Kreb C Vitamins

Kreb C Vitamins

Essential nutrient found in citrus fruits and other foods

Vitamin C

Clinical data
Pronunciation	,
Trade names	Ascor, Cevalin, others
Other names	l-ascorbic acid, ascorbic acid, ascorbate
AHFS/Drugs.com	Monograph
MedlinePlus	a682583
License data	US  DailyMed:Ascorbic_acid
Routes of administration	By mouth, intramuscular (IM), intravenous (IV), subcutaneous
ATC code	A11GA01 (WHO) A11GB01 (WHO) G01AD03 (WHO) S01XA15 (WHO)
Legal status
Legal status	AU: Unscheduled UK: POM (Prescription only) / GSL[1] [2] US: ℞-only / OTC/ Dietary Supplement[3] [4] [5]
Pharmacokinetic data
Bioavailability	Rapid and complete
Protein binding	Negligible
Elimination half-life	Varies according to plasma concentration
Excretion	Kidney
Identifiers
IUPAC name l-threo-Hex-2-enono-1,4-lactone or (R)-3,4-Dihydroxy-5-((S)- 1,2-dihydroxyethyl)furan-2(5H)-one
CAS Number	50-81-7 Y as salt:134-03-2 Y
PubChem CID	54670067 as salt: 23667548
IUPHAR/BPS	4781
DrugBank	DB00126 Y as salt:DB14482 Y
ChemSpider	10189562 Y as salt:16736174 Y
UNII	PQ6CK8PD0R as salt:S033EH8359 Y
KEGG	D00018 Y as salt:D05853 Y
ChEBI	CHEBI:29073 Y as salt:CHEBI:113451 Y
ChEMBL	ChEMBL196 Y as salt:ChEMBL591665 Y
NIAID ChemDB	002072
PDB ligand	ASC (PDBe, RCSB PDB)
E number	E300 (antioxidants, ...)
CompTox Dashboard (EPA)	DTXSID5020106
ECHA InfoCard	100.000.061
Chemical and physical data
Formula	C 6 H 8 O 6
Molar mass	176.124 g·mol−1
3D model (JSmol)	Interactive image
Density	1.694 g/cm3
Melting point	190 to 192 °C (374 to 378 °F) (some decomposition)[6]
Boiling point	552.7 °C (1,026.9 °F) [7]
SMILES OC[C@H](O)[C@H]1OC(=O)C(O)=C1O
InChI 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 Y Key:CIWBSHSKHKDKBQ-JLAZNSOCSA-N Y
(verify)

Vitamin C (also known as ascorbic acid and ascorbate) is a vitamin found in various foods and sold as a dietary supplement.^[9] It is used to prevent and treat scurvy.^[9] Vitamin C is an essential nutrient involved in the repair of tissue, the formation of collagen, and the enzymatic production of certain neurotransmitters.^{[9] [10]} It is required for the functioning of several enzymes and is important for immune system function.^{[10] [11]} It also functions as an antioxidant.^[12] Most animals are able to synthesize their own vitamin C, although humans, the other great and lesser apes, monkeys (but not all primates), most bats, some rodents, and certain other animals must acquire it from dietary sources.

There is some evidence that regular use of supplements may reduce the duration of the common cold, but it does not appear to prevent infection.^{[12] [13] [14]} It is unclear whether supplementation affects the risk of cancer, cardiovascular disease, or dementia.^{[15] [16]} It may be taken by mouth or by injection.^[9]

Vitamin C is generally well tolerated.^[9] Large doses may cause gastrointestinal discomfort, headache, trouble sleeping, and flushing of the skin.^{[9] [13]} Normal doses are safe during pregnancy.^[8] The United States Institute of Medicine recommends against taking large doses.^[10]

Vitamin C was discovered in 1912, isolated in 1928, and, in 1933, was the first vitamin to be chemically produced.^[17] It is on the World Health Organization's List of Essential Medicines.^[18] Vitamin C is available as an inexpensive generic and over-the-counter medication.^{[9] [19]} Partly for its discovery, Albert Szent-Györgyi and Walter Norman Haworth were awarded the 1937 Nobel Prizes in Physiology and Medicine and Chemistry, respectively.^{[20] [21]} Foods containing vitamin C include citrus fruits, kiwifruit, guava, broccoli, Brussels sprouts, bell peppers and strawberries.^[12] Prolonged storage or cooking may reduce vitaminC content in foods.^[12]

