Vitamin C in general
Vitamin C
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Vitamin C | |
| Systematic (IUPAC) name | |
| 2-oxo-L-threo-hexono-1,4- lactone-2,3-enediol or (R)-3,4-dihydroxy-5-((S)- 1,2-dihydroxyethyl)furan-2(5H)-one | |
| Identifiers | |
| CAS number | 50-81-7 |
| ATC code | A11G |
| PubChem | 5785 |
| Chemical data | |
| Formula | C6H8O6 |
| Mol. mass | 176.14 grams per mol |
| Synonyms | L-ascorbate |
| Physical data | |
| Melt. point | 190–192 °C (374–378 °F) decomposes |
| Pharmacokinetic data | |
| Bioavailability | rapid & complete |
| Protein binding | negligible |
| Metabolism | ? |
| Half life | 30 minutes |
| Excretion | renal |
| Therapeutic considerations | |
| Pregnancy cat. |
A |
| Legal status |
general public availability |
| Routes | oral |
 Y(what is this?) (verify) | |
Vitamin C or L-ascorbic acid is an essential nutrient for humans, in which it functions as a vitamin. Ascorbate (an ion of ascorbic acid) is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms; notable mammalian exceptions are most or all of the order chiroptera (bats), and the entire suborder Anthropoidea (Haplorrhini) (tarsiers, monkeys and apes). It is also needed by guinea pigs and some species of birds and fish. Deficiency in this vitamin causes the disease scurvy in humans.[1][2][3] It is also widely used as a food additive.[4]
The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an anti-oxidant, since it protects the body against oxidative stress,[5] and is a cofactor in several vital enzymatic reactions.[6]
Scurvy has been known since ancient times. People in many parts of the world assumed it was caused by a lack of fresh plant foods. The British Navy started giving sailors lime juice to prevent scurvy in 1795.[7] Ascorbic acid was finally isolated in 1933 and synthesized in 1934. The uses and recommended daily intake of vitamin C are matters of on-going debate, with RDI ranging from 45 to 95 mg/day. Proponents of megadosage propose from 200 to upwards of 2000 mg/day. A recent meta-analysis of 68 reliable antioxidant supplementation experiments, involving a total of 232,606 individuals, concluded that consuming additional ascorbate from supplements may not be as beneficial as thought.[8]
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[edit] Biological significance
Vitamin C is purely the L-enantiomer of ascorbate; the opposite D-enantiomer has no physiological significance. Both forms are mirror images of the same molecular structure. When L-ascorbate, which is a strong reducing agent, carries out its reducing function, it is converted to its oxidized form, L-dehydroascorbate.[6] L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione.[9] During this process semidehydroascorbic acid radical is formed. Ascorbate free radical reacts poorly with oxygen, and thus, will not create a superoxide. Instead two semidehydroascorbate radicals will react and form one ascorbate and one dehydroascorbate. With the help of glutathione, dehydroxyascorbate is converted back to ascorbate.[10] The presence of glutathione is crucial since it spares ascorbate and improves antioxidant capacity of blood.[11] Without it dehydroxyascorbate could not convert back to ascorbate.
L-ascorbate is a weak sugar acid structurally related to glucose which naturally occurs either attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate.
[edit] Biosynthesis
The vast majority of animals and plants are able to synthesize their own vitamin C, through a sequence of four enzyme-driven steps, which convert glucose to vitamin C.[6] The glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.[12] In reptiles and birds the biosynthesis is carried out in the kidneys.
Among the animals that have lost the ability to synthesise vitamin C are simians (specifically the suborder haplorrhini, which includes humans), guinea pigs, a number of species of passerine birds (but not all of them—there is some suggestion that the ability was lost separately a number of times in birds), and many (probably all) major families of bats, including major insect and fruit-eating bat families. These animals all lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last step of vitamin C synthesis, because they have a defective form of the gene for the enzyme (Pseudogene ΨGULO).[13] Some of these species (including humans) are able to make do with the lower levels available from their diets by recycling oxidised vitamin C.[14]
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans.[15] This discrepancy constitutes much of the basis of the controversy on current recommended dietary allowances. It is countered by arguments that humans are very good at conserving dietary vitamin C, and are able to maintain blood levels of vitamin C comparable with other simians, on a far smaller dietary intake.
