A vitamin is an organic compound required as a vital nutrient in tiny amounts by an organism.^[1] In other words, an organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and on the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals, and biotin and vitamin D are required in the human diet only in certain circumstances. By convention, the term vitamin does not include other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids (which are needed in larger amounts than vitamins), nor does it encompass the large number of other nutrients that promote health but are otherwise required less often.^[2] Thirteen vitamins are universally recognized at present.

Vitamins are classified by their biological and chemical activity, not their structure. Thus, each “vitamin” refers to a number of vitamer compounds that all show the biological activity associated with a particular vitamin. Such a set of chemicals is grouped under an alphabetized vitamin “generic descriptor” title, such as “vitamin A“, which includes the compounds retinal, retinol, and four known carotenoids. Vitamers by definition are convertible to the active form of the vitamin in the body, and are sometimes inter-convertible to one another, as well.

A vitamin is an organic compound required as a vital nutrient in tiny amounts by an organism.^[1] In other words, an organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and on the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals, and biotin and vitamin D are required in the human diet only in certain circumstances. By convention, the term vitamin does not include other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids (which are needed in larger amounts than vitamins), nor does it encompass the large number of other nutrients that promote health but are otherwise required less often.^[2] Thirteen vitamins are universally recognized at present.

Vitamins are classified by their biological and chemical activity, not their structure. Thus, each “vitamin” refers to a number of vitamer compounds that all show the biological activity associated with a particular vitamin. Such a set of chemicals is grouped under an alphabetized vitamin “generic descriptor” title, such as “vitamin A“, which includes the compounds retinal, retinol, and four known carotenoids. Vitamers by definition are convertible to the active form of the vitamin in the body, and are sometimes inter-convertible to one another, as well.

A granola bar and nuts make a healthy energy-dense snack.

Carol Gering

Vitamin A (or Vitamin A Retinol, retinal, and four carotenoids including beta carotene) is a vitamin that is needed by the retina of the eye in the form of a specific metabolite, the light-absorbing molecule retinal, that is necessary for both low-light (scotopic vision) and color vision. Vitamin A also functions in a very different role as an irreversibly oxidized form of retinol known as retinoic acid, which is an important hormone-like growth factor for epithelial and other cells.

In foods of animal origin, the major form of vitamin A is an ester, primarily retinyl palmitate, which is converted to the retinol (chemically an alcohol) in the small intestine. The retinol form functions as a storage form of the vitamin, and can be converted to and from its visually active aldehyde form, retinal. The associated acid (retinoic acid), a metabolite that can be irreversibly synthesized from vitamin A, has only partial vitamin A activity, and does not function in the retina for the visual cycle.

All forms of vitamin A have a beta-ionone ring to which an isoprenoid chain is attached, called a retinyl group. Both structural features are essential for vitamin activity.^[1] The orange pigment of carrots – beta-carotene – can be represented as two connected retinyl groups, which are used in the body to contribute to vitamin A levels. Alpha-carotene and gamma-carotene also have a single retinyl group, which give them some vitamin activity. None of the other carotenes have vitamin activity. The carotenoid beta-cryptoxanthin possesses an ionone group and has vitamin activity in humans.

Vitamin A can be found in two principal forms in foods:

• Retinol, the form of vitamin A absorbed when eating animal food sources, is a yellow, fat-soluble substance. Since the pure alcohol form is unstable, the vitamin is found in tissues in a form of retinyl ester. It is also commercially produced and administered as esters such as retinyl acetate or palmitate.

• The carotenes alpha-carotene, beta-carotene, gamma-carotene; and the xanthophyll beta-cryptoxanthin (all of which contain beta-ionone rings), but no other carotenoids, function as vitamin A in herbivores and omnivore animals, which possess the enzyme required to convert these compounds to retinal. In general, carnivores are poor converters of ionine-containing carotenoids, and pure carnivores such as cats and ferrets lack beta-carotene 15,15′-monooxygenase and cannot convert any carotenoids to retinal (resulting in none of the carotenoids being forms of vitamin A for these species).

