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7.3I: Vitamin C (Ascorbic acid)

Vitamin C (ascorbic acid and L-ascorbic acid) is a vitamin found in food and used as a dietary supplement. As a supplement it is used to treat and prevent scurvy. Evidence does not support use in the general population for the prevention of the common cold. It may be taken by mouth or by injection. It is generally well tolerated. Large doses may cause gastrointestinal upset, headache, trouble sleeping, and flushing of the skin. Normal doses are safe during pregnancy. Vitamin C is an essential nutrient involved in the repair of tissue. Foods that contain vitamin C include citrus fruit, tomatoes, and potatoes.

Vitamin C was discovered in 1912, isolated in 1928, and first made in 1933. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Vitamin C is available as a generic medication and over the counter. In 2015, the wholesale cost in the developing world was about 0.003 to 0.007 USD per tablet. In some countries, ascorbic acid may be added to foods such as breakfast cereal.

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

Medical uses

A 2012 Cochrane review found no effect of vitamin C supplementation on overall mortality.

  • Scurvy: Although rare in modern times, scurvy and its associated destabilization of collagen, connective tissue, and bone can be prevented by adequate vitamin C intake.
  • Cancer prevention: A 2014 review found that, "Currently, the use of high-dose IV vitamin C [as an anticancer agent] cannot be recommended outside of a clinical trial." A 2013 Cochrane review found no evidence that vitamin C supplementation reduces the risk of lung cancer in healthy or high risk (smokers and asbestos-exposed) people. A 2014 meta-analysis found that vitamin C intake might protect against lung cancer risk. A second meta-analysis found no effect on the risk of prostate cancer. Two meta-analyses evaluated the effect of vitamin C supplementation on the risk of colorectal cancer. One found a weak association between vitamin C consumption and reduced risk, and the other found no effect of supplementation. A 2011 meta-analysis failed to find support for the prevention of breast cancer with vitamin C supplementation,but a second study concluded that vitamin C may be associated with increased survival in those already diagnosed.
  • Cardiovascular disease: A 2013 meta-analysis found no evidence that vitamin C supplementation reduces the risk of myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality. However, a second analysis found an inverse relationship between circulating vitamin C levels or dietary vitamin C and the risk of stroke. A meta-analysis of 44 clinical trials has shown a significant positive effect of vitamin C on endothelial function when taken at doses greater than 500 mg per day. The researchers noted that the effect of vitamin C supplementation appeared to be dependent on health status, with stronger effects in those at higher cardiovascular disease risk.
  • Chronic diseases: A 2010 review found no role for vitamin C supplementation in the treatment of rheumatoid arthritis. Studies examining the effects of vitamin C intake on the risk of Alzheimer's disease have reached conflicting conclusions. Maintaining a healthy dietary intake is probably more important than supplementation for achieving any potential benefit. Vitamin C supplementation above the RDA has been used in trials to study a potential effect on preventing and slowing the progression of age-related cataract. However, no significant effects were found from the research.
  • Common cold: Vitamin C's effect on the common cold has been extensively researched. It has not been shown effective in prevention or treatment of the common cold, except in limited circumstances (specifically, individuals exercising vigorously in cold environments). Routine vitamin C supplementation does not reduce the incidence or severity of the common cold in the general population, though it may reduce the duration of illness.

Possible

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.

There is a longstanding belief among the mainstream medical community that vitamin C causes kidney stones, which is based on little science. Although recent studies have found a relationship, a clear link between excess ascorbic acid intake and kidney stone formation has not been generally established. Some case reports exist for a link between patients with oxalate deposits and a history of high-dose vitamin C usage.

In a study conducted on rats, during the first month of pregnancy, high doses of vitamin C may suppress the production of progesterone from the corpus luteum. Progesterone, necessary for the maintenance of a pregnancy, is produced by the corpus luteum for the first few weeks, until the placenta is developed enough to produce its own source. By blocking this function of the corpus luteum, high doses of vitamin C (1000+ mg) are theorized to induce an early miscarriage. In a group of spontaneously aborting women at the end of the first trimester, the mean values of vitamin C were significantly higher in the aborting group. However, the authors do state: 'This could not be interpreted as an evidence of causal association.' However, in a previous study of 79 women with threatened, previous spontaneous, or habitual abortion, Javert and Stander (1943) had 91% success with 33 patients who received vitamin C together with bioflavonoids and Vitamin K (only three abortions), whereas all of the 46 patients who did not receive the vitamins aborted.

