Vitamin C

This article is about the nutrient; for other uses see Vitamin C (disambiguation).

Vitamin C (Ascorbic acid)
General
Chemical formula	C6H8O6
Molecular weight	176.13 g/mol
Vitamin properties
Solubility	Water
RDA (adult male)	90 mg/day (US)
RDA (adult female)	75 mg/day (US)
Tolerable Upper Intake Level (UL) (adult male)	2000 mg/day
Tolerable Upper Intake Level (UL)t (adult female)	2000 mg/day
Deficiency symptoms
Scurvy
Excess symptoms
diarrhea indigestion
Common sources
fruits Leafy vegetables Ascorbic Acid Supplements

Vitamin C is a nutrient required in very small amounts to promote essential metabolic reactions in the body. Vitamin C is principally a water-soluble anti-oxidant that prevents scurvy. It is also known by the chemical name of its principal form, L-ascorbic acid or simply ascorbic acid. The guidance provided by the United States of America and Canada for Dietary Reference Intake (DRI) recommends 90mg per day and no more than 2g per day (2000mg/day). This article describes the biological functions, discovery and the continuing scientific debate of vitamin C and how it is used, including its widespread application in doses larger than the officially recommended upper limit.

Description

Vitamin C is a weak acid, called ascorbic acid, that can be deprotonated to become an ascorbate ion. It is the L-enantiomer of ascorbic acid. The D-enantiomer shows no biological activity. Both are mirror image forms of the same chemical molecular structure (see optical isomers).

It is a six carbon compound structurally related to glucose. It exists as two inter-convertible compounds: L-ascorbic acid, which is a strong reducing agent, and its oxidised derivative, L-dehydroascorbic acid.

The active part of the substance is the ascorbate ion. Commercial vitamin C is often a mixture of ascorbic acid, sodium ascorbate and/or other ascorbates. Some supplements contain in part the D-enantiomer, which is useless and harmless.

Vitamin C

Vitamin C, an enzyme cofactor

Vitamin C is required by some enzymes called hydroxylases to add hydroxyl radicals (O-H) to specific molecules.

Collagen synthesis

Collagen hydroxylase uses vitamin C to make the long collagen fibers hold together. Collagen is the most abundant protein in the human body. (in progress)

Norepinephrine synthesis

Norepineprine, (aka noradrenaline), is obtained from dopamine by the action of the enzyme dopamine beta-hydroxylase. Dopamine and norepinephrine are neurotransmitters which have different functions but which are closely involved in mood, learning, and movement. Many antidepressants raise dopamine and norepinephrine concentrations, by different mechanisms.

Carnitine synthesis

Carnitine is the molecule that allows most fat molecules to be carried in the mitochondria where they will be transformed into energy. Carnitine is also required to carry excess organic acids out of mitochondria, where they would otherwise impair energy production. The metabolic pathway that leads from the amino acid lysine to the conditionnaly essential vitamin carnitine requires vitamin C twice. The steps are the enzymes gamma-butyrobetaine hydroxylase and epsilon-N-trimethyl-lysine hydroxylase. Low vitamin C causes a decreases in carnitine production, which contributes to fat deposition and overweight. At present, the exact role of low vitamin C in the obesity epidemic is not clarified, but the normalisation of vitamin C levels in people with low vitamin C status was shown to raise their ability to burn fat 4-fold during submaximal exercise. Future studies should determine to what extent fruits and vegetables contibutes to carnitine synthesis and weight management.

The antioxidant functions of vitamin C

Vitamin C is also a major water phase low-molecular weight antioxidant. (in progress)

Biosynthesis

Some microorganisms, such as the yeast Saccharomyces cerevisiae, are able to synthesize ascorbic acid. [2] Almost all animals and plants can synthesize vitamin C.

Primates, including humans, and a small number of other animals, including guinea pigs, the red-vented bulbul, a fruit-eating bat and a species of trout are exceptions in the animal kingdom, in this respect. In addition, the Shionogi rat, much like the guinea pig, is used in laboratories to study hypoascorbemia, the inability to produce vitamin C, and its consequences.

According to the Online Mendeleian Inheritance in Man database, hypoascorbemia is a "public" inborn error of metabolism, as it affects all members of the human race. It is agreed that the loss of the ability to produce vitamin C, due to a mutation in the L-gulono-gamma-lactone oxidase gene, some 25 to 45 million years ago, occurred because the natural environment of the common ancestor of primates provided great amounts of vitamin C. Primates, who still live in this environment, consume 2000 to 6000 mg of vitamin C per day, which are indeed great amounts, compared to recommended doses for Modern man, which are at least 20 times lower.

The species-specific 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 (electron-donors). This has led to the suggestion [3] that in higher primates, uric acid has taken over some of the functions of ascorbate.

Another possible compensatory mechanism is the synthesis of lipoprotein(a). Lipoprotein(a), which is almost exclusively present in primates, might strengthen the extracellular matrix and compensate to some extent the relative lack of collagen and elastin synthesis. In addition, it is probable that lp(a), like vitamin C, delays lipid oxidation (peroxidation).

Transport

Vitamin C is transported in cells and organs through two very different transporters: SVCT (Sodium-dependent vitamin C transporters; there exists two forms of this protein, SVCT1 and SVCT2) and GLUT1, the glucose transporter 1.

• The SVCT1 and SVCT2 transporters have high affinity for vitamin C.

