Ascorbic acid
Natta projection of structural formula for L-ascorbic acid
Ball-and-stick model of L-ascorbic acid
Clinical data
Pronunciation/əˈskɔːrbɪk/, /əˈskɔːrbeɪt, -bɪt/
Trade namesAscor, Cecon, Cevalin, others
Other namesl-ascorbic acid, ascorbic acid, ascorbate
AHFS/Drugs.comMonograph
MedlinePlusa682583
License data
Routes of
administration		By mouth, intramuscular (IM), intravenous (IV), subcutaneous
ATC code
Legal status
Legal status
  • AU: Unscheduled
  • UK: POM (Prescription only) / GSL[1][2]
  • US: ℞-only / OTC/ Dietary Supplement[3]
Pharmacokinetic data
BioavailabilityRapid, diminishes as dose increases[4]
Protein bindingNegligible
Elimination half-lifeVaries according to plasma concentration
ExcretionKidney
Identifiers
  • l-threo-Hex-2-enono-1,4-lactone
    or
    (R)-3,4-Dihydroxy-5-((S)- 1,2-dihydroxyethyl)furan-2(5H)-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
PDB ligand
E numberE300 (antioxidants, ...)
CompTox Dashboard (EPA)
ECHA InfoCard100.000.061
Chemical and physical data
FormulaC6H8O6
Molar mass176.124 g·mol−1
3D model (JSmol)
Density1.694 g/cm3
Melting point190 to 192 °C (374 to 378 °F)
Boiling point552.7 °C (1,026.9 °F) [5]
  • OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
  • InChI=1S/C6H8O6/c7-1-2(8)5-3(9)4(10)6(11)12-5/h2,5,7-10H,1H2/t2-,5+/m0/s1 checkY
  • Key:CIWBSHSKHKDKBQ-JLAZNSOCSA-N checkY
  (verify)

Vitamin C (also known as ascorbic acid and ascorbate) is a water-soluble vitamin found in citrus and other fruits, berries and vegetables, also sold as a dietary supplement[6] and as a topical "serum" ingredient to treat melasma (dark pigment spots) and wrinkles on the face.[7] It is used to prevent and treat scurvy.[6] Vitamin C is an essential nutrient involved in the repair of tissue, the formation of collagen, and the enzymatic production of certain neurotransmitters.[6][8] It is required for the functioning of several enzymes and is important for immune system function.[8][9] It also functions as an antioxidant.[4] Most animals are able to synthesize their own vitamin C. However, apes (including humans) and monkeys (but not all primates), most bats, most fish, some rodents, and certain other animals must acquire it from dietary sources because a gene for a synthesis enzyme has mutations.

Vitamin C may be taken by mouth or by intramuscular, subcutaneous or intravenous injection.[6] Other than for treating scurvy, which is a vitamin C deficiency caused disease, there are a number of diseases and health conditions for which claims have been made for increased risk if moderately deficient, and for benefits from vitamin C supplementation in excess of recommended dietary consumption for people who are not considered vitamin C deficient. The long history of claimed benefits includes the common cold, cancer, heart disease and COVID-19.

Vitamin C is generally well tolerated.[6] Large doses may cause gastrointestinal discomfort, headache, trouble sleeping, and flushing of the skin.[6][10] Normal doses are safe during pregnancy.[11] The United States Institute of Medicine recommends against taking large doses.[8]

Vitamin C was discovered in 1912, isolated in 1928, and in 1933, the first vitamin to be chemically produced.[12] It is on the World Health Organization's List of Essential Medicines.[13] Vitamin C is available as an inexpensive generic and over-the-counter medication.[6][14] Partly for its discovery, Albert Szent-Györgyi and Walter Norman Haworth were awarded the 1937 Nobel Prizes in Physiology and Medicine and Chemistry, respectively.[15][16]

Definition

Vitamin C is an essential nutrient for certain animals including humans. The term vitamin C encompasses several vitamers that have vitamin C activity in animals. Ascorbate salts such as sodium ascorbate and calcium ascorbate are used in some dietary supplements. These release ascorbate upon digestion. Ascorbate and ascorbic acid are both naturally present in the body, since the forms interconvert according to pH.

Vitamin C functions as a cofactor in many enzymatic reactions in animals (including humans) that mediate a variety of essential biological functions, including wound healing and collagen synthesis. In humans, vitamin C deficiency leads to impaired collagen synthesis, contributing to the more severe symptoms of scurvy.[8] Another biochemical role of vitamin C is to act as an antioxidant (a reducing agent) by donating electrons to various enzymatic and non-enzymatic reactions.[8] Doing so converts vitamin C to an oxidized state – either as semidehydroascorbic acid or dehydroascorbic acid. These compounds can be restored to a reduced state by glutathione and NADPH-dependent enzymatic mechanisms.[8][17][18]

In plants, vitamin C is a substrate for ascorbate peroxidase. This enzyme utilizes ascorbate to neutralize excess hydrogen peroxide (H2O2) by converting it to water (H2O) and oxygen.[9][17][19]

Deficiency

While many tissues have vitamin C concentrations higher than plasma, these cannot be easily measured, so plasma vitamin C is the most widely applied test for vitamin C status.[17] Adequate levels are defined as near 50 μmol/L. Hypovitaminosis of vitamin C is defined as less thanb 23 μmol/L, and deficiency as less than 11.4 μmol/L.[20][21] For people 20 years of age or above, data from the US 2017-18 National Health and Nutrition Examination Survey showed mean serum concentrations of 53.4  μmol/L. The percent of people reported as deficient was 5.9%.[22] Globally, vitamin C deficiency is common in low and middle-income countries, and not uncommon in high income countries. In the latter, prevalence is higher in males than in females, and in the elderly compared to younger populations.[23]

