Vitamin C

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Vitamin C chemical structure
L-ascorbic-acid-3D-balls.png
Vitamin C
Systematic name
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 644104
Chemical data
Formula C6H8O6 
Mol. weight 176.13 grams per mol
Synonyms L-ascorbate
Physical data
Melt. point 190°C (374°F)
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


Vitamin C or L-ascorbate is an essential nutrient for higher primates, and a small number of other species. The presence of ascorbate is required for a range of essential metabolic reactions in all animals and in plants and is made internally by almost all organisms, (humans being one notable exception). It is widely known as the vitamin that prevents scurvy in humans.[1][2][3]

The pharmacophore of vitamin C is the ascorbate ion. In living organisms, ascorbate is an antioxidant, as it protects the body against oxidative stress,[4] and is a cofactor in several vital enzymatic reactions.[5]

As a nutrient, its uses and the daily requirement are matters of on-going debate. As a food additive, vitamin C is used as an antioxidant preservative and an acidity regulator. Several E numbers account for the vitamin, depending on its chemical structure: E300 as ascorbic acid, E301 as the salt sodium ascorbate, E302 as the salt calcium ascorbate, E303 as the salt potassium ascorbate, E304 for the esters ascorbyl palmitate and ascorbyl stearate, and E315 for the stereoisomer erythorbic acid.


The structure and properties of ascorbic acid

Ascorbic acid is an organic acid with antioxidant properties. Its appearance is white to light yellow crystals or powder. It is water soluble. The L-enantiomer of ascorbic acid is commonly known as vitamin C. The name is derived from a- and scorbuticus (Scurvy) as a shortage of this molecule may lead to scurvy. In 1937 the Nobel Prize for chemistry was awarded to Walter Haworth for his work in determining the structure of ascorbic acid (shared with Paul Karrer, who received his award for work on vitamins), and the prize for Physiology or Medicine that year went to Albert Szent-Györgyi for his studies of the biological functions of L-ascorbic acid. At the time of its discovery in the 1920s it was called hexuronic acid by some researchers.[6]

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.[5] L-dehydroscorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione.[7]

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.

Biological functions

In humans, vitamin C is a highly effective antioxidant, acting to lessen oxidative stress, a substrate for ascorbate peroxidase,[3] as well as an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for eight different enzymes:[8]

  • Three participate in collagen hydroxylation.[9][10][11] These reactions add hydroxyl groups to the amino acids proline or lysine in the collagen molecule (via prolyl hydroxylase and lysyl hydroxylase), thereby allowing the collagen molecule to assume its triple helix structure and making vitamin C essential to the development and maintenance of scar tissue, blood vessels, and cartilage.[12]
  • The remaining three have the following functions:

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.[21] 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.

Biosynthesis

Model of a vitamin C molecule. Black is carbon, red is oxygen, and white is hydrogen

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.[5] 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.[22] 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, guinea pigs, the red-vented bulbul,and fruit-eating bats.[5] Most notably, along with the rest of the ape family in which we reside, humans have no capability to manufacture vitamin C. The cause of this phenomenon is that the last enzyme in the synthesis process, L-gulonolactone oxidase, cannot be made by the listed animals because the gene for this enzyme, Pseudogene ΨGULO, is defective.[23] The mutation has not been lethal because vitamin C is prevalent in their food sources, with many of these species' natural diets consisting largely of fruit.

Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans.[24] 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.[25] Ascorbic acid can be oxidised (broken down) in the human body by the enzyme ascorbic acid oxidase.

An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and as much as 100,000 mg daily when faced with life-threatening disease, trauma or stress.[26] It is thought that the human Vitamin C requirement is far lower than that of Vitamin C-synthesizing mammals due to increased Vitamin C recycling efficiency. [27]

Trauma or injury has also been demonstrated to use up large quantities of vitamin C in humans.[28]

Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.[29][30]

Vitamin-C deficiency has been linked to scurvy

Scurvy is an avitaminosis resulting from lack of vitamin C, as without this vitamin, the synthesised collagen is too unstable to meet 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 cannot store vitamin C,[31] and so the body soon depletes itself if fresh supplies are not consumed through the digestive system.