The SVCT1 isoform is mostly found in the liver and the kidney. Worthy of note, the liver and the kidney are the two sites for vitamin C synthesis in the animal kingdom.

The SVCT2 isoform dominates in the brain, skeletal muscles, and the spleen.

• The GLUT1 transporter has a more complicated and paradoxical role in vitamin C regulation. The GLUT1 does not transport vitamin C, but dehydroascorbic acid, a major oxidized form of vitamin C. It is the existence of this transporter that explains a paradoxical finding made my James Lind in his Treatise of the Scurvy:

(Victims of scurvy had) "ravaged bodies" (but) "(W)hat was very surprising, the brains of those poor creatures were always sound and entire (...)"

It thus appears that the glucose transporter GLUT1, by transporting oxidized vitamin C, allows important organs to quickly store vitamin C in times of increased oxidative stress. Once dehydroascorbic acid has crossed the blood-brain barrier and is in the brain, it is recycled (reduced) back to vitamin C, which has no affinity with the GLUT1 transporter and thus can't undergo reverse transport. This allows the brain to accumulate concentrations of vitamin C that are 10 times greater than in the blood.

Distribution

In the blood

Vitamin C concentrations in the blood generally are between 10 and 160 micromol/L, with concentrations generally not exceeding 80 micromol/L after most meals Oral supplementation can raise levels to 220 micromol/L, while intravenous infusion of the vitamin can raise concentrations to 13 400 micromol/L.

In organs and tissues

Some glands, organs and tissues contain 100 times more vitamin C than the blood, including adrenal glands, pituitary gland, thymus, retina, corpus luteum, and various types of neurons.

Adrenal glands

High concentrations of vitamin C are required for the adequate synthesis of catecholamines and steroids in the adrenal gland (adrenal cortex and adrenal medulla). In addition, in response to stress, adrenals secrete vitamin C locally, creating high concentrations acting in a paracrine manner.

Thymus

(in progress)

Corpus luteum

The corpus luteum produces the steroid progesterone, which is required to achieve a normal pregnancy. Different enzymes involved in progesterone synthesis are enhanced by vitamin C at concentrations of 100 micromol/L (in the higher nutritional range). Also see Therapeutic uses - Pregnancy. Conversely, the prostaglandin PGF2, which is known to injure the corpus luteum, increases the secretion of vitamin C by the corpus luteum and its consecutive depletion.

The brain

The brain contains on average 10 times more vitamin C than the blood. Species that are exceptionally tolerant to oxygen deprivation and to reoxygenation concentrate even higher amounts of vitamin C. The fact that the brain has specific mechanisms to accumulate vitamin C (see Transport, above), prompted researchers to investigate the effect of (oxidized, brain transportable) vitamin C on experimental stroke (see Therapeutic uses, below). Conversely, in animal models of diabetes, where blood glucose levels are abnormally high, a drastic inhibition of vitamin C transport to the brain (through its oxidized form) is observed.

Hippocampus

The hippocampus, which is involved in memory and learning, concentrates more vitamin C than other brain regions. A recent study in an animal model of Alzheimer's disease and dementia showed vitamin C to be a "potent" memory enhancer, especially in aged animals.

Hypothalamus and the pituitary gland

The hypothalamus concentrates high concentrations of vitamin C using its glial cells (tanycytes), which highly express the specialized transporter SVCT2 (also see Transport, above).

Retina

The retina, like the brain, accumulates high concentrations of vitamin C using GLUT1 glucose transporters, which are distributed on the blood-retinal barrier. An experimental model of diabetes showed vitamin C concentrations in the retina to be drastically reduced by the high concentrations of glucose seen in diabetes, as a result of the competition of glucose with dehydroascorbic acid for entry in the retina (in this study, the transport of DHA was decreased by two thirds).

Vitamin C deficiency and scurvy

No bodily organ stores ascorbate as a primary function, and so the body soon depletes itself of ascorbate if fresh supplies are not consumed, eventually leading to the deficiency disease scurvy (a form of avitaminosis), which results in illness and death if consumption of vitamin C is not resumed in time.

History of vitamin C

Vitamin C was first isolated in 1928, and in 1932 it was shown to prevent scurvy. Both Charles Glen King at the University of Pittsburgh and Albert Szent-Györgyi (working with ex-Pittsburgh researcher Joseph Svirbely) came to discover what is now known as vitamin C around April of 1932. Although Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine, many feel King is as responsible for its development.

For more information, see History of vitamin C.

Daily requirements

The daily requirement for vitamin C is unclear. The United States and Canada recommend about twice the amount that the World Health Organization recommends. The Linus Pauling Institute recommends more than four times the amount that the US and Canada recommend, or ten times what the WHO recommends. The Linus Pauling Institute disagrees with Linus Pauling, as Pauling recommended doses in the same range as what other primates consume in the wild (about 100 times what the WHO recommends) (also see Biosynthesis, above).

	United Kingdom	United States	World Health Organization	Linus Pauling Institute	Vitamin C Foundation	Linus Pauling	Other primates
Daily vitamin C intake (in milligrams)	40	95	45	400	3000	6000-18000	2000-6000

The antiscorbutic range

In 1974, in the Proceedings of the National Academy of Sciences (USA), Linus Pauling pointed out that amounts of recommended vitamin C in the range of 45 mg per day (for adults) should be renamed Minimum Dietary Allowances to reflect the fact that they are only intended to prevent a deficiency disease, scurvy. Although this suggestion was not accepted by health authorities, more recent recommandations reflect the notion that vitamin C not only prevents scurvy but contributes to the attainment of the "best of health".