Biology [edit]

Significance [edit]

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. Oxidized forms of the molecule such as dehydroascorbic acid are converted back to ascorbic acid by reducing agents.^{[10] [22]}

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.^[10] 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.^[10] 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.^{[23] [24] [25]}

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.^{[11] [22] [26]}

Deficiency [edit]

Vitamin C blood serum levels are considered saturated at levels > 65 μmol/L (1.1 mg/dL), achieved by consuming amounts which are at, or above, the Recommended Dietary Allowance, while adequate levels are defined as ≥ 50 μmol/L. Hypovitaminosis in the case of vitamin C is defined as ≤ 23 μmol/L and deficiency occurs at ≤ 11.4 μmol/L.^{[27] [28]} For those 20 years of age or above, data from the U.S. 2003-04 NHANES survey showed mean and median serum concentrations of 49.0 and 54.4μmol/L, respectively. The percent of people reported as deficient was 7.1%.^[28]

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.^[11] 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.^[29]

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.^{[30] [31]}

People in sepsis or septic shock may have micronutrient deficiencies, including low levels of vitamin C.^[32]

Uses [edit]

Vitamin C supplements at a drug store.

Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitaminC deficiency. Beyond that, a role for vitaminC as prevention or treatment for various diseases is disputed, with reviews reporting conflicting results. A 2012 Cochrane review reported no effect of vitaminC supplementation on overall mortality.^[33] It is on the World Health Organization's List of Essential Medicines.^[18]

Scurvy [edit]

The disease scurvy is caused by vitaminC deficiency and can be prevented and treated with vitaminC-containing foods or dietary supplements.^{[9] [10]} It takes at least a month of little to no vitaminC before symptoms occur.^[30] 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.^[9] Until quite late in the disease the damage is reversible, as healthy collagen replaces the defective collagen with vitaminC repletion. Treatment can be oral supplementation of the vitamin or by intramuscular or intravenous injection.^[9] Scurvy was known to Hippocrates in the classical era. 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^[34] and from 1796 lemon juice was issued to all Royal Navy crewmen.^{[35] [34]}

Infection [edit]

Research on vitaminC 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 vitaminC 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 vitaminC on a regular basis did reduce the average duration by 8% in adults and 14% in children, and also reduced severity of colds.^[14] A subsequent meta-analysis in children found that vitaminC approached statistical significance for prevention and reduced the duration of upper respiratory tract infections.^[36] A subset of trials in adults reported that supplementation reduced the incidence of colds by half in marathon runners, skiers, or soldiers in subarctic conditions.^[14] Another subset of trials looked at therapeutic use, meaning that vitaminC was not started unless the people started to feel the beginnings of a cold. In these, vitaminC did not affect duration or severity.^[14] An earlier review stated that vitaminC did not prevent colds, did reduce duration, did not reduce severity.^[37] The authors of the Cochrane review concluded that:

The failure of vitamin C supplementation to reduce the incidence of colds in the general population indicates that routine vitamin C supplementation is not justified … Regular supplementation trials have shown that vitamin C reduces the duration of colds, but this was not replicated in the few therapeutic trials that have been carried out. Nevertheless, given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitaminC is beneficial for them."^[14]

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 indicating a prominent role in immune system regulation.^[38] 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.^{[39] [40]}

A study focusing on virus-induced respiratory infections reported that flu and cold symptoms in the test group decreased 85% compared with the control group after the administration of large doses of Vitamin C.^[41]

Several studies found ascorbate to have specific antiviral effects in which it inactivates the RNA or DNA of viruses^{[42] [43] [44]} or in the assembly of the virus. Vitamin C, not in combination with antivirals, supressed viral replication of herpes simplex virus-1 (HSV-1), influenza type A virus, poliovirus type 1 and rhinovirus.^{[45] [46]} Another study found Vitamin C to be an essential factor of immune responses at the initial stage of influenza A virus infection (H3N2) in mice.^[47]

COVID-19 [edit]