In some studies, the use of Vitamin A supplements has been linked to an increased rate mortality, but there is minimal evidence to show this.^[2]

[edit] History

The discovery of vitamin A may have stemmed from research dating back to 1906, indicating that factors other than carbohydrates, proteins, and fats were necessary to keep cattle healthy.^[3] By 1917 one of these substances was independently discovered by Elmer McCollum at the University of Wisconsin–Madison, and Lafayette Mendel and Thomas Burr 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).^[3] In 1919, Steenbock (University of Wisconsin) proposed a relationship between yellow plant pigments (beta-carotene) and vitamin A. Vitamin A was first synthesized in 1947 by two Dutch chemists, David Adriaan van Dorp and Jozef Ferdinand Arens.

[edit] Equivalencies of retinoids and carotenoids (IU)

As 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. The situation can be confusing because the accepted equivalences have changed. For many years, a system of equivalencies in which an international unit (IU) was equal to 0.3 μg of retinol, 0.6 μg of β-carotene, or 1.2 μg of other provitamin-A carotenoids was used.^[4] Later, a unit called retinol equivalent (RE) was introduced. Prior to 2001, one RE corresponded to 1 μg retinol, 2 μg β-carotene dissolved in oil (it is only partly dissolved in most supplement pills, due to very poor solubility in any medium), 6 μg β-carotene in normal food (because it is not absorbed as well as when in oils), and 12 μg of either α-carotene, γ-carotene, or β-cryptoxanthin in food.

Newer research has shown that the absorption of provitamin-A carotenoids is only half as much as previously thought. As a result, in 2001 the US Institute of Medicine recommended a new unit, the retinol activity equivalent (RAE). Each μg RAE corresponds to 1 μg retinol, 2 μg of β-carotene in oil, 12 μg of “dietary” beta-carotene, or 24 μg of the three other dietary provitamin-A carotenoids.^[5]

Because the conversion of retinol from provitamin carotenoids by the human body is actively regulated by the amount of retinol available to the body, the conversions apply strictly only for vitamin A-deficient humans. The absorption of provitamins depends greatly on the amount of lipids ingested with the provitamin; lipids increase the uptake of the provitamin.^[6]

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 IUs that these foods were reported to contain were worth much less than the same number of IUs of fat-dissolved oils and (to some extent) supplements. This is important for vegetarians, as 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^[5]). 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).

[edit] Recommended daily intake

Vitamin A Dietary Reference Intake^[7]:

(The limit is for synthetic and natural retinol ester forms of vitamin A. Carotene forms from dietary sources are not toxic.^[8][9])

According to the Institute of Medicine of the National Academies, “RDAs are set to meet the needs of almost all (97 to 98%) 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 prevents being able to specify with confidence the percentage of individuals covered by this intake.”^[10]

[edit] Sources

carrots

Vitamin A is found naturally in many foods:

Note: data taken from USDA database bracketed values are retinol activity equivalences (RAEs) and percentage of the adult male RDA, per 100 grams of the foodstuff (average).

Conversion of carotene to retinol varies from person to person and bioavailability of carotene in food varies.^[13][14]

[edit] Metabolic functions

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 and cellular health
• Antioxidant activity

[edit] Vision

The role of vitamin A in the visual 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 photo-bleaching. This isomerization induces a nervous signal along the optic nerve to the visual center of the brain. After separating from opsin, the all-”trans”-retinal is recycled and converted back to the 11-”cis”-retinal form by a series of enzymatic reactions. In addition, 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 for storage of all-trans-retinol within the pigment epithelial cells to be reused when needed.^[15] The final stage is conversion of 11-cis-retinal will rebind to opsin to reform rhodopsin in the retina. Rhodopsin is needed to see in low light (contrast) as well as for night vision. It is for this reason that a deficiency in vitamin A will inhibit the reformation of rhodopsin and lead to one of the first symptoms, night blindness.^[16]

