Vitamin A

The structure of retinol, the most common dietary form of vitamin A

Vitamin A is a fat-soluable vitamin that belongs to a family of similarly shaped molecules, the retinoids, and occurs in several chemical forms, notably an aldehyde (retinal), an alcohol (retinol), an acid (retinoic acid). In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl palmitate. Precursors to the vitamin (provitamins) are present in foods of plant origin as some of the members of the carotenoid family of compounds (Berdanier 1997).

Vitamin A is an essential human nutrient for normal metabolic functioning.

essential human nutrient. 

Overview and structure

Vitamins are organic (carbon-containing) nutrients obtained through the diet and essential in small amounts for normal metabolic reactions.

Vitamins can act both as catalysts and participants in the chemical reaction.

Vitamin A actually refers to a family of similarly shaped molecules: the retinoids. Its important part is the retinyl group, which can be found in several forms.

All forms of vitamin A have a Beta-ionone ring to which an isoprenoid chain is attached. This structure is essential for vitamin activity. The orange pigment of carrot - Beta-carotene - can be represented as two connected retinyl groups. The retinyl group, when attached to a specific protein, is the only primary light absorber in visual perception, and the compound name is related to the retina of the eye.

Vitamin A can be found in various forms:

• retinol, the form of vitamin A absorbed when eating animal food sources, is a yellow, fat-soluble, vitamin with importance in vision and bone growth. Since the alcohol form is unstable, the vitamin is usually produced and administered in a form of retinyl acetate or palmitate.

• other retinoids, a class of chemical compounds that are related chemically to vitamin A, are used in medicine.

In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl palmitate, which is converted to an alcohol (retinol) in the small intestine.  Vitamin A can also exist as an aldehyde (retinal), or as an acid (retinoic acid). 

Discovery of vitamin A

The discovery of vitamin A stemmed from research dating back to 1906, indicating that factors other than carbohydrates, proteins, and fats were necessary to keep cattle healthy. By 1917 one of these substances was independently discovered by Elmer McCollum at the University of Wisconsin-Madison, and Lafayette Mendel and Thomas Osborne at Yale University. Since "water-soluble factor B" (Vitamin B) had recently been discovered, the researchers chose the name "fat-soluble factor A" (vitamin A). Vitamin A was first synthesized in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.

Equivalencies of retinoids and carotenoids (IU)

Since some carotenoids can be converted into vitamin A, attempts have been made to determine how much of them in the diet is equivalent to a particular amount of retinol, so that comparisons can be made of the benefit of different foods. Unfortunately the situation is confusing because the accepted equivalences have changed. For many years, a system of equivalencies was used in which an international unit (IU) was equal to 0.3 micrograms of retinol, 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids. Later, a unit called retinol equivalent (RE) was introduced. 1 RE corresponded to 1 μg retinol, 2 μg β-carotene dissolved in oil (as in supplement pills), 6 μg β-carotene in normal food (because it is not absorbed as well as from supplements), and 12 μg of either α-carotene or β-cryptoxanthin in food.

However, new research showed that the absorption of provitamin-A carotenoids was only half as much as previously thought, so in 2001 the US Institute of Medicine recommended a new unit, the retinol activity equivalent (RAE). 1 μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of "dietary" beta-carotene, or 24 μg of other dietary provitamin-A carotenoids.

Substance and its chemical environment	Micrograms of retinol equivalent per microgram of the substance
retinol	1
beta-carotene, dissolved in oil	1/2
beta-carotene, common dietary	1/12
alpha-carotene, common dietary	1/24
beta-cryptoxanthin, common dietary	1/24

Because the production of retinol from provitamins by the human body is regulated by the amount of retinol available to the body, the conversions apply strictly only for vitamin A deficient humans. The absorption of provitamins also depends greatly on the amount of lipids ingested with the provitamin; lipids increase the uptake of the provitamin.