Plasma levels are considered saturated at about 65 μmol/L, achieved by intakes of 100 to 200 mg/day, which are well above the recommended intakes. Even higher oral intake does not further raise plasma nor tissue concentrations because absorption efficiency decreases and any excess that is absorbed is excreted in urine.[17]

Scurvy is a disease resulting from a deficiency of vitamin C. Without this vitamin, collagen made by the body is too unstable to perform its function and several other enzymes in the body do not operate correctly.[9] Scurvy is characterized by spots on and bleeding under the skin, spongy gums, 'corkscrew' hair growth, and poor wound healing. The skin lesions 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, loss of teeth, bone abnormalities and, eventually, death.[24]

Notable human dietary studies of experimentally induced scurvy were conducted on conscientious objectors during World War II in Britain and on Iowa state prisoners in the late 1960s to the 1980s. Men in the prison study developed the first signs of scurvy about four weeks after starting the vitamin C-free diet, whereas in the earlier 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 had blood levels of ascorbic acid too low to be accurately measured by the time they developed signs of scurvy. These studies both reported that all obvious symptoms of scurvy could be completely reversed by supplementation of only 10 mg a day.[25][26]

People in sepsis or septic shock may have micronutrient deficiencies, including low levels of vitamin C.[27] Reviews mention that an intake of 3.0 g/day, which requires intravenous administration, may needed to maintain normal plasma concentrations in people with sepsis or severe burn injury.[28][29]

Medical uses

Rows and rows of pill bottles on shelves
Vitamin C supplements at a drug store.

Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitamin C deficiency. Beyond that, a role for vitamin C as prevention or treatment for various diseases is disputed, with reviews often reporting conflicting results. A 2012 Cochrane review reported no effect of vitamin C supplementation on overall mortality.[30] It is on the World Health Organization's List of Essential Medicines[13] and on the World Health Organization's Model Forumulary.[10]

Scurvy

The disease scurvy is caused by vitamin C deficiency and can be treated with vitamin C-containing foods or dietary supplements or injection.[6][8] It takes at least a month of little to no vitamin C before symptoms occur.[25] Early symptoms are malaise and lethargy, progressing to shortness of breath, bone pain, bleeding gums, susceptibility to bruising, poor wound healing, and finally fever, convulsions and eventual death.[6] Until quite late in the disease the damage is reversible, as healthy collagen replaces the defective collagen with vitamin C repletion. Scurvy was known to Hippocrates in the classical era.[31] The disease was shown to be prevented by citrus fruits in an early controlled trial by a Royal Navy surgeon, James Lind, in 1747, on board HMS Salisbury.[32] From 1796 onward, lemon juice was issued to all Royal Navy crewmen.[33][32]

Common cold

Black and white photo of Nobel Prize winner, Linus Pauling.
The Nobel prizewinner Linus Pauling advocated taking vitamin C for the common cold in a 1970 book.

Research on vitamin C in the common cold has been divided into effects on prevention, duration, and severity. A Cochrane review which looked at at least 200 mg/day concluded that vitamin C taken on a regular basis was not effective in prevention of the common cold. Restricting analysis to trials that used at least 1000 mg/day also saw no prevention benefit. However, taking vitamin C on a regular basis did reduce the average duration of the illness by 8% in adults and 14% in children, and also reduced the severity of colds.[34] In a more recent meta-analysis, vitamin C taken on a regular basis reduced the duration of severe symptoms but had no effect on the duration of mild symptoms.[35]

A subset of trials looked at therapeutic use, meaning that the vitamin was not started unless the people started to feel the beginnings of a cold. In these, vitamin C did not affect the duration or severity of the illness.[34]

Vitamin C distributes readily in high concentrations into immune cells, has antimicrobial and natural killer cell activities, promotes lymphocyte proliferation, and is consumed quickly during infections, effects suggesting a prominent role in immune system regulation.[36] The European Food Safety Authority found a cause and effect relationship exists between the dietary intake of vitamin C and functioning of a normal immune system in adults and in children under three years of age.[37][38]

COVID-19

During March through July 2020, vitamin C was the subject of more US FDA warning letters than any other ingredient for prevention and/or treatment of COVID-19.[39]

In April 2021, the US National Institutes of Health (NIH) COVID-19 Treatment Guidelines stated that "there are insufficient data to recommend either for or against the use of vitamin C for the prevention or treatment of COVID-19."[40] In an update posted December 2022, the NIH position was unchanged:

  • There is insufficient evidence for the COVID-19 Treatment Guidelines Panel (the Panel) to recommend either for or against the use of vitamin C for the treatment of COVID-19 in nonhospitalized patients.
  • There is insufficient evidence for the Panel to recommend either for or against the use of vitamin C for the treatment of COVID-19 in hospitalized patients.[41]

Three meta-analyses of people hospitalized with severe COVID-19 - with a high overlap in the clinical trials being included - reported a significant reduction in the risk of all-cause, in-hospital mortality with the administration of vitamin C relative to no vitamin C. There were no significant differences in ventilation incidence, hospitalization duration or length of intensive care unit stay between the two groups. The majority of the trials used intravenous administration of the vitamin.[42][43][44] Acute kidney injury was lower in people treated with vitamin C treatment. There were no differences in the frequency of other adverse events due to the vitamin.[44] All three journal articles concluded that further large-scale studies are needed to affirm its mortality benefits before issuing updated guidelines and recommendations.[42][43][44]