[edit] 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 (retinaldehyde) by retinol dehydrogenases and then retinaldehyde can be oxidized to retinoic acid by retinaldehyde dehydrogenases.^[17] The conversion of retinaldehyde 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.^[15] The physiological form of retinoic acid (all-trans-retinoic acid) regulates gene transcription by binding to nuclear receptors known as retinoic acid receptors (RARs) which are bound to DNA as heterodimers with 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, may form 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).^[18] The RAR-RXR heterodimer recognizes retinoic acid response elements (RAREs) on the DNA whereas the RXR-RXR homodimer recognizes retinoid “X” response elements (RXREs) on the DNA; although several RAREs near target genes have been shown to control physiological processes,^[17] this has not been demonstrated for RXREs. The heterodimers of RXR with nuclear receptors other than RAR (i.e. TR, VDR, PPAR, LXR) bind to various distinct response elements on the DNA to control processes not regulated by vitamin A.^[15] Upon binding of retinoic acid to the RAR component of the RAR-RXR heterodimer, 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.^[18] This response can upregulate (or downregulate) the expression of target genes, including Hox genes as well as the genes that encode for the receptors themselves (i.e. RAR-beta in mammals).^[15]

[edit] Dermatology

Vitamin A, and more specifically, retinoic acid, appears to maintain normal skin health by switching on genes and differentiating keratinocytes (immature skin cells) into mature epidermal cells.^{[citation needed]} Exact mechanisms behind pharmacological retinoid therapy agents in the treatment of dermatological diseases are being researched. For the treatment of acne, the most prescribed retinoid drug is 13-cis retinoic acid (isotretinoin). It reduces the size and secretion of the sebaceous glands. Although it is known that 40 mg of isotretinoin will break down to an equivalent of 10 mg of ATRA — the mechanism of action of the drug (original brand name Accutane) remains unknown and is a matter of some controversy. 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 chemotactic responses of monocytes and neutrophils.^[15] Isotretinoin also has been shown to initiate remodeling of the sebaceous glands; triggering changes in gene expression that selectively induce apoptosis.^[19] Isotretinoin is a teratogen with a number of potential side-effects. Consequently, its use requires medical supervision.

[edit] Retinal/retinol versus retinoic acid

Vitamin A deprived rats can be kept in good general health with supplementation of retinoic acid. This reverses the growth-stunting effects of vitamin A deficiency, as well as early stages of xerophthalmia. However, such rats show infertility (in both male and females) and continued degeneration of the retina, showing that these functions require retinal or retinol, which are intraconvertable but which cannot be recovered from the oxidized retinoic acid. The requirement of retinol to rescue reproduction in vitamin A deficient rats is now known to be due to a requirement for local synthesis of retinoic acid from retinol in testis and embryos.^[20][21]

[edit] Deficiency

Vitamin A deficiency is estimated to affect approximately one third of children under the age of five around the world.^[22] It is estimated to claim the lives of 670,000 children under five annually.^[23] 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.^[24]

Vitamin A deficiency can occur as either a primary or a secondary deficiency. A primary vitamin A deficiency occurs among children and adults who do not consume an adequate intake of provitamin A carotenoids from fruits and vegetables or preformed vitamin A from animal and dairy products. Early weaning from breastmilk 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, and chronic exposure to oxidants, such as cigarette smoke, and chronic alcoholism. Vitamin A is a fat soluble vitamin and depends on micellar solubilization for dispersion into the small intestine, which results in poor use 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 as the cofactor in conversion of retinol to retinal. In malnourished populations, common low intakes of vitamin A and zinc increase the severity of vitamin A deficiency and lead physiological signs and symptoms of deficiency.^[15] A study in Burkina Faso showed major reduction of malaria morbidity with combined vitamin A and zinc supplementation in young children.^[25]

Due to the unique function of retinal as a visual chromophore, 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.^[26] Other changes include impaired immunity (increased risk of ear infections, urinary tract infections, Meningococcal disease), hyperkeratosis (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, but not excess vitamin A, is especially important for pregnant and breastfeeding women for normal fetal development. Deficiencies cannot be compensated by postnatal supplementation.^[27][28] Excess vitamin A, which is most common with high dose vitamin supplements, can cause birth defects and therefore should not exceed recommended daily values.^[17]

Vitamin A metabolic inhibition as a result of alcohol consumption during pregnancy is the elucidated mechanism for fetal alcohol syndrome and is characterized by teratogenicity closely matching maternal vitamin A deficiency.^[29]

[edit] Vitamin A supplementation

Global efforts to support national governments in addressing vitamin A deficiency are led by the Global Alliance for Vitamin A (GAVA), which is an informal partnership between A2Z, the Canadian International Development Agency, Helen Keller International, the Micronutrient Initiative, UNICEF, USAID, and the World Bank. Joint GAVA activity is coordinated by the Micronutrient Initiative.