The conclusion that can be drawn from the newer research is that fruits and vegetables are not as useful for obtaining vitamin A as was thought—in other words, the IU's that they were reported to contain were worth much less than the same number of IU's of fat-dissolved supplements. This is important for vegetarians. (Night blindness is prevalent in countries where little meat or vitamin A-fortified foods are available.) A sample vegan diet for one day that provides sufficient vitamin A has been published by the Food and Nutrition Board (page 120). On the other hand, reference values for retinol or its equivalents, provided by the National Academy of Sciences, have decreased. The RDA (for men) of 1968 was 5000 IU (1500 μg retinol). In 1974 the RDA was set to 1000 RE (1000 μg retinol), whereas now the Dietary Reference Intake is 900 RAE (900 μg or 3000 IU retinol). This is equivalent to 1800 μg of β-carotene supplement (3000 IU) or 10800 μg of β-carotene in food (18000 IU).

Recommended daily intake

Vitamin A
Dietary Reference Intake:

Life Stage Group	RDA/AI* ug/day	UL ug/day
Infants 0-6 months 7-12 months	400* 500*	600 600
Children 1-3 years 4-8 years	300 400	600 900
Males 9-13 years 14-18 years 19 - >70 years	600 900 900	1700 2800 3000
Females 9-13 years 14-18 years 19 - >70 years	600 700 700	1700 2800 3000
Pregnancy <19 years 19 - >50 years	750 770	2800 3000
Lactation <19 years 19 - >50 years	1200 1300	2800 3000

RDA = Recommended Dietary Allowances
AI* = Adequate Intakes
UL = Upper Limit

(Note that the limit refers to synthetic and natural retinoid forms of vitamin A. Carotene forms from dietary sources are not toxic.)

According to the Institute of Medicine of the National Academies, "RDAs are set to meet the needs of almost all (97 to 98 percent) individuals in a group. For healthy breastfed infants, the AI is the mean intake. The AI for other life stage and gender groups is believed to cover the needs of all individuals in the group, but lack of data prevent being able to specify with confidence the percentage of individuals covered by this intake."

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Sources of Vitamin A

Vitamin A is found naturally in many foods:

• liver (beef, pork, chicken, turkey, fish) (6500 μg 722%)
• carrots (835 μg 93%)
• Broccoli leaves (800 μg 89%) - Acc. to USDA database. Broccoli florets supposedly have much less - see note.
• sweet potatoes (709 μg 79%)
• kale (681 μg 76%)
• butter (684 μg 76%)
• spinach (469 μg 52%)
• leafy vegetables
• pumpkin (369 μg 41%)
• collard greens (333 μg 37%)
• cantaloupe melon (169 μg 19%)
• eggs (140 μg 16%)
• apricots (96 μg 11%)
• papaya (55 μg 6%)
• mango (38 μg 4%)
• peas (38 μg 4%)
• broccoli (31 μg 3%)
• winter squash

Note: bracketed values are retinol equivalences and percentage of the adult male RDA per 100g.

Conversion of carotene to retinol varies from person to person and bioavailability of carotene in food varies.

Metabolic Functions of Vitamin A

Vitamin A plays a role in a variety of functions throughout the body, such as:

• Vision
• Gene Transcription
• Immune Function
• Embryonic Development and Reproduction
• Bone Metabolism
• Haematopoiesis
• Skin Health
• Reducing Risk of Heart Disease and Cancer
• Antioxidant Activity

Vision

The role of vitamin A in the vision cycle is specifically related to the retinal form. Within the eye, 11-cis-retinal is bound to rhodopsin (rods) and iodopsin (cones) at conserved lysine residues. As light enters the eye the 11-cis-retinal is isomerized to the all-"trans" form. The all-"trans" retinal dissociates from the opsin in a series of steps called bleaching. This isomerization induces a nervous signal along the optic nerve to the visual center of the brain. Upon completion of this cycle, the all-"trans"-retinal can be recycled and converted back to the 11-"cis"-retinal form via a series of enzymatic reactions. Additionally, some of the all-"trans" retinal may be converted to all-"trans" retinol form and then transported with an interphotoreceptor retinol-binding protein (IRBP) to the pigment epithelial cells. Further esterification into all-"trans" retinyl esters allow this final form to be stored within the pigment epithelial cells to be reused when needed. The final conversion of 11-cis-retinal will rebind to opsin to reform rhodopsin in the retina. Rhodopsin is needed to see black and white as well as see at night. It is for this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin and lead to night blindness.