James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented the disease of scurvy in what was the first recorded controlled experiment.

condense: 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.[32][33]

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 B.C.E., 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.

Citrus fruits were one of the first sources of vitamin C available to ship's surgeons.

Lind's work was slow to be noticed. It was 1795 before the British navy adopted lemons or lime as standard issue at sea.

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.

Albert Szent-Györgyi, pictured here in 1948, was awarded the 1937 Nobel Prize in Medicine for the discovery of vitamin C

In 1912, the Polish-American biochemist Casimir Funk, while researching deficiency diseases, developed the concept of vitamins to refer to the nutrients which are essential to health. Then, 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 vitamin C and showed it to be ascorbic acid. For this, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine.[34]

Daily requirements

The North American Dietary Reference Intake recommends 90 milligrams per day and no more than 2 grams per day (2000 milligrams per day).[35] Other related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this reference intake.[36][37] There is continuing debate within the scientific community over the best dose schedule (the amount and frequency of intake) of vitamin C for maintaining optimal health in humans.[38] It is generally agreed that a balanced diet without supplementation contains enough vitamin C to prevent acute scurvy in an average healthy adult, while those who are pregnant, smoke tobacco, or are under stress require slightly more.[35]

High doses (thousands of milligrams) may result in diarrhea, which is harmless if the dose is reduced immediately. Some researchers[39] claim the onset of diarrhea to be an indication of where the body’s true vitamin C requirement lies. Both Cathcart[39] and Cameron have demonstrated that very sick patients with cancer or influenza do not display any evidence of diarrhea at all until ascorbate intake reaches levels as high as 200 grams (nearly half a pound).

United States vitamin C recommendations[35]
Recommended Dietary Allowance (adult male) 90 mg per day
Recommended Dietary Allowance (adult female) 75 mg per day
Tolerable Upper Intake Level (adult male) 2000 mg per day
Tolerable Upper Intake Level (adult female) 2000 mg per day

Government recommended intakes

Recommendations for vitamin C intake have been set by various national agencies:

  • 40 milligrams per day — the United Kingdom's Food Standards Agency[1]
  • 45 milligrams per day — the World Health Organization[40]
  • 60-95 milligrams per day — United States' National Academy of Sciences[35]

The United States defined Tolerable Upper Intake Level for a 25-year old male is 2000 milligrams per day.

Independent recommended intakes

Some independent researchers have calculated the amount needed for an adult human to achieve similar blood serum levels as vitamin C synthesising mammals as follows:

  • 400 milligrams per day — the Linus Pauling Institute[41]
  • 500 milligrams per 12 hours — Professor Roc Ordman, from research into biological free radicals[42]
  • 3,000 milligrams per day (or up to 300,000 mg during illness or pregnancy) — the Vitamin C Foundation[43]
  • 6,000–12,000 milligrams per day — Thomas E. Levy, Colorado Integrative Medical Centre.[44]
  • 6,000–18,000 milligrams per day — Linus Pauling's personal use[45]
  • 3,000–200,000 milligrams per day — Robert Cathcart's protocol known as a "vitamin C flush" wherein escalating doses of vitamin C are given until diarrhoea develops, then choosing the highest dose that does not cause diarrhea (the bowel tolerance threshold)<;ref name="Cathcart"/>