While strategies include intake of vitamin A through a combination of breast feeding and dietary intake, delivery of oral high-dose supplements remain the principal strategy for minimizing deficiency.^[30] Studies have shown vitamin A supplementation of children under five who are at risk of deficiency can reduce mortality by 23%.^[31] About 75% of the vitamin A required for supplementation activity by developing countries is supplied by the Micronutrient Initiative with support from the Canadian International Development Agency.^[32] Food fortification approaches are becoming increasingly feasible but cannot yet ensure coverage levels.^[30]

The World Health Organization estimates that Vitamin A supplementation has averted 1.25 million deaths due to vitamin A deficiency in 40 countries since 1998.^[33] In 2008 it was estimated that an annual investment of US$60 million in vitamin A and zinc supplementation combined would yield benefits of more than US$1 billion per year, with every dollar spent generating benefits of more than US$17.^[34] These combined interventions were ranked by the Copenhagen Consensus 2008 as the world’s best development investment.^[34]

[edit] Toxicity

Since vitamin A is fat-soluble, disposing of any excesses taken in through diet is much harder than with water-soluble B vitamins and vitamin C, vitamin A toxicity is possible.

In general, acute toxicity 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.^[35] 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, particularly with excessive consumption of alcohol. In people with renal failure, 4000 IU can cause substantial damage. In addition, excessive alcohol intake can increase toxicity. Children can reach toxic levels at 1,500 IU/kg of body weight.^[36]

Excessive vitamin A consumption can lead to nausea, irritability, anorexia (reduced appetite), vomiting, blurry vision, headaches, hair loss, muscle and abdominal pain and weakness, drowsiness, and altered mental status. In chronic cases, hair loss, dry skin, 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.^[37] Some of these symptoms are also common to acne treatment with Isotretinoin. Chronically high doses of vitamin A, and also pharmaceutical retinoids such as 13-cis retinoic acid, can produce the syndrome of pseudotumor cerebri.^[38] This syndrome includes headache, blurring of vision and confusion, associated with increased intracerebral pressure. Symptoms begin to resolve when intake of the offending substance is stopped.^[39]

Chronic intake of 1500 RAE of preformed vitamin A may be associated with osteoporosis and hip fractures. This may be due to the fact that an excess of vitamin A can block the expression of certain proteins dependent on vitamin K to reduce the efficacy of vitamin D, but has not yet been proven.^[40] 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 intakes. This interaction may occur because vitamins A and D may compete for the same receptor and then interact with parathyroid hormone, which regulates calcium.^[36] Indeed, a study by Forsmo et al. shows a correlation between low bone mineral density and too high intake of vitamin A.^[41]

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.^[15] 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, except with supplements and chronoic alcoholism, but excessive dietary intake of beta-carotene can lead to carotenodermia, which causes orange-yellow discoloration of the skin.^[42][43][44]

Smokers and chronic alcohol consumers have been observed to have increased risk of mortality due to lung cancer, esophageal cancer, gastrointestinal cancer and colon cancer.^[29] Hepatic (liver) injury been found in human and animal studies where consumption of alcohol is paired with high dose vitamin A and beta-carotene supplementation.

Researchers have succeeded in creating water-soluble forms of vitamin A, which they believed could reduce the potential for toxicity.^[45] However, a 2003 study found water-soluble vitamin A was approximately 10 times as toxic as fat-soluble vitamin.^[46] A 2006 study found 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.^[47]

[edit] Vitamin A and derivatives in medical use

Retinyl palmitate has been used in skin creams, where it is broken down to retinoic acid, which has potent biological activity, as described above.