Supplementation with vitamin C has been suggested as part of the supportive management of COVID-19, as levels of vitamin C in serum and leukocytes are depleted in the acute stage of infection owing to increased metabolic demands.^[48]

According to ClinicalTrials.gov, there are 50 completed or ongoing COVID-19 clinical trials including vitamin C as a treatment.^[49] A meta-analysis of six published trials was published in October 2021. Treatments were either oral or intravenous. Dose ranged from 50 mg/kg/day to 24 g/day. Reported outcomes were mortality, hospitalization duration, intensive care duration and need for ventilation. From the Conclusion: "The present meta-analysis showed that administration of vitamin C did not have any effect on major health outcomes in COVID infected patients, in comparison to either placebo/standard therapy. Sub-group analysis also revealed that irrespective of its dosage, route of administration and disease severity, it didn't have discernible benefit in such patients. Hence, larger prospective randomized trials are needed in order to evaluate the effect of isolated vitamin C administration, separately for both vitamin C replete and deplete individuals."^[50]

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.^[51]

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines states that "there are insufficient data to recommend either for or against the use of vitaminC for the prevention or treatment of COVID-19."^[52]

Cancer [edit]

There are two approaches to the question of whether vitamin C has an effect on cancer. First, within the normal range of dietary intake without additional dietary supplementation, are people who consume more vitamin C at lower risk for developing cancer, and if so, does an orally consumed supplement have the same benefit? Second, for people diagnosed with cancer, will large amounts of ascorbic acid administered intravenously treat the cancer, reduce the adverse effects of other treatments, and so prolong survival and improve quality of life? A 2013 Cochrane review found 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.^[53] A second meta-analysis found no effect on the risk of prostate cancer.^[54] 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.^{[55] [56]} A 2011 meta-analysis failed to find support for the prevention of breast cancer with vitamin C supplementation,^[57] but a second study concluded that vitamin C may be associated with increased survival in those already diagnosed.^[58]

Under the rubric of orthomolecular medicine, "Intravenous vitamin C is a contentious adjunctive cancer therapy, widely used in naturopathic and integrative oncology settings."^[59] With oral administration absorption efficiency decreases as amounts increase. Intravenous administration bypasses this.^[60] Doing so makes it possible to achieve plasma concentrations of 5 to 10 millimoles/liter (mmol/L), which far exceed the approximately 0.2 mmol/L limit from oral consumption.^[61] The theories of mechanism are contradictory. At high tissue concentrations ascorbic acid is described as acting as a pro-oxidant, generating hydrogen peroxide (H₂O₂) to kill tumor cells. The same literature claims that ascorbic acid acts as an antioxidant, thereby reducing the adverse effects of chemotherapy and radiation therapy.^{[59] [60]} Research continues in this field, but a 2014 review concluded: "Currently, the use of high-dose intravenous vitamin C [as an anticancer agent] cannot be recommended outside of a clinical trial."^[62] A 2015 review added: "There is no high-quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity. Evidence for ascorbate's anti-tumor effects was limited to case reports and observational and uncontrolled studies."^[63]

Cardiovascular disease [edit]

In 2017, an independent study evaluating 15,445 participants found no evidence to show vitamin C decreases the risk cardiovascular disease.^[64] These results supported one 2013 review which found no evidence that antioxidant vitamin supplementation reduces the risk of myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality (it did not provide subset analysis for trials that just used vitamin C).^[15]

However, another 2013 review found an association between higher circulating vitamin C levels or dietary vitamin C and a lower risk of stroke.^[65]

A 2014 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.^[66]

Brain function [edit]

A 2017 systematic review found lower vitamin C concentrations in people with cognitive impairment, including Alzheimer's disease and dementia, compared to people with normal cognition.^[67] The cognitive testing, however, relied on the Mini-Mental State Examination, which is only a general test of cognition, indicating an overall low quality of research assessing the potential importance of vitamin C on cognition in normal and impaired people.^[67] A review of nutrient status in people with Alzheimer's disease reported low plasma vitamin C, but also low blood levels of folate, vitamin B₁₂, and vitamin E.^[68]

Other diseases [edit]