A study in rats and humans suggested that adding Vitamin C supplements to an exercise training program lowered the expected effect of training on VO2 Max. Although the results in humans were not statistically significant, this study is often cited as evidence that high doses of Vitamin C have an adverse effect on exercise performance. In rats, it was shown that the additional Vitamin C resulted in lowered mitochondria production. Since rats are able to produce all of their needed Vitamin C, however, it is questionable whether they offer a relevant model of human physiological processes in this regard.

Biological Significance

Vitamin C is an essential nutrient for certain animals including humans. Vitamin C describes several vitamers that have vitamin C activity in animals, including ascorbic acid and its salts, and some oxidized forms of the molecule like dehydroascorbic acid. Ascorbate and ascorbic acid are both naturally present in the body when either of these is introduced into cells, since the forms interconvert according to pH. Vitamin C is a cofactor in at least eight enzymatic reactions, including several collagen synthesis reactions that, when dysfunctional, cause the most severe symptoms of scurvy. In animals, these reactions are especially important in wound-healing and in preventing bleeding from capillaries. Ascorbate also acts as an antioxidant, protecting against oxidative stress.

The biological role of ascorbate is to act as a reducing agent, donating electrons to various enzymatic and a few non-enzymatic reactions. The one- and two-electron oxidized forms of vitamin C, semidehydroascorbic acid and dehydroascorbic acid, respectively, can be reduced in the body by glutathione and NADPH-dependent enzymatic mechanisms. The presence of glutathione in cells and extracellular fluids helps maintain ascorbate in a reduced state.

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 in plants (APX is plant specific enzyme); and an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for important enzymes.

Ascorbate is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms; the main exceptions are most bats, all guinea pigs, capybaras, and the Haplorrhini (one of the two major primate suborders, consisting of tarsiers, monkeys, and humans and other apes). Ascorbate is also not synthesized by many species of birds and fish. All species that do not synthesize ascorbate require it in the diet.

Deficiency

Scurvy is an avitaminosis resulting from lack of vitamin C, since without this vitamin, the synthesized collagen is too unstable to perform its function. Scurvy leads to the formation of brown 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, and so the body stores are depleted if fresh supplies are not consumed. The time frame for onset of symptoms of scurvy in unstressed adults on a completely vitamin C free diet, however, may range from one month to more than six months, depending on previous loading of vitamin C.

Western societies generally consume far more than 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; these are higher than the RDA recommendations.

Notable human dietary studies of experimentally induced scurvy have been conducted on conscientious objectors during WWII in Britain and on Iowa state prisoners in the late 1960s to the 1980s. These studies both found that all obvious symptoms of scurvy previously induced by an experimental scorbutic diet with extremely low vitamin C content could be completely reversed by additional vitamin C supplementation of only 10 mg a day. In these experiments, there was no clinical difference noted between men given 70 mg vitamin C per day (which produced blood level of vitamin C of about 0.55 mg/dl, about 1/3 of tissue saturation levels) and those given 10 mg per day. Men in the prison study developed the first signs of scurvy about 4 weeks after starting the vitamin C-free diet, whereas in the British study, six to eight months were required, possibly due to the pre-loading of this group with a 70 mg/day supplement for six weeks before the scorbutic diet was fed.

Men in both studies on a diet devoid, or nearly devoid, of vitamin C had blood levels of vitamin C too low to be accurately measured when they developed signs of scurvy, and in the Iowa study, at this time were estimated (by labeled vitamin C dilution) to have a body pool of less than 300 mg, with daily turnover of only 2.5 mg/day, implying an instantaneous half-life of 83 days by this time (elimination constant of 4 months).

Absorption, transport, and excretion

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 import the reduced form of ascorbate across plasma membrane.GLUT1 and GLUT3 are the two glucose transporters, and transfer only the dehydroascorbic acid form of Vitamin C.[82] 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. 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,[81] the notable exception being red blood cells, which lose SVCT proteins during maturation.[85] "SVCT2 knockout" animals genetically engineered to lack this functional gene, die shortly after birth,[86] suggesting that SVCT2-mediated vitamin C transport is necessary for life.

With regular intake the absorption rate varies between 70 and 95%. However, the degree of absorption decreases as intake increases. At high intake (1.25 g), fractional human absorption of ascorbic acid may be as low as 33%; at low intake (<200 mg) the absorption rate can reach up to 98%.