The retinoids, (for example, 13-cis-retinoic acid), constitute a class of chemical compounds chemically related to retinoic acid, and are used in medicine to modulate gene functions in place of this compound. Like retinoic acid, the related compounds do not have full vitamin A activity, but do have powerful effects on gene expression and epithelial cell differentiation.^[48]

Pharmaceutics utilizing mega doses of naturally occurring retinoic acid derivatives are currently in use for cancer, HIV, and dermatological purposes.^[49] At high doses, side-effects are similar to vitamin A toxicity. Severe side effects related to vitamin A toxicity, and a small optimal range of use are key obstacles in developing vitamin A-derived pharmaceutics for therapeutic use.^{[verification needed]}

[edit] References

A vitamin is an organic compound required as a vital nutrient in tiny amounts by an organism. In other words, an organic chemical compound (or related set of compounds) is called a vitamin when it cannot be synthesized in sufficient quantities by an organism, and must be obtained from the diet. Thus, the term is conditional both on the circumstances and on the particular organism. For example, ascorbic acid (vitamin C) is a vitamin for humans, but not for most other animals, and biotin and vitamin D are required in the human diet only in certain circumstances. By convention, the term vitamin does not include other essential nutrients such as dietary minerals, essential fatty acids, or essential amino acids (which are needed in larger amounts than vitamins), nor does it encompass the large number of other nutrients that promote health but are otherwise required less often.^[2] Thirteen vitamins are universally recognized at present.

Vitamins are classified by their biological and chemical activity, not their structure. Thus, each “vitamin” refers to a number of vitamer compounds that all show the biological activity associated with a particular vitamin. Such a set of chemicals is grouped under an alphabetized vitamin “generic descriptor” title, such as “vitamin A“, which includes the compounds retinal, retinol, and four known carotenoids. Vitamers by definition are convertible to the active form of the vitamin in the body, and are sometimes inter-convertible to one another, as well.

Vitamins have diverse biochemical functions. Some have hormone-like functions as regulators of mineral metabolism (e.g., vitamin D), or regulators of cell and tissue growth and differentiation (e.g., some forms of vitamin A). Others function as antioxidants (e.g., vitamin E and sometimes vitamin C).^[3] The largest number of vitamins (e.g., B complex vitamins) function as precursors for enzyme cofactors, that help enzymes in their work as catalysts in metabolism. In this role, vitamins may be tightly bound to enzymes as part of prosthetic groups: For example, biotin is part of enzymes involved in making fatty acids. Vitamins may also be less tightly bound to enzyme catalysts as coenzymes, detachable molecules that function to carry chemical groups or electrons between molecules. For example, folic acid carries various forms of carbon group – methyl, formyl, and methylene – in the cell. Although these roles in assisting enzyme-substrate reactions are vitamins’ best-known function, the other vitamin functions are equally important.^[4]

Until the mid-1930s, when the first commercial yeast-extract and semi-synthetic vitamin C supplement tablets were sold, vitamins were obtained solely through food intake, and changes in diet (which, for example, could occur during a particular growing season) can alter the types and amounts of vitamins ingested. Vitamins have been produced as commodity chemicals and made widely available as inexpensive semisynthetic and synthetic-source multivitamin dietary supplements, since the middle of the 20^th century.

The term vitamin was derived from “vitamine,” a combination word made up by Polish scientist Casimir Funk from vital and amine, meaning amine of life, because it was suggested in 1912 that the organic micronutrient food factors that prevent beriberi and perhaps other similar dietary-deficiency diseases might be chemical amines. This proved incorrect for the micronutrient class, and the word was shortened to vitamin.

[edit] History

The value of eating a certain food to maintain health was recognized long before vitamins were identified. The ancient Egyptians knew that feeding liver to a person would help cure night blindness, an illness now known to be caused by a vitamin A deficiency.^[5] The advancement of ocean voyages during the Renaissance resulted in prolonged periods without access to fresh fruits and vegetables, and made illnesses from vitamin deficiency common among ships’ crews.^[6]