Vitamin C as a macronutrient

There is a strong advocacy movement for large doses of vitamin C, promoting a great deal of added benefits. Many pro-vitamin C organizations promote usage levels well beyond the current Dietary Reference Intake. The movement is led by scientists and doctors such as Robert Cathcart, Ewan Cameron, Steve Hickey, Irwin Stone and the twice Nobel Prize laureate Linus Pauling and the more controversial Matthias Rath. There is an extensive and growing scientific literature critical of governmental agency dose recommendations.[38][46] The biological halflife for vitamin C is fairly short, about 30 minutes in blood plasma, a fact which high dose advocates say that mainstream researchers have failed to take into account. Researchers at the National Institutes of Health decided upon the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. Hickey, on this matter, says "To be blunt, the NIH gave a dose of vitamin C, waited until it had been excreted, and then measured blood levels."[47]

Humans carry a mutated and ineffective form of the gene required by all mammals for manufacturing the fourth of the four enzymes that manufacture vitamin C.[48] The inability to produce vitamin C, hypoascorbemia, is, according to the Online Mendeleian Inheritance in Man database, a "public" inborn error of metabolism. The gene, Pseudogene ΨGULO, lost its function millions of years ago, when the anthropoids branched out.[49] In humans the three functional enzymes continue to produce the precursors to vitamin C, but the process is incomplete; these enzymes ultimately undergo proteolytic degradation. Stone[50] and Pauling[37] calculated, based on the diet of our primate cousins[36] (similar to what our common descents are likely to have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2300 milligrams for a human requiring 2500 kcal a day.

The established RDA has been criticised by Pauling to be one that will prevent acute scurvy, and is not necessarily the dosage for optimal health.[45]

The controversial Matthias Rath hypothesised that during the ice age, when vitamin C was scarce, natural selection favoured human individuals who could repair arteries with a layer of cholesterol. He suggests that although eventually harmful, cholesterol lining of artery walls would be beneficial in that it would keep the individual alive until access to vitamin C allowed arterial damage to be repaired. If this is true, atherosclerosis is in fact a vitamin C deficiency disease. As atherosclerosis is the main cause of ischaemic heart disease, which in turn is the leading cause of death in developed countries,[51] this would have a profound effect on western medicine.

Since its discovery vitamin C has been considered by some enthusiastic proponents a "universal panacea", although this led to suspicions by others of it being over-hyped.[52] Other proponents of high dose vitamin C consider that if it is given "in the right form, with the proper technique, in frequent enough doses, in high enough doses, along with certain additional agents and for a long enough period of time,"[53] it can prevent and, in many cases, cure, a wide range of common and/or lethal diseases, notably the common cold and heart disease,[54] although the NIH considers there to be "fair scientific evidence against this use."[55] Some proponents issued controversial statements involving it being a cure for AIDS,[56] bird flu, and SARS.[57][58][59]

Probably the most controversial issue, the putative role of ascorbate in the management of AIDS, is still unresolved, more than 16 years after the landmark study published in the prestigious Proceedings of National Academy of Sciences (USA) showing that non toxic doses of ascorbate suppress HIV replication in vitro.[60] Other studies expanded on those results, but still, no large scale trials have yet been conducted.[61][62][63]

A 1986 study indicates that vitamin C may be important in regulation of endogenous cholesterol synthesis.[64]

There have been studies suggesting that vitamin C detoxifies lead,[65][66] reduces the severity of symptoms in children with autism,[67] reduces multiple organ failure and length of stay in the intensive care unit in trauma victims,[68] improves sperm count, sperm motility, and sperm morphology in infertile men,[69] and improves immune function in aged persons and could contribute to the prevention and treatment of age-associated diseases.[70] Dehydroascorbic acid, a chemical relative of Vitamin C but distinct from the chemical itself, was shown to reduce neurological deficits and mortality following stroke, although "the antioxidant ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier".[71]

In January 2007 the US Food and Drug Administration approved a new trial of intravenous vitamin C as a cancer treatment for "patients who have exhausted all other conventional treatment options." Additional studies over several years would be needed to demonstrate whether it is effective.[72]

While being harmless in most typical quantities, as with all substances to which the human body is exposed, vitamin C can still cause harm under certain conditions.