Recommandations not based on scurvy

In line with Pauling's suggestion, Mark Levine and colleagues, from the National Institute of Diabetes and Digestive and Kidney diseases (US NIH), pioneered the use of pharmacokinetic studies in order to determine recommended dietary allowances based on physiological requirements. This approach influenced many countries accross the world (Japan, Canada, many European countries) and gave solid support to the 5 servings of fruits and vegetables a day recommandation made by the World Health Organization.

Recommandations based on evolutionary biology

(in progress)

The pharmacokinetics debate

(in progress)

In 2004, Pr. Steve Hickey, of the Manchester Metropolitan University, criticized the methodology used to determine the nutritional requirement of vitamin C. Hickey and Roberts argued, in 2005, based on a recent pharmacokinetics study, that high oral doses of vitamin C do raise plasma vitamin C and that the very notion of tissue saturation could not be applied, arguing that no data on saturation are available. They also questioned the use of white blood cell saturation as a measure of the body's needs for vitamin C on the grounds that those types of cells, due to their higher need for antioxidants, rapidly and massively accumulate vitamin C, and thus can't be representative.

An open letter calling for the revision of the RDI (Reference Daily Intake) written by a number of scientists and medical researchers, notably Steve Hickey, Hilary Roberts, Hugh Riordan (one of the authors of the pharcokinetics study mentioned above, as well as Ian Brighthope, Robert Cathcart, Abram Hoffer, Archie Kalokerinos, Tom Levy, Richard Passwater, Andrew Saul and Patrick Holford, was sent to the Institute of Medicine (IoM) and the NIH. According to Hickey and Roberts, this open letter remained unanswered.

In summary the biological halflife for higher-dose vitamin C is quite short, about 30 minutes in blood plasma, a fact which high dose advocates say NIH and IM researchers have failed to recognize. NIH researchers established the current RDA based upon tests conducted 12 hours (24 half lives) after consumption. "To be blunt," says Hickey, "the NIH gave a dose of vitamin C, waited until it had been excreted, and then measured blood levels." NIH don't take into account individual differences such as age, weight, etc. For example, heavier individuals generally need more vitamin C. They point out the figures represent the amount needed to prevent the acute form of deficiency disease, while subclinical levels of the disease are not even acknowledged. That the amount needed to prevent other diseases is not considered. The established RDA is one that will prevent the onset of scurvy and is not necessarily the most optimal dosage.

• Testing for ascorbate levels in the body

Simple tests exist which measure levels of ascorbate ion in urine, serum or blood plasma. However, these tests do not accurately reflect actual tissue ascorbate levels. Reverse-phase high-performance liquid chromatography (HPLC) is used for determining vitamin C levels within lymphocytes and other tissue. It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, levels within tissues are more stable and give a better determination of ascorbate availability within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories.

Therapeutic uses

Vitamin C is needed in the diet to prevent scurvy. However, from the time it became available in pure form in the 1930s, some practitioners experimented with vitamin C as a treatment for diseases other than scurvy.

Colds

A recent 55-study review found little positive effect of a vitamin C intake on common cold at low doses, but indication of prophylaxis benefits at higher doses especially where the subjects were in stressful situations.

At least 29 controlled clinical trials (many double-blind and placebo-controlled) involving a total of over 11,000 participants have been conducted into vitamin C and the Common cold. These trials were reviewed in the 1990s and again more recently. The trials show that vitamin C reduces the duration and severity of colds but not the frequency. The data indicate that there is a normal dose-response relationship. Vitamin C is more effective the higher the dose.

The vast majority of the trials were limited to doses below 1 g/day. As doses rise, it becomes increasingly difficult to keep the trials double blind because of the obvious gastro-intestinal side effects of heavy doses of Vitamin C. So, the most effective trials at doses between 2 and 10 g/day are generally met with skepticism.

The controlled trials and clinical experience prove that vitamin C in doses ranging from 0.1 to 2.0 g/day have a relatively small effect. The duration of colds was reduced by 7% for adults and 15% for children. The studies provide ample justification for businesses to encourage their employees to take 1 to 2 g/day during the cold season to improve workplace productivity and reduce sick days. The clinical reports provide the strongest possible evidence that vitamin C at higher doses is significantly more effective. However, the effectiveness typically comes at the price of gastro-intestinal side effects. It is easy for physicians to minimize these side effects since they cause no lasting harm. Adult patients, however, have proven reluctant to subject themselves to gas and cramping to deliver an unknown benefit (the duration and severity of colds is highly variable so the patient never knows what he/she is warding off). It is well worth the effort of identifying the small subset of individuals who can benefit from high daily doses (>10 g/day) of vitamin C without side effects and training them to regularly take 5 g/day during cold season and to increase the dose at the onset of a cold.

Hepatitis C virus infection

A phase I clinical trial was conducted to determine whether antioxidants could be beneficial in hepatitis C virus infection (HCV infection). This infection leads to a lack of antiviral defenses and to oxidative stress in the liver. Ultimately, oxidative stress, notably lipid-mediated oxidative stress (lipid peroxidation), causes liver cells to degenerate and die. Vitamin C was part of the protocol. The trial yielded favourable changes : normalization of liver enzymes (ALT returned to normal in 44 % of those who had abnormal ALT); decrease in viral load (25 % of patients); tissue changes (36.1 % had improvements histologic parameters); and 58 % of patients saw their quality of life improve with the antioxidant treatment (increase in the SF-36 score). It is impossible, using this trial, to determine the respective contribution of the antioxidants used, and whether changes in dosages and posology could yield better outcomes.