In 1749, the Scottish surgeon James Lind discovered that citrus foods helped prevent scurvy, a particularly deadly disease in which collagen is not properly formed, causing poor wound healing, bleeding of the gums, severe pain, and death.^[5] In 1753, Lind published his Treatise on the Scurvy, which recommended using lemons and limes to avoid scurvy, which was adopted by the British Royal Navy. This led to the nickname Limey for sailors of that organization. Lind’s discovery, however, was not widely accepted by individuals in the Royal Navy’s Arctic expeditions in the 19th century, where it was widely believed that scurvy could be prevented by practicing good hygiene, regular exercise, and maintaining the morale of the crew while on board, rather than by a diet of fresh food.^[5] As a result, Arctic expeditions continued to be plagued by scurvy and other deficiency diseases. In the early 20th century, when Robert Falcon Scott made his two expeditions to the Antarctic, the prevailing medical theory was that scurvy was caused by “tainted” canned food.^[5]

During the late 18th and early 19th centuries, the use of deprivation studies allowed scientists to isolate and identify a number of vitamins. Lipid from fish oil was used to cure rickets in rats, and the fat-soluble nutrient was called “antirachitic A”. Thus, the first “vitamin” bioactivity ever isolated, which cured rickets, was initially called “vitamin A”; however, the bioactivity of this compound is now called vitamin D.^[7] In 1881, Russian surgeon Nikolai Lunin studied the effects of scurvy while at the University of Tartu in present-day Estonia.^[8] He fed mice an artificial mixture of all the separate constituents of milk known at that time, namely the proteins, fats, carbohydrates, and salts. The mice that received only the individual constituents died, while the mice fed by milk itself developed normally. He made a conclusion that “a natural food such as milk must therefore contain, besides these known principal ingredients, small quantities of unknown substances essential to life.”^[8] However, his conclusions were rejected by other researchers when they were unable to reproduce his results. One difference was that he had used table sugar (sucrose), while other researchers had used milk sugar (lactose) that still contained small amounts of vitamin B.^{[citation needed]}

The Ancient Egyptians knew that feeding a person liver (back, right) would help cure night blindness.

In east Asia, where polished white rice was the common staple food of the middle class, beriberi resulting from lack of vitamin B₁ was endemic. In 1884, Takaki Kanehiro, a British trained medical doctor of the Imperial Japanese Navy, observed that beriberi was endemic among low-ranking crew who often ate nothing but rice, but not among officers who consumed a Western-style diet. With the support of the Japanese navy, he experimented using crews of two battleships; one crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice, and beans. The group that ate only white rice documented 161 crew members with beriberi and 25 deaths, while the latter group had only 14 cases of beriberi and no deaths. This convinced Takaki and the Japanese Navy that diet was the cause of beriberi, but mistakenly believed that sufficient amounts of protein prevented it.^[9] That diseases could result from some dietary deficiencies was further investigated by Christiaan Eijkman, who in 1897 discovered that feeding unpolished rice instead of the polished variety to chickens helped to prevent beriberi in the chickens. The following year, Frederick Hopkins postulated that some foods contained “accessory factors” — in addition to proteins, carbohydrates, fats etc. — that are necessary for the functions of the human body.^[5] Hopkins and Eijkman were awarded the Nobel Prize for Physiology or Medicine in 1929 for their discovery of several vitamins.^[10]

In 1910, the first vitamin complex was isolated by Japanese scientist Umetaro Suzuki, who succeeded in extracting a water-soluble complex of micronutrients from rice bran and named it aberic acid (later Orizanin). He published this discovery in a Japanese scientific journal.^[11] When the article was translated into German, the translation failed to state that it was a newly discovered nutrient, a claim made in the original Japanese article, and hence his discovery failed to gain publicity. In 1912 Polish biochemist Casimir Funk isolated the same complex of micronutrients and proposed the complex be named “vitamine” (a portmanteau of “vital amine”).^[12] The name soon became synonymous with Hopkins’ “accessory factors”, and, by the time it was shown that not all vitamins are amines, the word was already ubiquitous. In 1920, Jack Cecil Drummond proposed that the final “e” be dropped to deemphasize the “amine” reference, after researchers began to suspect that not all “vitamines” (in particular, vitamin A) have an amine component.^[9]