Gene Transcription

Vitamin A, in the retinoic acid form, plays an important role in gene transcription. Once retinol has been taken up by a cell, it can be oxidized to retinal (by retinol dehydrogenases) and then retinal can be oxidized to retinoic acid (by retinal oxidase). The conversion of retinal to retinoic acid is an irreversible step, meaning that the production of retinoic acid is tightly regulated, due to its activity as a ligand for nuclear receptors. Retinoic acid can bind to two different nuclear receptors to initiate (or inhibit) gene transcription: the retinoic acid receptors (RARs) or the retinoid "X" receptors (RXRs). RAR and RXR must dimerize before they can bind to the DNA. RAR will form a heterodimer with RXR (RAR-RXR), but it does not readily form a homodimer (RAR-RAR). RXR, on the other hand, readily forms a homodimer (RXR-RXR) and will form heterodimers with many other nuclear receptors as well, including the thyroid hormone receptor (RXR-TR), the Vitamin D₃ receptor (RXR-VDR), the peroxisome proliferator-activated receptor (RXR-PPAR) and the liver "X" receptor (RXR-LXR). The RAR-RXR heterodimer recognizes retinoid acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid "X" response elements (RXREs) on the DNA. The other RXR heterodimers will bind to various other response elements on the DNA. Once the retinoic acid binds to the receptors and dimerization has occurred, the receptors undergo a conformational change that causes co-repressors to dissociate from the receptors. Coactivators can then bind to the receptor complex, which may help to loosen the chromatin structure from the histones or may interact with the transcriptional machinery. The receptors can then bind to the response elements on the DNA and upregulate (or downregulate) the expression of target genes, such as cellular retinol-binding protein (CRBP) as well as the genes that encode for the receptors themselves.

Dermatology

Vitamin A appears to function in maintaining normal skin health. The mechanisms behind retinoid's therapeutic agents in the treatment of dermatological diseases are being researched. For the treatment of acne, the most effective drug is 13-cis retinoic acid (isotretinoin). Although its mechanism of action remains unknown, it is the only retinoid that dramatically reduces the size and secretion of the sebaceous glands. Isotretinoin reduces bacterial numbers in both the ducts and skin surface. This is thought to be a result of the reduction in sebum, a nutrient source for the bacteria. Isotretinoin reduces inflammation via inhibition of chemotatic responses of monocytes and neutrophils. Isotretinoin also has been shown to initiate remodeling of the sebaceous glands; triggering changes in gene expression that selectively induces apoptosis. Isotretinoin is a teratogen and its use is confined to medical supervision.

Deficiency

Vitamin A deficiency is estimated to affect millions of children around the world. Approximately 250,000-500,000 children in developing countries become blind each year owing to vitamin A deficiency, with the highest prevalence in Southeast Asia and Africa. According to the World Health Organization (WHO), vitamin A deficiency is under control in the United States, but in developing countries vitamin A deficiency is a significant concern. With the high prevalence of vitamin A deficiency, the WHO has implemented several initiatives for supplementation of vitamin A in developing countries. Some of these strategies include intake of vitamin A through a combination of breast feeding, dietary intake, food fortification, and supplementation. Through the efforts of WHO and its partners, an estimated 1.25 million deaths since 1998 in 40 countries due to vitamin A deficiency have been averted.

Vitamin A deficiency can occur as either a primary or secondary deficiency. A primary vitamin A deficiency occurs among children and adults who do not consume an adequate intake of yellow and green vegetables, fruits and liver. Early weaning can also increase the risk of vitamin A deficiency. Secondary vitamin A deficiency is associated with chronic malabsorption of lipids, impaired bile production and release, low fat diets, and chronic exposure to oxidants, such as cigarette smoke. Vitamin A is a fat soluble vitamin and depends on micellar solubilization for dispersion into the small intestine, which results in poor utilization of vitamin A from low-fat diets. Zinc deficiency can also impair absorption, transport, and metabolism of vitamin A because it is essential for the synthesis of the vitamin A transport proteins and the oxidation of retinol to retinal. In malnourished populations, common low intakes of vitamin A and zinc increase the risk of vitamin A deficiency and lead to several physiological events. A study in Burkina Faso showed major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children.