Polio

Most notable was Fred R. Klenner, a doctor in general practice in Reidsville, North Carolina. He utilized both oral and intravenous vitamin C to treat a wide range of infections and poisons. He published a paper in 1949 that described how he had seen poliomyelitis yield to vitamin C in sufficiently large doses.[4] No controlled clinical trials have been conducted to confirm effectiveness.[5]

Lead poisoning

There is also evidence that vitamin C is useful in preventing lead poisoning, possibly helping to chelate the toxic heavy metal from the body. [6]

Reduction of the spermatotoxicity of common pesticides and contaminants

There exists great concern about the impact of pesticides and other contaminants on the reproductive capabilities on animals, including humans. The toxicity of pesticides and contaminants can occur, notably, through endocrine disruption and/or oxidative stress.

The oxidative toxicity of bisphenol A to the epididymis and its effect on sperm motility and sperm count have been shown to be lessened by vitamin C. The oxidative toxicities of endosulfan, phosphamidon,mancozeb and PCB (Aroclor 1254) were also neutralized by vitamin C. It is important to note that the protective effects occurred irrespective of the chemical structure of the toxics, but rather addressed a common pathway of injury, i.e. oxidative stress, considering the very broad variety of chemical properties of toxics commonly encountered in the environment and in humans.

Reduction of Gentamicin nephrotoxicity

Vitamin C has been found to be effective in reducing or protecting against nephrotoxicity caused by the aminoglycoside antibiotic Gentamicin. [7]

Viral diseases, and poisons

Orthomolecular medicine and a minority of scientific opinion sees vitamin C as being a low cost and safe way to treat viral disease and to deal with a wide range of poisons.

Vitamin C has a growing reputation for being useful in the treatment of colds and flu, owing to its recommendation by prominent biochemist Linus Pauling. In the years since Pauling's popular books about vitamin C, general agreement by medical authorities about larger than RDA amounts of vitamin C in health and medicine has remained elusive. Ascorbate usage in studies of up to several grams per day, however, have been associated with decreased cold duration and severity of symptoms, possibly as a result of an antihistamine effect [8]. The highest dose treatments, published clinical results of specific orthomolecular therapy regimes pioneered by Drs. Klenner (repeated IV treatments, 400–700+ (mg/kg)/day [9][10]) and Cathcart (oral use to bowel tolerance, up to ~150 grams ascorbate per day for flu), have remained experimentally unaddressed by conventional medical authorities for decades.

The Vitamin C Foundation recommends an initial usage of up to 8 grams of vitamin C every 20–30 minutes [11] in order to show an effect on the symptoms of a cold infection that is in progress. Most of the studies showing little or no effect employ doses of ascorbate such as 100 mg to 500 mg per day, considered "small" by vitamin C advocates. Equally importantly, the plasma half life of high dose ascorbate is approximately 30 minutes, which implies that most high dose studies have been methodologically defective and would be expected to show a minimum benefit. Clinical studies of divided dose supplementation, predicted on pharmacological grounds to be effective, have only rarely been reported in the literature. Essentially all the claims for high dose vitamin C remain to be scientifically refuted. The clinical effectiveness of large and frequent doses of vitamin C is an open scientific question.

In 2002 a meta-study into all the published research on effectiveness of ascorbic acid in the treatment of infectious disease and toxins was conducted, by Thomas Levy, Medical Director of the Colorado Integrative Medical Centre in Denver. He claimed that evidence exists for its therapeutic role in a wide range of viral infections and for the treatment of snake bites.

Heart disease

Vitamin C is the main component of the three ingredients in Linus Pauling's patented preventive cure for Lp(a) related heart disease, the other two being the amino acid lysine and nicotinic acid (a form of Vitamin B3). Lp(a) as an atherosclerotic, evolutionary substitute for ascorbate is still discussed as a hypothesis by mainstream medical science and the Rath-Pauling related protocols have not been rigorously tested and evaluated as conventional medical treatment by the FDA.

Cancer

Two placebo-controlled trials could not show any positive effect of vitamin C in cancer patients.

In 2005 in vitro (test tube) research by the National Institutes of Health indicated that vitamin C administered in pharmacological concentrations (i.e. intravenous) was preferentially toxic to several strains of cancer cells. The authors noted: "These findings give plausibility to intravenous ascorbic acid in cancer treatment, and have unexpected implications for treatment of infections where H₂O₂ may be beneficial." This research appeared to support Linus Pauling's claims that vitamin C can be used to fight cancer.

In 2006 the Canadian Medical Association Journal published in vivo research that demonstrated that intravenous vitamin C can subdue advanced-stage cancer.

Stroke

Vitamin C is transported in its oxidized form (dehydroascorbic acid, DHA) to the brain at a high rate through glucose transporters (also see Vitamin C transport and distribution, above). In a study published in the Proceedings of the National Academy of Sciences, the administration of DHA to experimental models of thromboembolic stroke enhanced blood flow and decreased morbidity and mortality. Considering the lack of safe and accessible treatment for stroke, and because of the greater safety of DHA, which would allow early intervention, the authors concluded that increasing "cerebral levels of ascorbate in stroke has tremendous potential to represent the timely translation of basic research into a relevant therapy for thromboembolic stroke in humans".