Cancer

There is no evidence that vitamin C supplementation reduces the risk of lung cancer in healthy people or those at high risk due to smoking or asbestos exposure.[45] A second meta-analysis found no effect on the risk of prostate cancer.[46] 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 from supplementation.[47][48] A 2011 meta-analysis failed to find support for the prevention of breast cancer with vitamin C supplementation,[49] but a second study concluded that vitamin C may be associated with increased survival in those already diagnosed.[50] A 2015 meta-analysis showed no antitumor effect nor improvement in quality-of-life measures from high-dose vitamin C. This review included trials of oral and intravenous vitamin C.[51]

Cardiovascular disease

A review concluded there was no evidence that vitamin C supplementation decreases the risk cardiovascular disease.[52] An earlier review reported an association between higher circulating vitamin C levels or dietary vitamin C and a lower risk of stroke,[53] and another review found a positive effect of vitamin C on endothelial dysfunction when taken at doses greater than 500 mg per day. The endothelium is a layer of cells that line the interior surface of blood vessels.[54]

Blood pressure

Serum vitamin C was reported to be 15.13 μmol/L lower in people with hypertension compared to normotensives. The vitamin was inversely associated with both systolic blood pressure (SBP) and diastolic blood pressure (DBP).[55] Two meta-analyses of intervention clinical trials with oral supplementation of the vitamin reported a very modest but statistically significant decrease in SBP in people with hypertension.[56][57] The more recent meta-analysis of the two stated that the median supplementation of vitamin C was 757.5 mg/d[57] The proposed explanation is that vitamin C increases intracellular concentrations of tetrahydrobiopterin, an endothelial nitric oxide synthase cofactor that promotes the production of nitric oxide, which is a potent vasodilator. Vitamin C supplementation might also reverse the nitric oxide synthase inhibitor NG-monomethyl-L-arginine 1, and there is also evidence cited that vitamin C directly enhances the biological activity of nitric oxide.[56]

Type 2 diabetes

A 2021 review concluded that vitamin C supplementation cannot be recommended for management of type 2 diabetes.[58] In contrast, a 2023 review found that supplementation with high doses of vitamin C (one gram or more per day) over 12 weeks or longer can decrease blood glucose, insulin, and hemoglobin A1c in people with type 2 diabetes.[59]

Iron deficiency

One of the causes of iron-deficiency anemia is reduced absorption of iron. Iron absorption can be enhanced though ingestion of vitamin C alongside iron-containing food or supplements. Vitamin C helps to keep iron in the reduced ferrous state, which is more soluble and more easily absorbed.[60]

Topical application to prevent signs of skin aging

Human skin contains vitamin C, which supports collagen synthesis, decreases collagen degradation, and assists in antioxidant protection against UV-induced photo-aging, including photocarcinogenesis. This knowledge is often used as a rationale for the marketing of vitamin C as a topical "serum" ingredient to prevent or treat facial skin aging, melasma (dark pigmented spots) and wrinkles. The purported mechanism is that it functions as an antioxidant, neutralizing free radicals from sunlight exposure, air pollutants or normal metabolic processes.[7] The efficacy of topical treatment, as opposed to oral intake is poorly understood.[61][62] Two reviews published in 2023 characterize the clinical trial literature as insufficient to support health claims, one reason being put forward was that "All the studies used vitamin C in combination with other ingredients or therapeutic mechanisms, thereby complicating any specific conclusions regarding the efficacy of vitamin C.[63] A systematic review noted that only a few clinical trials met design criteria. It reported smoother and less wrinkled skin and significant lightening of skin, but concluded that more studies are needed.[64]

Other diseases

Several reviews reported lower vitamin C concentrations in people with cognitive impairment and Alzheimer's disease compared to people with normal cognition. Some of these reported multiple vitamin shortfalls and none were reviews of intervention trials.[65][66][67][68] A 2010 review found no role for vitamin C supplementation in the treatment of rheumatoid arthritis.[69] Vitamin C supplementation does not prevent or slow the progression of age-related cataract.[70] A systematic review reported that low intake and low serum concentration was associated with greater progression of periodontal disease.[71]

Adverse effects

Vitamin C is a water-soluble vitamin,[72] with dietary excesses poorly absorbed,[4] and excesses in the blood rapidly excreted in the urine, so it exhibits low acute toxicity.[9] More than two to three grams, consumed orally, may cause nausea, abdominal cramps and diarrhea. These effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine.[8] In theory, high vitamin C intake may cause excessive absorption of iron. A summary of reviews of supplementation in healthy subjects did not report this problem, but left as untested the possibility that individuals with hereditary hemochromatosis might be adversely affected.[8]

There is a longstanding belief among the mainstream medical community that vitamin C increases risk of kidney stones.[73] "Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease".[8] Reviews state that "data from epidemiological studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals",[8][74] although one large, multi-year trial did report a nearly two-fold increase in kidney stones in men who regularly consumed a vitamin C supplement.[75]

There is extensive research on the purported benefits of intravenous vitamin C for treatment of sepsis,[28] severe COVID-19[42][43] and cancer.[51] Reviews list trials with doses as high as 24 grams per day.[42] Concerns about possible adverse effects are that intravenous high-dose vitamin C leads to a supraphysiological level of vitamin C followed by oxidative degradation to dehydroascorbic acid and hence to oxalate, increasing the risk of oxalate kidney stones and oxalate nephropathy. The risk may be higher in people with renal impairment, as kidneys efficiently excrete excess vitamin C. Second, treatment with high dose vitamin C should be avoided in patients with glucose-6-phosphate dehydrogenase deficiency as it can lead to acute haemolysis. Third, treatment might interfere with the accuracy of glucometer measurement of blood glucose levels, as both vitamin C and glucose have similar molecular structure, which could lead to false high blood glucose readings. Despite all these concerns, meta-analyses of patients in intensive care for sepsis, septic shock, COVID-19 and other acute conditions reported no increase in new-onset kidney stones, acute kidney injury or requirement for renal replacement therapy for patients receiving short-term, high-dose, intravenous vitamin C treatment. This suggests that intravenous vitamin C is safe under these short-term applications.[76][77][78]