Relatively large doses of vitamin C may cause indigestion, particularly when taken on an empty stomach. This unpleasant but harmless side-effect can be avoided by taking the vitamin along with meals or by offsetting its acidity by taking an antacid such as baking soda or calcium carbonate.

When taken in huge doses, vitamin C causes diarrhea. The minimum dose that brings about this effect varies with the individual. Robert Cathcart has called this limit the "bowel tolerance threshold" and observed that it is higher in people with serious illness than those in good health.[39] It ranges from 5 to 25 grams per day in healthy individuals to 300 grams per day in those that are severely ill. Diarrhea is not harmful, as long as the dose is reduced quickly.

In one trial, doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes.[73]

As vitamin C enhances iron absorption, iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD), can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C. However, there is a test available for G6PD deficiency,[74] and it has been proposed that high doses of vitamin E may protect against this problem.

In addition, large doses of vitamin C (2 g per day) trigger oxalate formation and increase absorption of dietary oxalate, possibly causing kidney stones[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15987848&query_hl=1&itool=pubmed_docsum.

Natural and artificial dietary sources

Rose hips are a particularly rich source of vitamin C

The richest natural sources are fruits and vegetables, and of those, the camu camu fruit and the Kakadu plum contain the highest concentration of the vitamin. It is also present in some cuts of meat, especially liver. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, crystals in capsules or naked crystals.

Plant sources

While plants are generally a good source of vitamin C, the amount in foods of plant origin depends on: the precise variety of the plant, the soil condition, the climate in which it grew, the length of time since it was picked, the storage conditions, and the method of preparation.[75]

The following table is approximate and shows the relative abundance in different raw plant sources.[76][77][78] The amount is given in milligrams per 100 grams of fruit or vegetable and is a rounded average from multiple authoritative sources:

Plant source Amount
(mg / 100g)
Kakadu plum 3150
Camu Camu 2800
Rose hip 2000
Acerola 1600
Amla 720
Jujube 500
Baobab 400
Blackcurrant 200
Red pepper 190
Parsley 130
Seabuckthorn 120
Guava 100
Kiwifruit 90
Broccoli 90
Loganberry 80
Redcurrant 80
Brussels sprouts 80
Lychee 70
Cloudberry 60
Persimmon 60
Plant source Amount
(mg / 100g)
Papaya 60
Strawberry 60
Orange 50
Lemon 40
Melon, cantaloupe 40
Cauliflower 40
Grapefruit 30
Raspberry 30
Tangerine 30
Mandarin orange 30
Passion fruit 30
Spinach 30
Cabbage raw green 30
Lime 20
Mango 20
Potato 20
Melon, honeydew 20
Mango 16
Tomato 10
Blueberry 10
Pineapple 10
Plant source Amount
(mg / 100g)
Pawpaw 10
Grape 10
Apricot 10
Plum 10
Watermelon 10
Banana 9
Carrot 9
Avocado 8
Crabapple 8
Peach 7
Apple 6
Blackberry 6
Beetroot 5
Pear 4
Lettuce 4
Cucumber 3
Eggplant 2
Fig 2
Bilberry 1
Horned melon 0.5
Medlar 0.3


Animal sources

Goats, like almost all animals, make their own vitamin C. An adult goat will manufacture more than 13,000 mg of vitamin C per day in normal health and as much as 100,000 mg daily when faced with life-threatening disease, trauma or stress.

The overwhelming majority of species of animals and plants synthesise their own vitamin C, making some, but not all, animal products, sources of dietary vitamin C.

Vitamin C is most present in the liver and least present in the muscle. Since muscle provides the majority of meat consumed in the western human diet, animal products are not a reliable source of the vitamin. Vitamin C is present in mother's milk and, in lower amounts, in raw cow's milk, with pasteurized milk containing only trace amounts.[79] All excess Vitamin C is disposed of through the urinary system.