Cataracts

It has been also suggested that vitamin C might prevent the formation of cataracts.

Autism

A recent internet survey found that 30.8% of parents use vitamin C as a therapy for their child with autism (Green 2006). So far, however, only one study has shown that vitamin C can help treat behavioral problems associated with autism. While this small double-blind trial found that high doses of vitamin C had a significant positive effect on behavior in children with autism, it has not been replicated (Dolske 1993). The study used approximately 2 grams daily (divided into 2 or 3 doses) for a 40-pound child.

Other effects

Contraindications

A Contraindication is a condition which makes an individual more likely to be harmed by a dose of vitamin C than an average person.

• A primary concern is people with unusual or unaddressed iron overload conditions, including hemochromatosis. Vitamin C enhances iron absorption. If sufferers of iron overload conditions take gram sized doses of vitamin C, they may worsen the iron overload due to enhanced iron absorption.

• Inadequate Glucose-6-phosphate dehydrogenase enzyme (G6PD) levels, a genetic condition, may predispose some individuals to hemolytic anemia after intake of specific oxidizing substances present in some food and drugs. This includes repeated, very large intravenous or oral dosages of vitamin C. There is a test available for G6PD deficiency [12]. High dose of Vitamin E has been proposed as a potential protective factor.

Side-effects

• Vitamin C causes diarrhea if taken in quantities beyond a certain limit, which varies by individual. Cathcart has called this limit the Bowel Tolerance Limit and observed that it is higher in people with serious illness than those in good health. It ranges from 5 to 25 grams per day in healthy individuals to 300 grams per day in the seriously ill people, such as those with AIDS and cancer. The diarrhea side-effect is harmless, though it can be inconvenient. The diarrhea will cease as soon as the dose is reduced.

• Large doses of vitamin C may cause acid 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.

Effects of overdose

Vitamin C exhibits remarkably low toxicity. For example, in a rat, the LD50 (the dose that will kill 50% of a population) has been reported as 11900 mg/kg. For a 70 kg (155 pound) human, this means that 833,000 mg (0.833kg or 1.8 pounds) of vitamin C would need to be ingested to stand a 50% chance of killing the person. However, vitamin C could not result in death when administered orally as large amounts of the vitamin cause diarrhea and are not absorbed. An extremely large amount of vitamin C would need to be rapidly injected by IV to stand any chance of killing a person. Robert Cathcart, MD, has used intravenous doses of vitamin C of 250 grams and reports that he has had no problems. The Council for Responsible Nutrition has set an Upper Level (UL) of 2 grams, based on transient diarrhea. Their publication on vitamin C safety notes that

“

...very large doses of vitamin C have been taken daily over the course of many years, and only minor undesirable effects have been attributed with any certainty to the vitamin’s use[...] Clearly, vitamin C has a low order of toxicity.

”

Alleged harmful effects

Reports of harmful effects of vitamin C tend to receive prominent media coverage. As such, these reports tend to generate much debate and more research into vitamin C. Some of the harmful effects described below were proven invalid in later studies, while other effects are still being analysized.

• In April 1998, the journal Nature reported alleged carcinogenic and teratogenic effects of excessive doses of vitamin C. The effects were noted in test tube experiments and on only two of the 20 markers of free radical damage to DNA. These results have not been observed in living organisms.

• The authors of the "Nature" study later clarified their position, stating that their results "show a definite increase in 8-oxoadenine after supplementation with vitamin C. This lesion is at least ten times less mutagenic than 8-oxoguanine, and hence our study shows an overall profound protective effect of this vitamin".

• In April 2000, University of Southern California researchers reported a thickening of the arteries of the neck in persons taking high vitamin C doses. It was later pointed out by vitamin C advocates that this can be explained by vitamin C's collagen synthesising role leading to thicker and stronger artery walls. (ref. para 10)

• In June 2004, Duke University researchers reported an increased susceptibility to osteo-arthritis in guinea pigs fed a diet high in vitamin C. However, a 2003 study at Umeå University in Sweden, found that "the plasma levels of vitamin C, retinol and uric acid were inversely correlated to variables related to rheumatoid arthritis disease activity."

• A speculated increased risk of kidney stones may be a side effect of taking vitamin C in larger than normal amounts (>1 g). The potential mechanism of action is through the metabolism of vitamin C (ascorbic acid) to dehydroascorbic acid, which is then metabolized to oxalic acid, a known constituent of kidney stones. However, this oxalate issue is still controversial, with evidence being presented for and against the possibility of this side effect. Vitamin C has long been advocated, and used, by some less conventional physicians to prevent or alleviate some kinds of non-oxalate kidney stone formation. after addressing the oxalate issue. Vitamin B6 may mitigate the general risk of oxalate stones by decreasing oxalate production. Additionally, thiamine may inhibit oxalate formation. Furthermore, correcting any magnesium deficiency may decrease the risk of kidney stones by decreasing oxalate crystallization. Increasing one's fluid intake also helps to prevent oxalate crystallization in the kidney. There is evidence that certain intestinal flora influence how much oxalate is destroyed and that their absence is a significant causal risk factor in oxalate stone formers. Patients with a predispostion to form oxalate stones or those on hemodialysis should avoid excess use of vitamin C.