Diet

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

US vitamin C recommendations (mg per day)[8]
RDA (children ages 1–3 years) 15
RDA (children ages 4–8 years) 25
RDA (children ages 9–13 years) 45
RDA (girls ages 14–18 years) 65
RDA (boys ages 14–18 years) 75
RDA (adult female) 75
RDA (adult male) 90
RDA (pregnancy) 85
RDA (lactation) 120
UL (adult female) 2,000
UL (adult male) 2,000

In 2000, the chapter on Vitamin C in the North American Dietary Reference Intake was updated to give the Recommended Dietary Allowance (RDA) as 90 milligrams per day for adult men, 75 mg/day for adult women, and setting a Tolerable upper intake level (UL) for adults of 2,000 mg/day.[8] The table (right) shows RDAs for the United States and Canada for children, and for pregnant and lactating women,[8] as well as the ULs for adults.

For the European Union, the EFSA set higher recommendations for adults, and also for children: 20 mg/day for ages 1–3, 30 mg/day for ages 4–6, 45 mg/day for ages 7–10, 70 mg/day for ages 11–14, 100 mg/day for males ages 15–17, 90 mg/day for females ages 15–17. For pregnancy 100 mg/day; for lactation 155 mg/day.[84]

India, on the other hand, has set recommendations much lower: 40 mg/day for ages 1 through adult, 60 mg/day for pregnancy, and 80 mg/day for lactation.[79] Clearly, there is not consensus among countries.

Cigarette smokers and people exposed to secondhand smoke have lower serum vitamin C levels than nonsmokers.[21] The thinking is that inhalation of smoke causes oxidative damage, depleting this antioxidant vitamin.[8] The US Institute of Medicine estimated that smokers need 35 mg more vitamin C per day than nonsmokers, but did not formally establish a higher RDA for smokers.[8] One meta-analysis showed an inverse relationship between vitamin C intake and lung cancer, although it concluded that more research is needed to confirm this observation.[85]

The US National Center for Health Statistics conducts biannual National Health and Nutrition Examination Survey (NHANES) to assess the health and nutritional status of adults and children in the United States. Some results are reported as What We Eat In America. The 2013–2014 survey reported that for adults ages 20 years and older, men consumed on average 83.3 mg/d and women 75.1 mg/d. This means that half the women and more than half the men are not consuming the RDA for vitamin C.[86] The same survey stated that about 30% of adults reported they consumed a vitamin C dietary supplement or a multi-vitamin/mineral supplement that included vitamin C, and that for these people total consumption was between 300 and 400 mg/d.[87]

Tolerable upper intake level

In 2000, the Institute of Medicine of the US National Academy of Sciences set a Tolerable upper intake level (UL) for adults of 2,000 mg/day. The amount was chosen because human trials had reported diarrhea and other gastrointestinal disturbances at intakes of greater than 3,000 mg/day. This was the Lowest-Observed-Adverse-Effect Level (LOAEL), meaning that other adverse effects were observed at even higher intakes. ULs are progressively lower for younger and younger children.[8] In 2006, the European Food Safety Authority (EFSA) also pointed out the disturbances at that dose level, but reached the conclusion that there was not sufficient evidence to set a UL for vitamin C,[88] as did the Japan National Institute of Health and Nutrition in 2010.[83]

Food labeling

For US 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 27, 2016, it was revised to 90 mg to bring it into agreement with the RDA.[89][90] A table of the old and new adult daily values is provided at Reference Daily Intake.

European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For vitamin C, 100% RI was set at 80 mg in 2011.[91]

Sources

Although also present in other plant-derived foods, the richest natural sources of vitamin C are fruits and vegetables.[9] The vitamin is the most widely taken dietary supplement.[9]

Plant sources

While plant foods are generally a good source of vitamin C, the amount in foods of plant origin depends on the variety of the plant, soil condition, climate where it grew, length of time since it was picked, storage conditions, and method of preparation.[92][93] Organically farmed citrus may have a higher vitamin C content than conventionally farmed.[92] The following table is approximate and shows the relative abundance in different raw plant sources.[94][95] Generally, cooking reduces the amount of vitamin C. As some plants were analyzed fresh while others were dried (thus, artificially increasing concentration of individual constituents such as vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of the edible portion of the fruit or vegetable:

Animal sources

Compared to plant sources, animal-sourced foods do not provide so great an amount of vitamin C, and what there is, is largely destroyed by the heat used when it is cooked. For example, raw chicken liver contains 17.9 mg/100 g, but fried, the content is reduced to 2.7 mg/100 g. Smoked products, such as beef sticks, retain some vitamin C.[103] Vitamin C is present in human breast milk at 5.0 mg/100 g. Raw cow's milk contains 1.0 mg/100 g, but the heat of pasteurization destroys it.[104]

Food preparation

Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Vitamin C concentrations in various food substances decrease with time in proportion to the temperature at which they are stored.[105] Cooking can reduce the vitamin C content of vegetables by around 60%, possibly due to increased enzymatic destruction.[106] Longer cooking times may add to this effect.[107] Another cause of vitamin C loss from food is leaching, which transfers vitamin C to the cooking water, which is decanted and not consumed.[108]