Ascorbate concentrations over the renal re-absorption threshold pass freely into the urine and are excreted. At high dietary doses (corresponding to several hundred mg/day in humans) ascorbate is accumulated in the body until the plasma levels reach the renal resorption threshold, which is about 1.5 mg/dL in men and 1.3 mg/dL in women. Concentrations in the plasma larger than this value (thought to represent body saturation) are rapidly excreted in the urine with a half-life of about 30 minutes. Concentrations less than this threshold amount are actively retained by the kidneys, and the excretion half-life for the remainder of the vitamin C store in the body thus increases greatly, with the half-life lengthening as the body stores are depleted. This half-life rises until it is as long as 83 days by the onset of the first symptoms of scurvy.[88]

Although the body's maximal store of vitamin C is largely determined by the renal threshold for blood, there are many tissues that maintain vitamin C concentrations far higher than in blood. 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.[89] 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.

Ascorbic acid can be oxidized (broken down) in the human body by the enzyme L-ascorbate oxidase. Ascorbate that is not directly excreted in the urine as a result of body saturation or destroyed in other body metabolism is oxidized by this enzyme and removed.

Immune system

Vitamin C is found in high concentrations in immune cells, and is consumed quickly during infections. It is not certain how vitamin C interacts with the immune system; it has been hypothesized to modulate the activities of phagocytes, the production of cytokines and lymphocytes, and the number of cell adhesion molecules in monocytes.[101]

Daily Requirements

The North American Dietary Reference Intake recommends 90 milligrams per day for adult men, 75 mg/day for adult women, and no more than 2 grams (2,000 milligrams) per day. A balanced diet without supplementation usually contains enough vitamin C to prevent scurvy in an average healthy adult, while those who smoke tobacco or are under stress require slightly more.

United States vitamin C recommendations
Recommended Dietary Allowance (adult male) 90 mg per day
Recommended Dietary Allowance (adult female) 75 mg per day
Recommended Dietary Allowance (pregnancy) 85 mg per day
Recommended Dietary Allowance (lactation) 120 mg per day
Tolerable Upper Intake Level (adult male) 2,000 mg per day
Tolerable Upper Intake Level (adult female) 2,000 mg per day

Recommended intake

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

  • 40 milligrams per day or 280 milligrams per week taken all at once: the United Kingdom's Food Standards Agency
  • 40 milligrams per day as per the recommendations of India's National Institute of Nutrition, Hyderabad
  • 45 milligrams per day 300 milligrams per week: the World Health Organization
  • 80 milligrams per day: the European Commission's Council on nutrition labeling
  • 90 mg/day (males) and 75 mg/day (females): Health Canada 2007
  • 90 mg/day (males) and 75 mg/day (females): United States' National Academy of Sciences.
  • 100 milligrams per day: Japan's National Institute of Health and Nutrition.

For U.S. food and dietary supplement labeling purposes the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin C labeling purposes 100% of the Daily Value was 60 mg, but as of May 2016 it has been revised to 90 mg. A table of the pre-change adult Daily Values is provided at Reference Daily Intake. Food and supplement companies have until July 28, 2018 to comply with the change.

Dietary Sources

The richest natural sources are fruits and vegetables. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, and in capsules. 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. The presence of large quantities of sugar either in the intestines or in the blood can slow absorption.

Rosa_rubiginosa_hips.jpg

Rose hips are a particularly rich source of vitamin C. Image used with permission (CC BY-SA 3.0; en:User:MPF)

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, soil condition, climate where it grew, length of time since it was picked, storage conditions, and method of preparation. The following table is approximate and shows the relative abundance in different raw plant sources. As some plants were analyzed fresh while others were dried (thus, artifactually increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. 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 1000–5300
Camu Camu 2800
Acerola 1677
Seabuckthorn 695
Indian gooseberry 445
Rose hip 426
Baobab 400
Chili pepper (green) 244
Guava (common, raw) 228.3
Blackcurrant 200
Red pepper 190
Chili pepper (red) 144
Parsley 130
Kiwifruit 90
Broccoli 90
Loganberry 80
Redcurrant 80
Brussels sprouts 80
Wolfberry (Goji) 73 †
Lychee 70
Persimmon (native, raw) 66.0
Cloudberry 60
Elderberry 60

† average of 3 sources; dried

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