Studies examining the effects of vitamin C intake on the risk of Alzheimer's disease have reached conflicting conclusions.^{[69] [70]} Maintaining a healthy dietary intake is probably more important than supplementation for achieving any potential benefit.^[71] A 2010 review found no role for vitamin C supplementation in the treatment of rheumatoid arthritis.^[72] Vitamin C supplementation does not prevent or slow the progression of age-related cataract.^[73] A systematic review reported that low intake and low serum concentration was associated with greater progression of periodontal disease.^[74]

Side effects [edit]

Vitamin C is a water-soluble vitamin,^[75] with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine, so it exhibits remarkably low acute toxicity.^[11] More than two to three grams may cause indigestion, particularly when taken on an empty stomach. However, taking vitamin C in the form of sodium ascorbate and calcium ascorbate may minimize this effect.^[76] Other symptoms reported for large doses include nausea, abdominal cramps and diarrhea. These effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine.^[10] 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.^[10]

There is a longstanding belief among the mainstream medical community that vitamin C increases risk of kidney stones.^[77] "Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease".^[10] 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",^{[10] [78]} 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.^[79]

Diet [edit]

Recommended levels [edit]

US vitamin C recommendations (mg per day)[10]
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

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

• 40 milligrams per day: India National Institute of Nutrition, Hyderabad^[80]
• 45 milligrams per day or 300 milligrams per week: the World Health Organization^[81]
• 80 milligrams per day: the European Commission Council on nutrition labeling^[82]
• 90 mg/day (males) and 75 mg/day (females): Health Canada 2007^[83]
• 90 mg/day (males) and 75 mg/day (females): United States National Academy of Sciences.^[10]
• 100 milligrams per day: Japan National Institute of Health and Nutrition.^[84]
• 110 mg/day (males) and 95 mg/day (females): European Food Safety Authority^[85]

In 2000 the North American Dietary Reference Intake chapter on vitamin C updated the Recommended Dietary Allowance (RDA) to 90 milligrams per day for adult men and 75 mg/day for adult women, and set a Tolerable upper intake level (UL) for adults of 2,000 mg/day.^[10] The table shows RDAs for the United States and Canada for children, and for pregnant and lactating women.^[10] 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.^[85] 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.^[80] Clearly, there is not consensus among countries.

Cigarette smokers and people exposed to secondhand smoke have lower serum vitamin C levels than nonsmokers.^[28] The thinking is that inhalation of smoke causes oxidative damage, depleting this antioxidant vitamin.^[10] The U.S. 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.^[10] 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.^[86]

The U.S. 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.^[87] 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.^[88]

Tolerable upper intake level [edit]

In 2000 the Institute of Medicine of the U.S. 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 higher intakes. ULs are progressively lower for younger and younger children.^[10] The European Food Safety Authority (EFSA) in 2006 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,^[89] as did the Japan National Institute of Health and Nutrition in 2010.^[84]

Food labeling [edit]

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 27, 2016, it was revised to 90 mg to bring it into agreement with the RDA.^{[90] [91]} Compliance with the updated labeling regulations was required by January 1, 2020, for manufacturers with US$10 million or more in annual food sales, and by January 1, 2021, for manufacturers with lower volume food sales.^{[92] [93]} 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.^[94]

Sources [edit]

The richest natural sources of vitamin C are fruits and vegetables.^[11] The vitamin is the most widely taken dietary supplement.^[11]

Plant sources [edit]

For vitamin C content in ten common staple foods such as corn, rice, and wheat, see Staple food § Nutrition.

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.^{[95] [96]} The following table is approximate and shows the relative abundance in different raw plant sources.^{[97] [98]} As some plants were analyzed fresh while others were dried (thus, artificially 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 the edible portion of the fruit or vegetable:

Animal sources [edit]

Animal-sourced foods do not provide much vitamin C, and what there is, is largely destroyed by the heat of cooking. For example, raw chicken liver contains 17.9 mg/100 g, but fried, the content is reduced to 2.7 mg/100 g. Chicken eggs contain no vitamin C, raw or cooked.^[99] Vitamin C is present in human breast milk at 5.0 mg/100 g and 6.1 mg/100 g in one tested sample of infant formula, but cow's milk contains only 1.0 mg/ 100 g.^[105]

Food preparation [edit]

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.^[106] Cooking can reduce the vitamin C content of vegetables by around 60%, possibly due to increased enzymatic destruction.^[107] Longer cooking times may add to this effect.^[108]