Supplements

Vitamin C dietary supplements are available as tablets, capsules, drink mix packets, in multi-vitamin/mineral formulations, in antioxidant formulations, and as crystalline powder.[6] Vitamin C is also added to some fruit juices and juice drinks. Tablet and capsule content ranges from 25 mg to 1500 mg per serving. The most commonly used supplement compounds are ascorbic acid, sodium ascorbate and calcium ascorbate.[6] Vitamin C molecules can also be bound to the fatty acid palmitate, creating ascorbyl palmitate, or else incorporated into liposomes.[109]

Food fortification

Countries fortify foods with nutrients to address known deficiencies.[110] While many countries mandate or have voluntary programs to fortify wheat flour, maize (corn) flour or rice with vitamins,[111] none include vitamin C in those programs.[111] As described in Vitamin C Fortification of Food Aid Commodities (1997), the United States provides rations to international food relief programs, later under the asupices of the Food for Peace Act and the Bureau for Humanitarian Assistance.[112] Vitamin C is added to corn-soy blend and wheat-soy blend products at 40 mg/100 grams. (along with minerals and other vitamins). Supplemental rations of these highly fortified, blended foods are provided to refugees and displaced persons in camps and to beneficiaries of development feeding programs that are targeted largely toward mothers and children.[108] The report adds: "The stability of vitamin C (L-ascorbic acid) is of concern because this is one of the most labile vitamins in foods. Its main loss during processing and storage is from oxidation, which is accelerated by light, oxygen, heat, increased pH, high moisture content (water activity), and the presence of copper or ferrous salts. To reduce oxidation, the vitamin C used in commodity fortification is coated with ethyl cellulose (2.5 percent). Oxidative losses also occur during food processing and preparation, and additional vitamin C may be lost if it dissolves into cooking liquid and is then discarded."[108]

Food additives

Ascorbic acid and some of its salts and esters are common additives added to various foods, such as canned fruits, mostly to slow oxidation and enzymatic browning.[113] It may be used as a flour treatment agent used in breadmaking.[114] As food additives, they are assigned E numbers, with safety assessment and approval the responsibility of the European Food Safety Authority.[115] The relevant E numbers are:

  1. E300 ascorbic acid (approved for use as a food additive in the UK,[116] US[117] Canada,[118] Australia and New Zealand[119])
  2. E301 sodium ascorbate (approved for use as a food additive in the UK,[116] US,[120] Canada,[118] Australia and New Zealand[119])
  3. E302 calcium ascorbate (approved for use as a food additive in the UK,[116] US[117] Canada,[118] Australia and New Zealand[119])
  4. E303 potassium ascorbate (approved in Australia and New Zealand,[119] but not in the UK, US or Canada)
  5. E304 fatty acid esters of ascorbic acid such as ascorbyl palmitate (approved for use as a food additive in the UK,[116] US,[117] Canada,[118] Australia and New Zealand[119])

The stereoisomers of Vitamin C have a similar effect in food despite their lack of efficacy in humans. They include erythorbic acid and its sodium salt (E315, E316).[116]

Pharmacology

Pharmacodynamics is the study of how the drug – in this instance vitamin C – affects the organism, whereas pharmacokinetics is the study of how an organism affects the drug. Pharmacodynamics should include enzymes for which vitamin C is a cofactor, with function potentially compromised in a deficiency state, and any enzyme cofactor or other physiological function affected by administration of vitamin C, orally or parenterally, in excess of normal requirements.

Pharmacodynamics

Vitamin C, in the form of ascorbate, performs numerous physiological functions in the human body by serving as an enzyme substrate or cofactor and an electron donor. These functions include the synthesis of collagen, carnitine, and neurotransmitters; the synthesis and catabolism of tyrosine; and the metabolism of microsomes.[18] During biosynthesis, ascorbate acts as a reducing agent, donating electrons and preventing oxidation to keep iron and copper atoms in their reduced states.

Vitamin C functions as a cofactor for the following enzymes:

Pharmacokinetics

Ascorbic acid is absorbed in the body by both active transport and simple diffusion. From the US National Institutes of Health: [In humans] "Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1,000 mg/day, absorption falls to less than 50%."[4] Sodium-Dependent Active Transport – Sodium-Ascorbate Co-Transporters (SVCTs) and Hexose transporters (GLUTs) – are the two transporter proteins required for active absorption. SVCT1 and SVCT2 import the reduced form of ascorbate across plasma membranes.[130] GLUT1 and GLUT3 are glucose transporters, and transfer only the dehydroascorbic acid (DHA) form of vitamin C.[131] 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.[132]

SVCTs appear to be the predominant system for vitamin C transport in the body,[130] the notable exception being red blood cells, which lose SVCT proteins during maturation.[133] In both vitamin C synthesizers (example: rat) and non-synthesizers (example: human) cells with few exceptions maintain ascorbic acid concentrations much higher than the approximately 50 micromoles/liter (µmol/L) found in plasma. For example, the ascorbic acid content of pituitary and adrenal glands can exceed 2,000 µmol/L, and muscle is at 200–300 µmol/L.[134] The known coenzymatic functions of ascorbic acid do not require such high concentrations, so there may be other, as yet unknown functions. A consequence of all this high concentration organ content is that plasma vitamin C is not a good indicator of whole-body status, and people may vary in the amount of time needed to show symptoms of deficiency when consuming a diet very low in vitamin C.[134]