Since the unique function of retinyl group is the light absorption in Retinylidene protein, one of the earliest and specific manifestations of vitamin A deficiency is impaired vision, particularly in reduced light - Night blindness. Persistent deficiency gives rise to a series of changes, the most devastating of which occur in the eyes. Some other ocular changes are referred to as xerophthalmia. First there is dryness of the conjunctiva (xerosis) as the normal lacrimal and mucus secreting epithelium is replaced by a keratinized epithelium. This is followed by the build-up of keratin debris in small opaque plaques (Bitot's spots) and, eventually, erosion of the roughened corneal surface with softening and destruction of the cornea (keratomalacia) and total blindness. Other changes include impaired immunity, hypokeratosis (white lumps at hair follicles), keratosis pilaris and squamous metaplasia of the epithelium lining the upper respiratory passages and urinary bladder to a keratinized epithelium. With relations to dentistry, a deficiency in Vitamin A leads to enamel hypoplasia.

Adequate supply of Vitamin A is especially important for pregnant and breastfeeding women, since deficiencies cannot be compensated by postnatal supplementation..

Toxicity

As vitamin A is fat-soluble, disposing of any excesses taken in through diet is much harder than with water-soluble vitamins B and C. As such, vitamin A toxicity can result. This can lead to nausea, jaundice, irritability, anorexia (not to be confused with anorexia nervosa, the eating disorder), vomiting, blurry vision, headaches, muscle and abdominal pain and weakness, drowsiness and altered mental status.

Acute toxicity generally occurs at doses of 25,000 IU/kg of body weight, with chronic toxicity occurring at 4,000 IU/kg of body weight daily for 6-15 months. However, liver toxicities can occur at levels as low as 15,000 IU per day to 1.4 million IU per day, with an average daily toxic dose of 120,000 IU per day. In people with renal failure 4000 IU can cause substantial damage. Additionally excessive alcohol intake can increase toxicity. Children can reach toxic levels at 1500IU/kg of body weight.

In chronic cases, hair loss, drying of the mucous membranes, fever, insomnia, fatigue, weight loss, bone fractures, anemia, and diarrhea can all be evident on top of the symptoms associated with less serious toxicity.

It has been estimated that 75% of people may be ingesting more than the RDA for vitamin A on a regular basis in developed nations. Intake of twice the RDA of preformed vitamin A chronically may be associated with osteoporosis and hip fractures. High vitamin A intake has been associated with spontaneous bone fractures in animals. Cell culture studies have linked increased bone resorption and decreased bone formation with high vitamin A intakes. This interaction may occur because vitamins A and D may compete for the same receptor and then interact with parathyoid hormone which regulates calcium.

Toxic effects of vitamin A have been shown to significantly affect developing fetuses. Therapeutic doses used for acne treatment have been shown to disrupt cephalic neural cell activity. The fetus is particularly sensitive to vitamin A toxicity during the period of organogenesis.

These toxicities only occur with preformed (retinoid) vitamin A (such as from liver). The carotenoid forms (such as beta-carotene as found in carrots), give no such symptoms, but excessive dietary intake of beta-carotene can lead to carotenodermia, which causes orange-yellow discoloration of the skin.

A study by Siri Forsmo et al. shows a correlation between low bone mineral density and too high intake of vitamin A.

Researchers have succeeded in creating water-soluble forms of vitamin A, which they believed could reduce the potential for toxicity. However, a 2003 study found that water-soluble vitamin A was approximately 10 times as toxic as fat-soluble vitamin. A 2006 study found that children given water-soluble vitamin A and D, which are typically fat-soluble, suffer from asthma twice as much as a control group supplemented with the fat-soluble vitamins.

Chronically high doses of Vitamin A can produce the syndrome of "pseudotumor cerebri". This syndrome includes headache, blurring of vision and confusion. It is associated with increased intracerebral pressure.

See also

• Beta carotene
• Retinoids
• Hypervitaminosis A

Further reading

• Litwack, Gerald (2007). Vitamin A, Vitamins and Hormones. San Diego, CA: Elsevier Academic Press. ISBN 9780127098753. 

External links

• MeSH Vitamin+A

• vitaminA.org

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