A has changed over
time from 6:1 to 12:1 and currently is estimated to be 21:1 from
recent studies and experimental trials carried out in the
developing nations. The implication of the current ratio is that
large quantities of β-carotene are needed for conversion to yield
the desired dietary requirement of vitamin A for deficient group of
the population. This also means that more continents are now being
affected by the deficiency of vitamin A, not just the peculiar ones
(Africa and Asia). South America also is likely to be affected if
the current conversion ratio is applied and if urgent steps are not
taken to change the global health policy to combat this eminent
disease threatening the world, there will possibly be a looming
disaster ahead of us.
The Food Standards Agency
states that an average adult should not consume more than 1500
micrograms (5000 IU) per day, because this increases the chance of
During the absorption process in the intestines
, retinol is incorporated into chylomicrons
as the ester form, and it is these
particles that mediate transport to the liver
Liver cells (hepatocytes
) store vitamin A
as the ester, and when retinol is needed in other tissues, it is
de-esterifed and released into the blood as the alcohol. Retinol
then attaches to a serum carrier, retinol binding protein
transport to target tissues. A binding protein inside cells,
acid binding protein
, serves to store and move retinoic acid
. Carotenoid bioavailability
ranges between 1/5 to 1/10
of retinol's. Carotenoids are better absorbed when ingested as part
of a fatty meal. Also, the carotenoids in vegetables, especially
those with tough cell walls (e.g. carrots), are better absorbed
when these cell walls are broken up by cooking or mincing.
- see Vitamin A
deficiency for details
Vitamin A deficiency is common in developing countries but rarely
seen in developed countries. Approximately 250,000 to 500,000
malnourished children in the developing world go blind each year
from a deficiency of vitamin A. Night
is one of the first signs of vitamin A deficiency.
Vitamin A deficiency contributes to blindness by making the
very dry and damaging the retina
Interventions or remedies in vitamin A deficiency in a deficient
population may be enforced using three approaches:(A) through
dietary modification involving the adjustment of menu choices of
affected persons from available food sources to optimize vitamin A
content, (B) enriching commonly eaten and affordable foods with
vitamin A, a process called fortification. It involves addition of
synthetic vitamin A to staple foods like margarine, bread, flours,
cereals and other infant formulae during processing and (C) giving
high-doses of vitamin A to the targeted deficient population, a
method known as supplementation. Caution should however be
exercised when using supplementation as a method of replenishing
vitamin A in the body so that upper harmful limits are not
Retinoid overdose (toxicity)
- see Hypervitaminosis A
The Tolerable Upper Intake
(UL) for vitamin A, for a 25-year old male, is 3,000
micrograms/day, or about 10,000 IU.
Too much vitamin A in retinoid form can be harmful or fatal,
resulting in what is known as hypervitaminosis A
. The body converts the
dimerized form, carotene
, into vitamin A as
it is needed, therefore high levels of carotene are not toxic
compared to the ester (animal) forms. The livers of certain
animals, especially those adapted to polar environments, often
contain amounts of vitamin A that would be toxic to humans. Thus,
vitamin A toxicity is typically reported in Arctic explorers and
people taking large doses of synthetic vitamin A. The first documented
death due to vitamin A poisoning was Xavier
Mertz, a Swiss scientist
who died in January 1913 on an Antarctic expedition that had lost its food supplies and fell
to eating its sled dogs.
Mertz consumed lethal amounts of
vitamin A by eating the dogs' livers.
Vitamin A toxicity occurs when an individual ingests vitamin A in
large amounts more than the daily recommended value in the
threshold of 25,000IU/Kg or more. Often, the individual consumes
about 3-4 times the RDA's specification Toxicity of vitamin A is
believed to be associated with the intervention methods used to
upgrade vitamin A levels in the body such as food modification,
fortification and supplementation, all of which are employed to
combat vitamin A deficiency Toxicity is classified into two
categories: Acute and chronic toxicities. The former occurs few
hours or days after ingestion of large amounts of vitamin A
accidentally or via inappropriate therapy. The later toxicity
(Chronic) takes place when about 25,000IU/Kg or more of vitamin A
is consumed for a prolonged period of time. Symptoms associated
with both toxicities include, but not limited to nausea, blurred
vision, fatigue, weight-loss, menstrual abnormalities etc.