Excretion can be as ascorbic acid, via urine. In humans, during times of low dietary intake, vitamin C is reabsorbed by the kidneys rather than excreted. This salvage process delays onset of deficiency. Only when plasma concentrations are 1.4 mg/dL or higher does re-absorption decline and the excess amounts pass freely into the urine.[135] Ascorbic acid also converts (reversibly) to dehydroascorbate (DHA) and from that compound non-reversibly to 2,3-diketogulonate and then oxalate. These three compounds are also excreted via urine. Humans are better than guinea pigs at converting DHA back to ascorbate, and thus take much longer to become vitamin C deficient.[136]

Chemistry

The name "vitamin C" always refers to the l-enantiomer of ascorbic acid and its oxidized forms, such as dehydroascorbate (DHA). Therefore, unless written otherwise, "ascorbate" and "ascorbic acid" refer in the nutritional literature to l-ascorbate and l-ascorbic acid respectively. Ascorbic acid is a weak sugar acid structurally related to glucose. In biological systems, ascorbic acid can be found only at low pH, but in solutions above pH 5 is predominantly found in the ionized form, ascorbate. All of these molecules have vitamin C activity and thus are used synonymously with vitamin C, unless otherwise specified.[17]

Numerous analytical methods have been developed for ascorbic acid detection. For example, vitamin C content of a food sample such as fruit juice can be calculated by measuring the volume of the sample required to decolorize a solution of dichlorophenolindophenol (DCPIP) and then calibrating the results by comparison with a known concentration of vitamin C.[137][138]

Testing

Simple tests are available to measure the levels of vitamin C in urine and serum.[20][21] These better reflect recent dietary intake rather than total body content.[8] It has been observed that while serum concentrations follow a circadian rhythm or reflect short-term dietary influence, content within cells or tissues is more stable and can give a better view of the availability of ascorbate within the entire organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses.[139][140]

Synthesis

Most animals and plants are able to synthesize vitamin C through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C. Yeasts do not make l-ascorbic acid but rather its stereoisomer, erythorbic acid.[141] In plants, synthesis is accomplished through the conversion of mannose or galactose to ascorbic acid.[142][143] In animals, the starting material is glucose. In some species that synthesize ascorbate in the liver (including mammals and perching birds), the glucose is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.[144] In humans and in animals that cannot synthesize vitamin C, the enzyme l-gulonolactone oxidase (GULO), which catalyses the last step in the biosynthesis, is highly mutated and non-functional.[145][146][147][148]

Animal synthesis

There is some information on serum vitamin C concentrations maintained in animal species that are able to synthesize vitamin C. One study of several breeds of dogs reported an average of 35.9 μmol/L.[149] A report on goats, sheep and cattle reported ranges of 100–110, 265–270 and 160–350 μmol/L, respectively.[150]

The biosynthesis of ascorbic acid in vertebrates starts with the formation of UDP-glucuronic acid. UDP-glucuronic acid is formed when UDP-glucose undergoes two oxidations catalyzed by the enzyme UDP-glucose 6-dehydrogenase. UDP-glucose 6-dehydrogenase uses the co-factor NAD+ as the electron acceptor. The transferase UDP-glucuronate pyrophosphorylase removes a UMP and glucuronokinase, with the cofactor ADP, removes the final phosphate leading to d-glucuronic acid. The aldehyde group of this compound is reduced to a primary alcohol using the enzyme glucuronate reductase and the cofactor NADPH, yielding l-gulonic acid. This is followed by lactone formation—utilizing the hydrolase gluconolactonase—between the carbonyl on C1 and hydroxyl group on C4. l-Gulonolactone then reacts with oxygen, catalyzed by the enzyme L-gulonolactone oxidase (which is nonfunctional in humans and other Haplorrhini primates; see Unitary pseudogenes) and the cofactor FAD+. This reaction produces 2-oxogulonolactone (2-keto-gulonolactone), which spontaneously undergoes enolization to form ascorbic acid.[143][151][136] Reptiles and older orders of birds make ascorbic acid in their kidneys. Recent orders of birds and most mammals make ascorbic acid in their liver.[143]

Non-synthesizers

Some mammals have lost the ability to synthesize vitamin C, including simians and tarsiers, which together make up one of two major primate suborders, Haplorhini. This group includes humans. The other more primitive primates (Strepsirrhini) have the ability to make vitamin C. Synthesis does not occur in some species in the rodent family Caviidae, which includes guinea pigs and capybaras, but does occur in other rodents, including rats and mice.[152]

Synthesis does not occur in most bat species,[153] but there are at least two species, frugivorous bat Rousettus leschenaultii and insectivorous bat Hipposideros armiger, that retain (or regained) their ability of vitamin C production.[154][155] A number of species of passerine birds also do not synthesize, but not all of them, and those that do not are not clearly related; it has been proposed that the ability was lost separately a number of times in birds.[156] In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases.[157] The ability to synthesize vitamin C has also been lost in about 96% of extant fish[158] (the teleosts).[157]

On a milligram consumed per kilogram of body weight basis, simian non-synthesizer species consume the vitamin in amounts 10 to 20 times higher than what is recommended by governments for humans.[159] This discrepancy constituted some of the basis of the controversy on human recommended dietary allowances being set too low.[160] However, simian consumption does not indicate simian requirements. Merck's veterinary manual states that daily intake of vitamin C at 3–6 mg/kg prevents scurvy in non-human primates.[161] By way of comparison, across several countries, the recommended dietary intake for adult humans is in the range of 1–2 mg/kg.