• "Rebound scurvy" is a theoretical, never observed, condition that could occur when daily intake of vitamin C is rapidly reduced from a very large amount to a relatively low amount. Advocates suggest this is an exaggeration of the rebound effect which occurs because ascorbate-dependent enzyme reactions continue for 24–48 hours after intake is lowered, and use up vitamin C which is not being replenished. The effect is to lower one's serum vitamin C blood concentration to less than normal for a short amount of time. During this period of time there is a slight risk of cold or flu infection through reduced resistance. Within a couple of days the enzyme reactions shut down and blood serum returns to the normal level of someone not taking large supplements. This is not scurvy, which takes weeks of zero vitamin C consumption to produce symptoms. It is something people who take large vitamin C supplements need to be aware of in order to gradually reduce dosage rather than quit taking vitamin C suddenly. (ref. para 4) This is a theoretical risk for those taking supplements, e.g., if they find themselves severely ill, and in a hospital without the supplements, at a time when they need normal or better levels of vitamin C to fight the disease (ref. and search for "The major problem"). At this time, many doctors and hospital staff do not know much about nor administer megadosing of supplements, so that patients may have to rely on friends or relatives to bring them their supplements.

• Some writers have identified a theoretical risk of poor copper absorption from high doses of vitamin C, although little experimental evidence supports this. However, ceruloplasmin levels seem specifically lowered by high vitamin C intake. In one study, 600 milligrams of vitamin C daily did not decrease copper absorption or overall body copper status in young men, but led to lower ceruloplasmin levels similar to those caused by copper deficiency. In another, ceruloplasmin levels were significantly reduced.

• There are stories circulating among some folk remedy proponents that doses of around 12 grams per day of vitamin C can induce an abortion in women under 4 weeks of pregnancy. This is not supported by scientific research however.

• Recent studies into the use of a combination of Vitamin E ("natural" source isomer moiety, d-alpha tocopheryl ester) and vitamin C (unspecified ascorbate) in preventing oxidative stress leading to pre-eclampsia have failed to show significant (p=0.05) positive benefit at the dosage tested, Drs. Padayatty and Levine with NIH in a "Letter to the Editor" stated that the studies and another "Letter to the Editor" overlooked a key reason for the lack of vitamin C on the prevention of preeclampsia. Because plasma ascorbate concentrations were not reported, we estimated them from known data, the placebo and treatment groups in the study probably had similar plasma and tissue ascorbate concentrations. Doses of 1 g per day have little effect on plasma or intracellular ascorbate concentrations. In another study the same dosage did decrease average gestational time resulting in a higher incidence of low birthweight babies in one study. Several other studies have been more favorable but large studies into antioxidants for pre-eclampsia are continuing.

Conflicts with prescription drugs

Pharmaceuticals designed to reduce stomach acid such as the proton pump inhibitors (PPIs), are among the most widely-sold drugs in the world. One PPI, omeprazole, has been found to lower the bioavailability of vitamin C by 12%, independent of dietary intake. This means that one would have to consume 14% more vitamin C to counteract the use of 40 mg/day of omeprazole. The probable mechanism of vitamin C reduction, intragastric pH elevated into alkalinity, would apply to all other PPI drugs, though not necessarily to doses of PPIs low enough to keep the stomach slightly acidic.

Sources of vitamin C

Vitamin C is obtained through the diet by the vast majority of the world's population. The richest natural sources are fruits and vegetables, and of those, the camu camu fruit and the billygoat plum contain the highest concentration of the vitamin. It is also present in some cuts of meat, especially liver. Vitamin C as ascorbic acid is the most widely taken nutritional supplement and is available in a variety of forms from tablets and drink mixes to pure ascorbic acid crystals in capsules or as plain powder.

Plant sources

Citrus fruits (orange, lemon, grapefruit, lime), tomatoes, and potatoes are good common sources of vitamin C. Other foods that are good sources of vitamin C include papaya, broccoli, brussels sprouts, black currants, strawberries, cauliflower, spinach, cantaloupe, kiwifruit, cranberries and red peppers.

Emblica officinalis often referred to as Indian gooseberry or amla, is one of the richest known sources of vitamin C (720 mg/100 g of fresh pulp or up to 900 mg/100 g of pressed juice. — it contains 30 times the amount found in oranges.

The amount of vitamin C 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,
• the method of preparation. Cooking in particular is often said to destroy vitamin C — but see the section on Food preparation.

The following table is approximate and shows the relative abundance in different raw plant sources. The amount is given in milligrams per 100 grams of fruit or vegetable (for comparison, one 5 ml teaspoon of pure vitamin C powder weighs 5,000 milligrams).

Plant source	Amount (mg/100 g)
Billy Goat plum	3150
Camu Camu	2800
Wolfberry	2500
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/100 g)
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/100 g)
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
cranberries	?

Animal sources

The overwhelming majority of species of animals and plants synthesise their own vitamin C. Synthesis is achieved through a sequence of four enzyme driven steps, which convert glucose to ascorbic acid. It is carried out either in the kidneys, in reptiles and birds, or the liver, in mammals and perching birds. The last enzyme in the process, l-gulonolactone oxidase, cannot be made by humans because the gene for this enzyme is defective (Pseudogene ΨGULO). The loss of an enzyme concerned with ascorbic acid synthesis has occurred quite frequently in evolution and has affected most fish; many birds; some bats; guinea pigs; and most primates, including humans. The mutations have not been lethal because ascorbic acid is so prevalent in the surrounding food sources (it may be noted that many of these species' diet consists largely of fruit).