An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13 g of vitamin C per day in normal health and the biosynthesis will increase "many fold under stress".[16] Trauma or injury has also been demonstrated to use up large quantities of vitamin C in humans.[17] Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.[18][19]
[edit] Vitamin C in evolution
Venturi and Venturi[20][21] suggested that the antioxidant action of ascorbic acid developed firstly in plant kingdom when, about 500 Mya, plants began to adapting themselves to mineral deficient fresh-waters of estuary of rivers. Some biologists suggested that many vertebrates had developed their metabolic adaptive strategies in estuary environment.[22] In this theory, some 400-300 million years ago when living plants and animals first began the move from the sea to rivers and land, environmental iodine deficiency was a challenge to the evolution of terrestrial life.[23] In plants, animals and fishes, the terrestrial diet became deficient in many essential marine micronutrients, including iodine, selenium, zinc, copper, manganese, iron, etc. Freshwater algae and terrestrial plants, in replacement of marine antioxidants, slowly optimized the production of other endogenous antioxidants such as ascorbic acid, polyphenols, carotenoids, flavonoids, tocopherols etc., some of which became essential “vitamins” in the diet of terrestrial animals (vitamins C, A, E, etc.).
Ascorbic acid or vitamin C is a common enzymatic cofactor in mammals used in the synthesis of collagen. Ascorbate is a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). Freshwater teleost fishes also require dietary vitamin C in their diet or they will get scurvy (Hardie et al.,1991). The most widely recognized symptoms of vitamin C deficiency in fishes are scoliosis, lordosis and dark skin coloration. Terrestrial freshwaters salmonids also show impaired collagen formation, internal/fin haemorrhage, spinal curvature and increased mortality. If these fishes are housed in seawater with algae and phytoplankton, then vitamin supplementation seems to be less important, presumably because of the availability of other, more ancient, antioxidants in natural marine environment.[24]
Some scientists have suggested that the loss of human ability to make vitamin C may have caused a rapid simian evolution into modern man.[25][26][27] However, the loss of ability to make vitamin C in simians must have occurred much further back in evolutionary history than the emergence of humans or even apes, since it evidently occurred sometime after the split in the Haplorrhini (which cannot make vitamin C) and its sister clade which retained the ability, the Strepsirrhini ("wet-nosed" primates). These two branchs parted ways about 63 million years ago (Mya). Approximately 5 million years later (58 Mya), only a short time afterward from an evolutionary perspective, the infraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae), branched off from the other haplorrhines. Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 Mya).
It has been noted that the loss of the ability to synthesize ascorbate strikingly parallels the evolutionary loss of the ability to break down uric acid. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that in higher primates, uric acid has taken over some of the functions of ascorbate.[28] Ascorbic acid can be oxidized (broken down) in the human body by the enzyme L-ascorbate oxidase.
[edit] Absorption and transport
Ascorbic acid is absorbed in the body by both active transport and simple diffusion. Sodium Dependent Active Transport - Sodium-Ascorbate Co-Transporters (SVCTs) and Hexose transporters (GLUTs) are the two transporters required for absorption. SVCT1 and SVCT2 imported the reduced form of ascorbate across plasma membrane.[29] GLUT1 and GLUT3 are the two glucose transporters and only transfer dehydroascorbic acid form of Vitamin C.[30] Although dehydroascorbic acid is absorbed in higher rate than ascorbate, the amount of dehydroascorbic acid found in plasma and tissues under normal conditions is low, as cells rapidly reduce dehydroascorbic acid to ascorbate.[31][32] Thus, SVCTs appear to be the predominant system for vitamin C transport in the body.