Evolution of animal synthesis

Ascorbic acid is a common enzymatic cofactor in mammals used in the synthesis of collagen, as well as a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). Given that ascorbate has these important functions, it is surprising that the ability to synthesize this molecule has not always been conserved. In fact, anthropoid primates, Cavia porcellus (guinea pigs), teleost fishes, most bats, and some passerine birds have all independently lost the ability to internally synthesize vitamin C in either the kidney or the liver.[162][157] In all of the cases where genomic analysis was done on an ascorbic acid auxotroph, the origin of the change was found to be a result of loss-of-function mutations in the gene that encodes L-gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above.[163] One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of genetic drift; assuming that the diet was rich in vitamin C, natural selection would not act to preserve it.[164][165]

In the case of the simians, it is thought that the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders Haplorrhini (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the Strepsirrhini ("wet-nosed" primates), which retained the ability to make vitamin C.[166] According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.[167] Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae), branched off from the other haplorrhines.[168][169] Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 million years ago).[166]

It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down uric acid, also a characteristic of primates. 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.[170]

Plant synthesis

Vitamin C biosynthesis in plants

There are many different biosynthesis pathways for ascorbic acid in plants. Most of these pathways are derived from products found in glycolysis and other pathways. For example, one pathway goes through the plant cell wall polymers.[145] The plant ascorbic acid biosynthesis pathway most principal seems to be l-galactose. l-Galactose reacts with the enzyme l-galactose dehydrogenase, whereby the lactone ring opens and forms again but with lactone between the carbonyl on C1 and hydroxyl group on C4, resulting in l-galactonolactone.[151] l-Galactonolactone then reacts with the mitochondrial flavoenzyme l-galactonolactone dehydrogenase.[171] to produce ascorbic acid.[151] l-Ascorbic acid has a negative feedback on l-galactose dehydrogenase in spinach.[172] Ascorbic acid efflux by embryo of dicots plants is a well-established mechanism of iron reduction, and a step obligatory for iron uptake.[lower-alpha 1]

All plants synthesize ascorbic acid. Ascorbic acid functions as a cofactor for enzymes involved in photosynthesis, synthesis of plant hormones, as an antioxidant and also regenerator of other antioxidants.[174] Plants use multiple pathways to synthesize vitamin C. The major pathway starts with glucose, fructose or mannose (all simple sugars) and proceeds to L-galactose, L-galactonolactone and ascorbic acid.[174][175] There is feedback regulation in place, in that the presence of ascorbic acid inhibits enzymes in the synthesis pathway.[176] This process follows a diurnal rhythm, so that enzyme expression peaks in the morning to support biosynthesis later on when mid-day sunlight intensity demands high ascorbic acid concentrations.[175] Minor pathways may be specific to certain parts of plants; these can be either identical to the vertebrate pathway (including the GLO enzyme), or start with inositol and get to ascorbic acid via L-galactonic acid to L-galactonolactone.[174]

Industrial synthesis

Vitamin C can be produced from glucose by two main routes. The no longer utilized Reichstein process, developed in the 1930s, used a single 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. The Reichstein process and the modern two-step fermentation processes both use glucose as the starting material, convert that to sorbitol, and then to sorbose using fermentation.[177] The two-step fermentation process then converts sorbose to 2-keto-l-gulonic acid (KGA) through another fermentation step, avoiding an extra intermediate. Both processes yield approximately 60% vitamin C from the glucose starting point.[178] Researchers are exploring means for one-step fermentation.[179][180]

China produces about 70% of the global vitamin C market. The rest is split among European Union, India and North America. The global market is expected to exceed 141 thousand metric tons in 2024.[181] Cost per metric ton (1000 kg) in US dollars was $2,220 in Shanghia, $2,850 in Hamburg and $3,490 in the US.[182]

History

Scurvy at sea

Citrus fruits were among the first sources of vitamin C available to ships' surgeons.

In the 1497 expedition of Vasco da Gama, the curative effects of citrus fruit were known.[183][184] Later, the Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, which sustained passing ships.[185] Authorities occasionally recommended plant food to prevent scurvy during long sea voyages. John Woodall, the first surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his 1617 book, The Surgeon's Mate.[186] In 1734, the Dutch writer Johann Bachstrom gave the firm opinion, "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens."[187][188] Scurvy had long been a principal killer of sailors during the long sea voyages.[189] According to Jonathan Lamb, "In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;...all mainly to scurvy."[190]

James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented scurvy in one of the first recorded controlled experiments[32]

The first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the Royal Navy, James Lind. 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 one of the world's first controlled experiments.[32] The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.[33][191]

Fresh fruit was expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles).[107] It was 1796 before the British navy adopted lemon juice as standard issue at sea. In 1845, ships in the West Indies were provided with lime juice instead, and in 1860 lime juice was used throughout the Royal Navy, giving rise to the American use of the nickname "limey" for the British.[32] Captain James Cook had previously demonstrated the advantages of carrying "Sour krout" on board, by taking his crew on a 1772-75 Pacific Ocean voyage without losing any of his men to scurvy.[192] For his report on his methods the British Royal Society awarded him the Copley Medal in 1776.[193]

The name antiscorbutic was used in the eighteenth and nineteenth centuries for foods known to prevent scurvy. These foods included lemons, limes, oranges, sauerkraut, cabbage, malt, and portable soup.[194] In 1928, the Canadian Arctic anthropologist Vilhjalmur Stefansson showed that the Inuit avoid scurvy on a diet of largely raw meat. Later studies on traditional food diets of the Yukon First Nations, Dene, Inuit, and Métis of Northern Canada showed that their daily intake of vitamin C averaged between 52 and 62 mg/day,[195] comparable with the Estimated Average Requirement.[8]