For example 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.

Trauma or injury has been demonstrated to use up large quantities of vitamin C in animals, including humans.

It was only realised in the 1920s that some cuts of meat and fish are also a source of vitamin C for humans. The muscle and fat that make up the modern western diet are, however, poor sources. As with fruit and vegetables, cooking degrades the vitamin C content.

Vitamin C is present in mother's milk and in less amounts in raw cow's milk (but pasteurized milk contains only trace amounts of the vitamin).

The following table shows the relative abundance of vitamin C in various foods of animal origin, given in mg of vitamin C per 100 grams of food:

Food	Amount (mg/100 g)
Calf liver (raw)	36
Beef liver (raw)	31
Oysters (raw)	30
Cod roe (fried)	26
Pork liver (raw)	23
Lamb brain (boiled)	17
Chicken liver (fried)	13
Lamb liver (fried)	12
Lamb heart (roast)	11

Food	Amount (mg/100 g)
Lamb tongue (stewed)	6
Human milk (fresh)	4
Goat milk (fresh)	2
Cow milk (fresh)	2
Beef steak (fried)	0
Hen's egg (raw)	0
Pork bacon (fried)	0
Calf veal cutlet (fried)	0
Chicken leg (roast)	0

Food preparation

It is important to choose a suitable method of food preparation that conserves vitamin C content. When cooking vegetables, one should seek to minimize temperature and duration of cooking and not discard water used in preparation (e.g., by steam cooking or by making soup). Food source vitamin C is identical to that in supplements. The structure of vitamin C is well understood, see ascorbic acid, and there is no difference in benefit between natural and synthetic forms (although fruits and vegetables contain various other nutrients, and vitamin C is not their only health benefit).

Recent observations suggest that the impact of temperature and cooking on vitamin C may have been overestimated, since it decomposes around 190–192°C, well above the boiling point of water:

1. Since it is water soluble, vitamin C will strongly leach into the cooking water while cooking most vegetables — but this doesn't necessarily mean the vitamin is destroyed — it's still there, but it's in the cooking water. (This may also suggest how the apparent misconception about the extent to which boiling temperatures destroy vitamin C might have been the result of flawed research: If the vitamin C content of vegetables (and not of the water) was measured subsequent to cooking them, then that content would have been much lower, though the vitamin has not actually been destroyed.)
2. Not only the temperature, but also the exposure time is significant. Contrary to what was previously and is still commonly assumed, it can take much longer than two or three minutes to destroy vitamin C at boiling point

It also appears that cooking doesn't necessarily leach vitamin C in all vegetables at the same rate; it has been suggested that the vitamin is not destroyed when boiling broccoli. This may be a result of vitamin C leaching into the cooking water at a slower rate from this vegetable.

Copper pots will destroy the vitamin.

Some research shows that fresh-cut fruit may not lose much of its nutrients when stored in the refrigerator for a few days.

Vitamin C enriched teas and infusions have increasingly appeared on supermarket shelves. Such products would be nonsense if boiling temperatures did indeed destroy vitamin C at the rate it had previously been suggested. It should be noted however that as of 2004 most academics not directly involved in vitamin C research still teach that boiling temperatures will destroy vitamin C very rapidly.

Vitamin C supplements

Vitamin C is the most widely taken dietary supplement. It is available in many forms including caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple anti-oxidant formulations, as chemically pure crystalline powder, time release versions, and also including bioflavonoids such as quercetin, hesperidin and rutin. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (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). Other forms of Vitamin C as sodium ascorbate, magnesium ascorbate, calcium ascorbate, mixed mineral ascorbates (e.g. Na, K, Mg, Ca, Zn), and Ester-C are also available, though less popular.

Methods of manufacture (chemical 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 more modern two-step fermentation process was 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.

Research is underway at the Scottish Crop Research Institute to create yeast micro organisms to synthesise ascorbic acid in a single fermentation step, a technology which is expected to reduce manufacturing costs considerably.

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.

Vitamin C hypothesis

Since its discovery vitamin C has been considered a universal panacea by some, although this led to suspicions of it being overhyped by others.

The fact that man possesses three of the four enzymes that animals employ to manufacture ascorbates in relatively large amounts, has led researchers such as Irwin Stone and Linus Pauling to hypothesize that man's ancestors once manufactured this substance in the body millions of years ago in quantities roughly estimated at 3,000–4,000 mg daily, but later lost the ability to do this through a chance of evolution. If true, this would mean that vitamin C was misnamed as a vitamin and is in fact a vital macronutrient like fat or carbohydrate. {Irwin Stone: "The Healing Factor"}

Dr. Hickey, of Manchester Metropolitan University, believes that man carries a mutated and ineffective form of the genetic machinery for manufacturing the fourth of the four enzymes used by all mammals to make ascorbic acid. Cosmic rays or a retrovirus could have caused this mutation, millions of years ago. {Hickey: "Ascorbate"} In humans the three surviving enzymes continue to produce the precursors to ascorbic acid but the process is incomplete and the body then disassembles them.

In the 1960s Nobel-Prize winning chemist Linus Pauling, after contact with Irwin Stone, began actively promoting vitamin C as a means to greatly improve human health and resistance to disease. His book How to Live Longer and Feel Better was a bestseller and advocated taking more than 10,000 milligrams per day. It sold widely and many advocates today see its influence as the reason there was a marked downward trend in US heart disease from the early 1980s onwards.