In 1931, Albert Szent-Györgyi and a fellow researcher Joseph Svirbely suspected that “hexuronic acid” was actually vitamin C, and gave a sample to Charles Glen King, who proved its anti-scorbutic activity in his long-established guinea pig scorbutic assay. In 1937, Szent-Györgyi was awarded the Nobel Prize in Physiology or Medicine for his discovery. In 1943, Edward Adelbert Doisy and Henrik Dam were awarded the Nobel Prize in Physiology or Medicine for their discovery of vitamin K and its chemical structure. In 1967, George Wald was awarded the Nobel Prize (along with Ragnar Granit and Haldan Keffer Hartline) for his discovery that vitamin A could participate directly in a physiological process.^[10]

[edit] In humans

Vitamins are classified as either water-soluble or fat-soluble. In humans there are 13 vitamins: 4 fat-soluble (A, D, E, and K) and 9 water-soluble (8 B vitamins and vitamin C). Water-soluble vitamins dissolve easily in water and, in general, are readily excreted from the body, to the degree that urinary output is a strong predictor of vitamin consumption.^[13] Because they are not readily stored, consistent daily intake is important.^[14] Many types of water-soluble vitamins are synthesized by bacteria.^[15] Fat-soluble vitamins are absorbed through the intestinal tract with the help of lipids (fats). Because they are more likely to accumulate in the body, they are more likely to lead to hypervitaminosis than are water-soluble vitamins. Fat-soluble vitamin regulation is of particular significance in cystic fibrosis.^[16]

[edit] List of vitamins

Each vitamin is typically used in multiple reactions, and, therefore, most have multiple functions.^[17]

[edit] In nutrition and diseases

Vitamins are essential for the normal growth and development of a multicellular organism. Using the genetic blueprint inherited from its parents, a fetus begins to develop, at the moment of conception, from the nutrients it absorbs. It requires certain vitamins and minerals to be present at certain times. These nutrients facilitate the chemical reactions that produce among other things, skin, bone, and muscle. If there is serious deficiency in one or more of these nutrients, a child may develop a deficiency disease. Even minor deficiencies may cause permanent damage.^[31]

For the most part, vitamins are obtained with food, but a few are obtained by other means. For example, microorganisms in the intestine — commonly known as “gut flora” — produce vitamin K and biotin, while one form of vitamin D is synthesized in the skin with the help of the natural ultraviolet wavelength of sunlight. Humans can produce some vitamins from precursors they consume. Examples include vitamin A, produced from beta carotene, and niacin, from the amino acid tryptophan.^[18]

Once growth and development are completed, vitamins remain essential nutrients for the healthy maintenance of the cells, tissues, and organs that make up a multicellular organism; they also enable a multicellular life form to efficiently use chemical energy provided by food it eats, and to help process the proteins, carbohydrates, and fats required for respiration.^[3]

[edit] Deficiencies

It was suggested that, when plants and animals began to transfer from the sea to rivers and land about 500 million years ago, environmental deficiency of marine mineral antioxidants was a challenge to the evolution of terrestrial life. Terrestrial plants slowly optimized the production of “new” endogenous antioxidants such as ascorbic acid (Vitamin C), polyphenols, flavonoids, tocopherols, etc. Since this age, dietary vitamin deficiencies appeared in terrestrial animals.^[32] Humans must consume vitamins periodically but with differing schedules, to avoid deficiency. Human bodily stores for different vitamins vary widely; vitamins A, D, and B₁₂ are stored in significant amounts in the human body, mainly in the liver,^[28] and an adult human’s diet may be deficient in vitamins A and D for many months and B₁₂ in some cases for years, before developing a deficiency condition. However, vitamin B₃ (niacin and niacinamide) is not stored in the human body in significant amounts, so stores may last only a couple of weeks.^[19][28] For vitamin C, the first symptoms of scurvy in experimental studies of complete vitamin C deprivation in humans have varied widely, from a month to more than six months, depending on previous dietary history that determined body stores.^[33]

Deficiencies of vitamins are classified as either primary or secondary. A primary deficiency occurs when an organism does not get enough of the vitamin in its food. A secondary deficiency may be due to an underlying disorder that prevents or limits the absorption or use of the vitamin, due to a “lifestyle factor”, such as smoking, excessive alcohol consumption, or the use of medications that interfere with the absorption or use of the vitamin.^[28] People who eat a varied diet are unlikely to develop a severe primary vitamin deficiency. In contrast, restrictive diets have the potential to cause prolonged vitamin deficits, which may result in often painful and potentially deadly diseases.