SVCT2 is involved in vitamin C transport in almost every tissue,[29] the notable exception being red blood cells which lose SVCT proteins during maturation.[33] Knockout animals for SVCT2 die shortly after birth,[34] suggesting that SVCT2-mediated vitamin C transport is necessary for life.
With regular intake the absorption rate varies between 70 to 95%. However, the degree of absorption decreases as intake increases. At high intake (12g), human body can absorb ascorbic acid as low as 16%; while, at low intake (<20 mg) the absorption rate could reach up to 98%.[35]
Biological tissues that accumulate over 100 times the level in blood plasma of vitamin C are the adrenal glands, pituitary, thymus, corpus luteum, and retina.[36] Those with 10 to 50 times the concentration present in blood plasma include the brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa, leukocytes, pancreas, kidney and salivary glands.
[edit] Deficiency
Scurvy is an avitaminosis resulting from lack of vitamin C, since without this vitamin, the synthesised collagen is too unstable to perform its function. Scurvy leads to the formation of liver spots on the skin, spongy gums, and bleeding from all mucous membranes. The spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth and, eventually, death. The human body can store only a certain amount of vitamin C,[37] and so the body soon depletes itself if fresh supplies are not consumed.
It has been shown that smokers who have diets poor in vitamin C are at a higher risk of lung-borne diseases than those smokers who have higher concentrations of vitamin C in the blood.[38]
Nobel prize winner Linus Pauling and Dr. G. C. Willis have asserted that chronic long term low blood levels of vitamin C or Chronic Scurvy is a cause of atherosclerosis.
Western societies generally consume sufficient Vitamin C to prevent scurvy. In 2004 a Canadian Community health survey reported that Canadians of 19 years and above have intakes of vitamin C from food of, 133 mg/d for males and 120 mg/d for females,[39] which is higher than the RDA recommendation.
[edit] History of human understanding
The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native peoples living in marginal areas incorporated this into their medicinal lore. For example, spruce needles were used in temperate zones in infusions, or the leaves from species of drought-resistant trees in desert areas. In 1536, the French explorer Jacques Cartier, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams.[40][41]
Throughout history, the benefit of plant food to survive long sea voyages has been occasionally recommended by authorities. John Woodall, the first appointed surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his book "The Surgeon's Mate", in 1617. The Dutch writer, Johann Bachstrom, in 1734, gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens; which is alone the primary cause of the disease."
While the earliest documented case of scurvy was described by Hippocrates around the year 400 BC, the first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the British Royal Navy, James Lind. Scurvy was common among those with poor access to fresh fruit and vegetables, such as remote, isolated sailors and soldiers. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations. In the history of science this is considered to be the first occurrence of a controlled experiment comparing results on two populations of a factor applied to one group only with all other factors the same. The results conclusively showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.[42]
Lind's work was slow to be noticed, partly because his Treatise was not publish until six years after his study, and also because he recommended a lemon juice extract known as "rob".[43] Fresh fruit was very expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles).[44] Ship captains concluded wrongly that Lind's other suggestions were ineffective because those juices failed to prevent or cure scurvy.
It was 1795 before the British navy adopted lemons or lime as standard issue at sea. Limes were more popular as they could be found in British West Indian Colonies, unlike lemons which weren't found in British Dominions, and were therefore more expensive. This practice led to the American use of the nickname "limey" to refer to the British. Captain James Cook had previously demonstrated and proven the principle of the advantages of carrying "Sour krout" on board, by taking his crews to the Hawaiian Islands and beyond without losing any of his men to scurvy.[45] For this otherwise unheard of feat, the British Admiralty awarded him a medal.
The name "antiscorbutic" was used in the eighteenth and nineteenth centuries as general term for those foods known to prevent scurvy, even though there was no understanding of the reason for this. These foods included but were not limited to: lemons, limes, and oranges; sauerkraut, cabbage, malt, and portable soup.