Stone's work also informed the practise of Dr. Robert F. Cathcart III, in the 1970s and 1980s. He applied extremely large doses of ascorbate (300 grams = 0.66 pounds per day) to a wide range of viral diseases with successful results. Cathcart developed the concept of Bowel tolerance, the use of the onset of diarrhea as an indication of when the body's true requirement of ascorbic acid had been reached. He found that seriously ill people could often tolerate levels of tens of grams per day before their tolerance limit is reached.

Matthias Rath is a controversial German physician who once worked with Pauling. He is an active proponent and publicist for high dose vitamin C. He has published a theory that deaths from scurvy in humans during the ice age, when vitamin C was scarce, selected for individuals who could repair arteries with a layer of cholesterol. He theorises 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. Atherosclerosis is thus a vitamin C deficiency disease. Rath has also argued publicly that high doses of vitamin C can be effectively used against viral epidemics such as HIV, SARS and bird flu.

It has been suggested by some advocates that ascorbic acid is really a food group in its own right like carbohydrates or protein and should not be seen as a pharmaceutical or vitamin at all. {Irwin Stone: "The Healing Factor"}

Chronic scurvy

Nobel laureate chemist Linus Pauling stated that "chronic scurvy" or "subclinical scurvy" is a condition of vitamin C deficiency which is not as easily noticeable as acute scurvy (because chronic scurvy is mostly internal), characterized by micro lesions of tissues (such as that caused by blood pulsing through arteries, which stretches the arterial walls causing them to tear slightly). It is a major contributing factor to cardiovascular disease. Pauling stated that this condition is almost entirely preventable with supplementation of larger doses of vitamin C (8 grams or more per day). Chronic scurvy is believed by high-dose advocates to be commonplace, even in industrialized countries.

Politics of vitamin C

Regulation

There are regulations in most countries which limit the claims on the treatment of disease that can be placed on food, drug, and nutrient product labels. Regulations include:

• Claims of therapeutic effect with respect to the treatment of any medical condition or disease are prohibited by the Food and Drug Administration (in the USA, and by the corresponding regulatory agencies in other countries) unless the substance has gone through a lengthy (10+ years) and expensive (200 million US dollars+) approval process, for which the applicant seeking approval must pay.
• In the United States, the following notice is mandatory on food, drug, and nutrient product labels which make health claims: These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease. This statement must be included even if substantial scientific evidence exists showing that the message isn't true. This may lead consumers to the false belief that vitamin C has no value in preventing or treating diseases other than scurvy (for which treatment claims are allowed).

Advocacy arguments

Vitamin C advocates argue that there is a large body of scientific evidence that the vitamin has a wide range of health and therapeutic benefits but which they claim have been ignored. They claim the following factors affect the marketing and distribution of vitamin C, and the dissemination of information concerning the nutrient:

• There is increasing evidence of the applications and efficacy of vitamin C, but governmental agency dose and frequency of intake recommendations have remained relatively fixed. This has lead some researchers to challenge the recommendations.

• Research and the treatment approval process are so expensive, pharmaceutical companies rarely apply for approval of an unpatentable product. To do so without the protection of a patent would allow competitors to manufacture the product too, which would drive the price (and profit margin) down to a point much less desirable than the price point (and profit margin) of patentable products. The lower price would also reduce the likelihood of recuperating the company's exorbitant research funding and treatment approval costs. Vitamin C is not eligible for patenting because it is a natural substance, and because it has already been marketed to the public for some time. As of yet, no company has applied to the FDA (nor paid) for approval of vitamin C as a treatment for any disease.

• Companies selling a treatment product are not required to inform consumers or patients of other treatments, even if those treatments are more effective, less expensive, and have fewer side-effects. Medical practitioners are not required to inform their patients of treatments for which treatment approval has not been granted. This situation, coupled with the label censorship explained above makes it more difficult to keep the public informed about the benefits of and new discoveries concerning the applications and effective dosage levels of vitamin C.

• Matthias Rath and others point to low doses of vitamin C as the cause of the current epidemics of heart disease and cancer, and have termed the situation "a genocide", implying that health care providers (and particularly cardiologists and pharmaceutical companies) are aware of vitamin C's benefits and are deliberately seeking to block its acceptance as a therapeutic agent for financial gain. He claims that governments have also colluded in this technology blockade by their expensive and bureaucratic systems of treatment approval which place barriers to new, inexpensive but not patentable approaches.

Sources

• Pauling, Linus (1986) How to Live Longer and Feel Better W. H. Freeman and Company, ISBN 0-380-70289-4
• Levy Thomas (2002). Vitamin C, Infectious Diseases, and Toxins. Xlibris Corporation (Paperback). ISBN 1-4010-6963-0. (Note: Xlibris is a print on demand self-publishing house.)
• Hickey, Steve; Roberts, Hilary (May, 2004) Ascorbate: The Science of Vitamin C, Lulu Press, Inc. ISBN 1-4116-0724-4 (Note: Lulu is a print on demand self-publishing house.)
• Dolske, M.C., et al. 1993. "A preliminary trial of ascorbic acid as a supplemental therapy for autism." Prog. Neuropsychopharmacol. Biol. Psychiatry, 17(5):765–774.
• Green, V.A., K.A. Pituch, J. Itchon, A. Choi, M. O'Reilly, J. Sigafoos, "Internet survey of treatments used by parents of children with autism," Res Dev Disabil, 2006, 27(1):70–84.