Food preparation

Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Normally, boiling water at 100°C is not hot enough to cause any significant destruction of the nutrient, which only decomposes at 190°C, despite popular opinion. However, pressure cooking, roasting, frying and grilling food is more likely to reach the decomposition temperature of vitamin C. Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition.[80]

Another cause of vitamin C being lost from food is leaching, where the water-soluble vitamin dissolves into the cooking water, which is later poured away and not consumed. However, vitamin C doesn't leach in all vegetables at the same rate; research shows broccoli seems to retain more than any other.[81] Research has also shown that fresh-cut fruit don't lose significant nutrients when stored in the refrigerator for a few days.[82]

Vitamin C supplements

File:RedoxonVitaminC.jpg
Vitamin C is widely available in the form of tablets and powders. The Redoxon brand, launched in 1934 by Hoffmann-La Roche, was the first mass-produce synthetic vitamin C.

Vitamin C is the most widely taken dietary supplement.[83] It is available in many forms including caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple antioxidant formulations, as chemically pure crystalline powder, timed release versions, and also including bioflavonoids such as quercetin, hesperidin and rutin. The use of vitamin C supplements with added bioflavonoids and, often, flavours and sweeteners, can be problematic at gram dosages, since those additives are not so well studied as vitamin C. Also, the presence of glucose in the intestines or bloodstream inhibits the absorption of vitamin C. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (as ascorbic acid) crystals are typically available in bottles containing 300 g to 1 kg of powder (a teaspoon of vitamin C crystals equals 5,000 mg). In supplements, vitamin C most often comes in the form of various mineral ascorbates, as they are easier to absorb, more easily tolerated and provide a source of several dietary minerals.

Absorption of Vitamin C

Vitamin C is absorbed by the intestines using a sodium-ion dependent channel. It is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms. Having a lot of sugar either in your intestines or in your blood (as in diabetes mellitus) can slow absorption, which is relevant when megadosing.[84]

Artificial modes of synthesis

Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. Both processes yield approximately 60% vitamin C from the glucose feed.[85]

Research is underway at the Scottish Crop Research Institute in the interest of creating a strain of yeast that can synthesise vitamin C in a single fermentation step from galactose, a technology expected to reduce manufacturing costs considerably.[29]

World production of synthesised vitamin C is currently estimated at approximately 110,000 tonnes annually. Main producers today are BASF/Takeda, DSM, Merck and the China Pharmaceutical Group Ltd. of the People's Republic of China. China is slowly becoming the major world supplier as its prices undercut those of the US and European manufacturers.[86]

References
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    "Plasma vitamin C concentrations are maintained between 10 and 160 μM, and any excess of the vitamin is excreted by the kidney. In contrast, the vitamin is concentrated to at least 100 times the plasma level in specific tissues such as the adrenal glands, pituitary gland, thymus, retina, corpus luteum, and a variety of neuronal cell types."
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    "Our results show that plasma ascorbic acid levels following trauma and during infection are extremely low and are not normalized with 300 or even 1000 mg/day supplemented TPN."
  29. ↑ 29.0 29.1 R.D. Hancock & R. Viola. Ascorbic acid biosynthesis in higher plants and micro-organisms. Scottish Crop Research Institute. Retrieved 2007-02-20.