If eaten in one meal, 30 to 90 grams of polar
liver is enough to kill a human being, or to make even
sled dogs very ill.
Excess vitamin A has also been suspected to be a contributor to
. This seems to happen at
much lower doses than those required to induce acute intoxication.
Only preformed vitamin A can cause these problems, because the
conversion of carotenoids into vitamin A is downregulated when
physiological requirements are met. An excessive uptake of
carotenoids can, however, cause carotenosis
The carotenoid beta carotene
interestingly associated with an increase in lung cancer
when it was studied in a lung cancer
prevention trial in male smokers. In non-smokers, the opposite
effect has been noted.
Excess preformed vitamin A during early pregnancy has also been
associated with a significant increase in birth defects. These
defects may be severe, even life-threatening. Even twice the daily
recommended amount can cause severe birth defects. The FDA
currently recommends that pregnant women get their Vitamin A from
foods containing beta carotene and that they should ensure that
they consume no more than 5,000 IU of preformed Vitamin A (if any)
per day. Although Vitamin A is necessary for fetal development,
most women carry stores of Vitamin A in their fat cells, so
oversupplementation should be strictly avoided.
A review of all randomized controlled trials in the scientific
literature by the Cochrane
published in JAMA
found that supplementation with beta-carotene or vitamin
mortality by 5% and 16%, respectively.
Contrary to earlier observations, recent studies emerging from some
developing countries(India, Bangladesh and Indonesia) have strongly
suggested that dosing expectant mothers in the population in which
vitamin A deficiency is common and maternal mortality is high can
greatly reduce maternal mortality ratio Similarly, dosing newborn
infants with 50,000IU(15 mg) of vitamin A within 2 days of
birth, can significantly reduce neonatal mortality
All sources of vitamin A
provide retinol, but retinoids are found naturally in some foods of
animal origin. Each of the following contains at least 0.15 mg
of retinoids per :
retinol is marketed
under the following trade names: Acon, Afaxin, Agiolan, Alphalin,
Anatola, Aoral, Apexol, Apostavit, Atav, Avibon, Avita, Avitol,
Axerol, Dohyfral A, Epiteliol, Nio-A-Let, Prepalin, Testavol,
Vaflol, Vi-Alpha, Vitpex, Vogan, and Vogan-Neu.
Night blindness—the inability to see well in dim light—is
associated with a deficiency of vitamin A
At first, the most light sensitive (containing more retinal)
is influenced. Less
pigmented by retinal iodopsins
forms/colors in humans), responsible for color vision
and sensing relatively high light
intensities (day vision), are less impaired at early stages of the
deficiency. All these
protein-pigment complexes are located in the light-sensing cells in
When stimulated by light, rhodopsin splits into a protein and a
cofactor: opsin and all-trans
-retinal (a form of vitamin
A). The regeneration of active rhodopsin requires opsin and
-retinal. The regeneration of
-retinal occurs in vertebrates via a sequence of
chemical transformations that constitute "the visual cycle" and
which occurs primarily in the retinal pigmented epithelial
Without adequate amounts of retinal, regeneration of rhodopsin is
incomplete and night blindness occurs.
Closely related chemicals
Genetically engineered vitamin A enriched rice
Due to the high prevalence of vitamin A deficiency in developing countries
, there are efforts
to produce genetically modified
rice rich in beta carotene. The idea is that this would help poor
people, who can not afford a varied diet containing sufficient
natural sources of vitamin A, meet their dietary needs. The
project is one such effort,
and is already undergoing trials.
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