In 1907, Axel Holst and Theodor Frølich, two Norwegian physicians studying beriberi contracted aboard ship's crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons they used. They fed guinea pigs their test diet, which had earlier produced beriberi in their pigeons, and were surprised when scurvy resulted instead. Until that time scurvy had not been observed in any organism apart from humans, and had been considered an exclusively human disease.
[edit] Discovery of ascorbic acid
In 1912, the Polish-American biochemist Casimir Funk, while researching deficiency diseases, developed the concept of vitamins to refer to the non-mineral micro-nutrients which are essential to health. The name is a blend of "vital", due to the vital role they play biochemically, and "amines" because Funk thought that all these materials were chemical amines. One of the "vitamines" was thought to be the anti-scorbutic factor, long thought to be a component of most fresh plant material.
In 1928 the Arctic anthropologist Vilhjalmur Stefansson attempted to prove his theory of how the Eskimos are able to avoid scurvy with almost no plant food in their diet, despite the disease striking European Arctic explorers living on similar high-meat diets. Stefansson theorised that the natives get their vitamin C from fresh meat that is minimally cooked. Starting in February 1928, for one year he and a colleague lived on an exclusively minimally-cooked meat diet while under medical supervision; they remained healthy. (Later studies done after vitamin C could be quantified in mostly-raw traditional food diets of the Yukon, Inuit, and Métís of the Northern Canada, showed that their daily intake of vitamin C averaged between 52 and 62 mg/day, an amount approximately the dietary reference intake (DRI), even at times of the year when little plant-based food were eaten.)[46]
From 1928 to 1933, the Hungarian research team of Joseph L Svirbely and Albert Szent-Györgyi and, independently, the American Charles Glen King, first isolated the anti-scorbutic factor, calling it "ascorbic acid" for its vitamin activity. Ascorbic acid turned out not to be an amine, nor even to contain any nitrogen. For their accomplishment, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine "for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid".[47]
Between 1933 and 1934, the British chemists Sir Walter Norman Haworth and Sir Edmund Hirst and, independently, the Polish chemist Tadeus Reichstein, succeeded in synthesizing the vitamin, making it the first to be artificially produced. This made possible the cheap mass-production of what was by then known as vitamin C. Only Haworth was awarded the 1937 Nobel Prize in Chemistry for this work, but the "Reichstein process" retained Reichstein's name.
In 1933 Hoffmann–La Roche became the first pharmaceutical company to mass-produce synthetic vitamin C, under the brand name of Redoxon.
In 1957 the American J.J. Burns showed that the reason some mammals were susceptible to scurvy was the inability of their liver to produce the active enzyme L-gulonolactone oxidase, which is the last of the chain of four enzymes which synthesize vitamin C.[48][49] American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the theory that humans possess a mutated form of the L-gulonolactone oxidase coding gene.
In 2008 researchers at the University of Montpellier discovered that in humans and other primates the red blood cells have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized L-dehydroascorbic acid (DHA) back into ascorbic acid which can be reused by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.[50]
[edit] Physiological function
In humans, vitamin C is essential to a healthy diet as well as being a highly effective antioxidant, acting to lessen oxidative stress; a substrate for ascorbate peroxidase;[3] and an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for important enzymes:[51]
[edit] Collagen, carnitine, and tyrosine synthesis, and microsomal metabolism
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Ascorbic acid performs numerous physiological functions in human body. These functions include the synthesis of collagen, carnitine and neurotransmitters, the synthesis and catabolism of tyrosine and the metabolism of microsome.[52] Ascorbate acts as a reducing agent (i.e. electron donor, anti-oxidant) in the above-described syntheses, maintaining iron and copper atoms in their reduced states.
Vitamin C acts as an electron donor for eight different enzymes:[51]
- Three participate in collagen hydroxylation.[53][54][