    "Our results demonstrate that yeast cells are capable of direct fermentation of L-galactose to L-AA. However, given that L-galactose is an extremely rare and expensive sugar a process using L-galactose as a starting material could never be economical. In order to overcome this problem, we are currently developing new yeast strains with extended metabolic competence for the synthesis of L-galactose directly from inexpensive substrates."
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  38. ↑ 38.0 38.1 Linus Pauling Vindicated; Researchers Claim RDA For Vitamin C is Flawed. PR Newswire (6 July 2004). Retrieved 2007-02-20.
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  41. ↑ Higdon, Jane. Linus Pauling Institute Recommendations. Oregon State University. Retrieved 2007-04-11.
  42. ↑ Roc Ordman. The Scientific Basis Of The Vitamin C Dosage Of Nutrition Investigator. Beloit College. Retrieved 2007-02-22.
  43. ↑ Vitamin C Foundation's RDA. Retrieved 2007-02-12.
  44. ↑ Levy, Thomas E. (2002). Vitamin C Infectious Diseases, & Toxins. Xlibris. ISBN 1401069630.  Chapter 5 - Vitamin C optidosing.
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  46. ↑ Forman, Robert (1981). Medical Resistance To Innovation. Medical Hypotheses 7 (8): 1009-1017.
  47. ↑ Sardi, Bill (July 09, 2004). The Vitamin C Fanatics Were Right All Along. Knowledge of Health, Inc.. Retrieved 2007-02-22.
  48. ↑ OMIM. Online Mendeleian Inheritance in Man. HYPOASCORBEMIA.
  49. ↑ Hickey, Steve and Roberts, Hilary (2004). Ascorbate: The Science of Vitamin C. Lulu Press, Inc.. ISBN 1-4116-0724-4. 
  50. ↑ Stone, Irwin (1972). The Healing Factor: Vitamin C Against Disease. Grosset and Dunlap. ISBN 0-448-11693-6. 
  51. ↑ WHO World Health Report 2002
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  73. ↑ Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents. World Health Organization (4 July 1973). Retrieved 2007-04-13.
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  75. ↑ The vitamin and mineral content is stable. Danish Veterinary and Food Administration. Retrieved 2007-03-07.
  76. ↑ National Nutrient Database. Nutrient Data Laboratory of the US Agricultural Research Service. Retrieved 2007-03-07.
  77. ↑ Vitamin C Food Data Chart. Healty Eating Club. Retrieved 2007-03-07.
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  80. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named oxford
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  83. ↑ The Diet Channel Vitamin C might be the most widely known and most popular vitamin purchased as a supplement.
  84. ↑ Wilson JX (2005). Regulation of vitamin C transport. Annu. Rev. Nutr. 25: 105-25.
  85. ↑ The production of vitamin C. Competition Commission (2001). Retrieved 2007-02-20.
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Further reading

Portal Vitamin C Portal
Portal Vitamin C Portal
Journals
  • Dolske, M.C., et al. (1993). A preliminary trial of ascorbic acid as supplemental therapy for autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 17 (5): 765-74.
  • Green VA, Pituch KA, Itchon J, Choi A, O'Reilly M, Sigafoos J (2006). Internet survey of treatments used by parents of children with autism. Research in developmental disabilities 27 (1): 70-84.
Books
  • Pauling, Linus (1970). Vitamin C and the Common Cold. W. H. Freeman & Company. ISBN 071670160X. 
  • Pauling, Linus (1976). Vitamin C, the Common Cold, and the Flu. W H Freeman & Co. ISBN 0716703610. 
  • Cameron, Ewan and Linus Pauling, (1979). Cancer and Vitamin C. Pauling Institute of Science and Medicine. ISBN 0393500004. 
  • Kent, Saul (1980). Life Extension Revolution. Morrow. 
  • Pearson, Durk and Sandy Shaw (1982). Life Extension: A Practical Scientific Approach. Warner Books. ISBN 0446387355.  see Part IV, Chapter 7: Vitamin C
  • Pelton, Ross (1986). Mind Food and Smart Pills: How to Increase Your Intelligence and Prevent Brain Aging. T & R Pub. ISBN 0936809000.  see Chapter 3: Vitamin C, The Champion Free Radical Scavenger
  • Clemetson, C.A.B (1989). Vitamin C. Boca Raton, Florida: CRC Press. ISBN 0-8493-4841-2.  Monograph - Volumes I, II, III.
  • Levy, Thomas E. (2002). Vitamin C Infectious Diseases, & Toxins. Xlibris. ISBN 1401069630. 

External links

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