Discovery

Two yellow and one red pepper with dozens of 500 mg white vitamin tablets in front of them
Albert Szent-Györgyi wrote that he won a Nobel Prize after he found a way to mass-produce vitamin C for research purposes when he lived in Szeged, which had become the center of the paprika (red pepper) industry.[196]

Vitamin C was discovered in 1912, isolated in 1928 and synthesized in 1933, making it the first vitamin to be synthesized.[12] Shortly thereafter Tadeus Reichstein succeeded in synthesizing the vitamin in bulk by what is now called the Reichstein process.[197] This made possible the inexpensive mass-production of vitamin C. In 1934, Hoffmann–La Roche bought the Reichstein process patent, trademarked synthetic vitamin C under the brand name Redoxon, and began to market it as a dietary supplement.[198][199]

In 1907, a laboratory animal model which would help to identify the antiscorbutic factor was discovered by the Norwegian physicians Axel Holst and Theodor Frølich, who when studying shipboard beriberi, fed guinea pigs their test diet of grains and flour and were surprised when scurvy resulted instead of beriberi. Unknown at that time, this species did not make its own vitamin C (being a caviomorph), whereas mice and rats do.[200] In 1912, the Polish biochemist Casimir Funk developed the concept of vitamins. One of these was thought to be the anti-scorbutic factor. In 1928, this was referred to as "water-soluble C", although its chemical structure had not been determined.[201]

Albert Szent-Györgyi, pictured here in 1948, was awarded the 1937 Nobel Prize in Medicine "for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid".[16]

From 1928 to 1932, Albert Szent-Györgyi and Joseph L. Svirbely's Hungarian team, and Charles Glen King's American team, identified the anti-scorbutic factor. Szent-Györgyi isolated hexuronic acid from animal adrenal glands, and suspected it to be the antiscorbutic factor.[202] In late 1931, Szent-Györgyi gave Svirbely the last of his adrenal-derived hexuronic acid with the suggestion that it might be the anti-scorbutic factor. By the spring of 1932, King's laboratory had proven this, but published the result without giving Szent-Györgyi credit for it. This led to a bitter dispute over priority.[202] In 1933, Walter Norman Haworth chemically identified the vitamin as l-hexuronic acid, proving this by synthesis in 1933.[203][204][205][206] Haworth and Szent-Györgyi proposed that L-hexuronic acid be named a-scorbic acid, and chemically l-ascorbic acid, in honor of its activity against scurvy.[206][12] The term's etymology is from Latin, "a-" meaning away, or off from, while -scorbic is from Medieval Latin scorbuticus (pertaining to scurvy), cognate with Old Norse skyrbjugr, French scorbut, Dutch scheurbuik and Low German scharbock.[207] Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine,[208] and Haworth shared that year's Nobel Prize in Chemistry.[16]

In 1957, J. J. Burns showed that some mammals are susceptible to scurvy as their liver does not produce the enzyme l-gulonolactone oxidase, the last of the chain of four enzymes that synthesize vitamin C.[209][210] American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the idea that humans possess a mutated form of the l-gulonolactone oxidase coding gene.[211] Stone introduced Linus Pauling to the theory that humans needed to consume vitamin C in quantities far higher than what was considered a recommended daily intake in order to optimize health.[212]

In 2008, researchers discovered that in humans and other primates the red blood cells have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized l-dehydroascorbic acid (DHA) back into ascorbic acid for reuse by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.[213]

History of large doses

Vitamin C megadosage is a term describing the consumption or injection of vitamin C in doses comparable to or higher than the amounts produced by the livers of mammals which are able to synthesize vitamin C. An argument for this, although not the actual term, was described in 1970 in an article by Linus Pauling. Briefly, his position was that for optimal health, humans should be consuming at least 2,300 mg/day to compensate for the inability to synthesize vitamin C. The recommendation also fell into the consumption range for gorillas – a non-synthesizing near-relative to humans.[160] A second argument for high intake is that serum ascorbic acid concentrations increase as intake increases until it plateaus at about 190 to 200 micromoles per liter (µmol/L) once consumption exceeds 1,250 milligrams.[214] As noted, government recommendations are a range of 40 to 110 mg/day and normal plasma is approximately 50 µmol/L, so 'normal' is about 25% of what can be achieved when oral consumption is in the proposed megadose range.

Pauling popularized the concept of high dose vitamin C as prevention and treatment of the common cold in 1970. A few years later he proposed that vitamin C would prevent cardiovascular disease, and that 10 grams/day, initially administered intravenously and thereafter orally, would cure late-stage cancer.[215] Mega-dosing with ascorbic acid has other champions, among them chemist Irwin Stone[212] and the controversial Matthias Rath and Patrick Holford, who both have been accused of making unsubstantiated treatment claims for treating cancer and HIV infection.[216][217] The idea that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer or ameliorate the toxicity of chemotherapy is – some forty years after Pauling's seminal paper – still considered unproven and still in need of high quality research.[218][219][51] However, a lack of conclusive evidence has not stopped individual physicians from prescribing intravenous ascorbic acid to people with cancer.[51]

Society and culture

In February 2011, the Swiss Post issued a postage stamp bearing a depiction of a model of a molecule of vitamin C to mark the International Year of Chemistry.[220]

Pharmacopoeias

Notes

  1. ↑ Dicot plants transport only ferrous iron (Fe2+), but if the iron circulates as ferric complexes (Fe3+), it has to undergo a reduction before it can be actively transported. Plant embryos efflux high amounts of ascorbate that chemically reduce iron(III) from ferric complexes.[173]

References

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