Well-known human vitamin deficiencies involve thiamine (beriberi), niacin (pellagra), vitamin C (scurvy), and vitamin D (rickets). In much of the developed world, such deficiencies are rare; this is due to (1) an adequate supply of food and (2) the addition of vitamins and minerals to common foods, often called fortification.^[18][28] In addition to these classical vitamin deficiency diseases, some evidence has also suggested links between vitamin deficiency and a number of different disorders.^[34][35]

[edit] Side-effects and overdose

In large doses, some vitamins have documented side-effects that tend to be more severe with a larger dosage. The likelihood of consuming too much of any vitamin from food is remote, but overdosing (vitamin poisoning) from vitamin supplementation does occur. At high enough dosages, some vitamins cause side-effects such as nausea, diarrhea, and vomiting.^[19][36] When side-effects emerge, recovery is often accomplished by reducing the dosage. The doses of vitamins differ because individual tolerances can vary widely and appear to be related to age and state of health.^[37]

In 2008, overdose exposure to all formulations of vitamins and multivitamin-mineral formulations was reported by 68,911 individuals to the American Association of Poison Control Centers (nearly 80% of these exposures were in children under the age of 6), leading to 8 “major” life-threatening outcomes and 0 deaths.^[38]

[edit] Supplements

Dietary supplements, often containing vitamins, are used to ensure that adequate amounts of nutrients are obtained on a daily basis, if optimal amounts of the nutrients cannot be obtained through a varied diet. Scientific evidence supporting the benefits of some vitamin supplements is well established for certain health conditions, but others need further study.^[39] In some cases, vitamin supplements may have unwanted effects, especially if taken before surgery, with other dietary supplements or medicines, or if the person taking them has certain health conditions.^[39] Dietary supplements may also contain levels of vitamins many times higher, and in different forms, than one may ingest through food.^[40]

There have been mixed studies on the importance and safety of dietary supplementation. A meta-analysis published in 2006 suggested that Vitamin A and E supplements not only provide no tangible health benefits for generally healthy individuals but may actually increase mortality, although two large studies included in the analysis involved smokers, for which it was already known that beta-carotene supplements can be harmful.^[41] Another study published in May 2009 found that antioxidants such as vitamins C and E may actually curb some benefits of exercise.^[42] While others findings suggest that evidence of Vitamin E toxicity is limited to specific form taken in excess.^[43] A double-blind trial published in 2011 found that vitamin E increases the risk of prostate cancer in healthy men.^[44]

[edit] Governmental regulation of vitamin supplements

Most countries place dietary supplements in a special category under the general umbrella of foods, not drugs. This necessitates that the manufacturer, and not the government, be responsible for ensuring that its dietary supplement products are safe before they are marketed. Regulation of supplements varies widely by country. In the United States, a dietary supplement is defined under the Dietary Supplement Health and Education Act of 1994.^[45] In addition, the Food and Drug Administration uses the Adverse Event Reporting System to monitor adverse events that occur with supplements.^[46] In the European Union, the Food Supplements Directive requires that only those supplements that have been proven safe can be sold without a prescription.^[47]

[edit] Names in current and previous nomenclatures

The reason that the set of vitamins skips directly from E to K is that the vitamins corresponding to letters F-J were either reclassified over time, discarded as false leads, or renamed because of their relationship to vitamin B, which became a complex of vitamins.

The German-speaking scientists who isolated and described vitamin K (in addition to naming it as such) did so because the vitamin is intimately involved in the Koagulation of blood following wounding. At the time, most (but not all) of the letters from F through to J were already designated, so the use of the letter K was considered quite reasonable.^[48][51] The table on the right lists chemicals that had previously been classified as vitamins, as well as the earlier names of vitamins that later became part of the B-complex.

[edit] Anti-vitamins

Anti-vitamins are chemical compounds that inhibit the absorption or actions of vitamins. For example, avidin is a protein in egg whites that inhibits the absorption of biotin.^[52] Pyrithiamine is similar to thiamine, vitamin B1, and inhibits the enzymes that use thiamine.^[53]

[edit] See also

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