Another cause of vitaminC loss from food is leaching, which transfers vitaminC to the cooking water, which is decanted and not consumed. Broccoli may retain vitaminC during cooking or storage more than most vegetables.^[109]

Supplements [edit]

Vitamin C dietary supplements are available as tablets, capsules, drink mix packets, in multi-vitamin/mineral formulations, in antioxidant formulations, and as crystalline powder.^[9] 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.^[9] Vitamin C molecules can also be bound to the fatty acid palmitate, creating ascorbyl palmitate, or else incorporated into liposomes.^[110]

Food fortification [edit]

In 2014, the Canadian Food Inspection Agency evaluated the effect of fortification of foods with ascorbate in the guidance document, Foods to Which Vitamins, Mineral Nutrients and Amino Acids May or Must be Added.^[111] Voluntary and mandatory fortification was described for various classes of foods. Among foods classified for mandatory fortification with vitaminC were fruit-flavored drinks, mixes, and concentrates, foods for a low-energy diet, meal replacement products, and evaporated milk.^[111]

Food additives [edit]

Ascorbic acid and some of its salts and esters are common additives added to various foods, such as canned fruits, mostly to retard oxidation and enzymatic browning.^[112] It may be used as a flour treatment agent used in breadmaking.^[113] As food additives, they are assigned E numbers, with safety assessment and approval the responsibility of the European Food Safety Authority.^[114] The relevant E numbers are:

1. E300 ascorbic acid (approved for use as a food additive in the EU,^[115] U.S.^[116] and Australia and New Zealand)^[117]
2. E301 sodium ascorbate (approved for use as a food additive in the EU,^[115] U.S.^[118] and Australia and New Zealand)^[117]
3. E302 calcium ascorbate (approved for use as a food additive in the EU,^[115] U.S.^[116] and Australia and New Zealand)^[117]
4. E303 potassium ascorbate (approved in Australia and New Zealand,^[117] but not in U.S.)
5. E304 fatty acid esters of ascorbic acid such as ascorbyl palmitate (approved for use as a food additive in the EU,^[115] U.S.^[116] and Australia and New Zealand)^[117]

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).^[115]

Pharmacology [edit]

Pharmacodynamics [edit]

This section needs expansion with: the content specified on the talk page. You can help by adding to it. Relevant discussion may be found on Talk:Vitamin C. (December 2018)

Vitamin C – specifically, in the form of ascorbate – performs numerous physiological functions in the human body by serving as an enzyme substrate and/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 microsome.^[25] 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:

• Three groups of enzymes (prolyl-3-hydroxylases, prolyl-4-hydroxylases, and lysyl hydroxylases) that are required for the hydroxylation of proline and lysine in the synthesis of collagen.^{[119] [120] [121]} These reactions add hydroxyl groups to the amino acids proline or lysine in the collagen molecule via prolyl hydroxylase and lysyl hydroxylase, both requiring vitamin C as a cofactor. The role of vitamin C as a cofactor is to oxidize prolyl hydroxylase and lysyl hydroxylase from Fe²⁺ to Fe³⁺ and to reduce it from Fe³⁺ to Fe²⁺. Hydroxylation allows the collagen molecule to assume its triple helix structure, and thus vitamin C is essential to the development and maintenance of scar tissue, blood vessels, and cartilage.^[75]
• Two enzymes (ε-N-trimethyl-L-lysine hydroxylase and γ-butyrobetaine hydroxylase) that are necessary for synthesis of carnitine.^[122] Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.
• Hypoxia-inducible factor-proline dioxygenase enzymes (isoforms: EGLN1, EGLN2, and EGLN3)^{[122] [123]}
• Dopamine beta-hydroxylase participates in the biosynthesis of norepinephrine from dopamine.^{[124] [125]}
• Peptidylglycine alpha-amidating monooxygenase amidates peptide hormones by removing the glyoxylate residue from their c-terminal glycine residues. This increases peptide hormone stability and activity.^{[126] [127]}

Pharmacokinetics [edit]

Absorption [edit]

From the U.S. 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%."^[12] It is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms, so the presence of large quantities of sugar in the intestine can slow absorption.^[128]

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 transporter proteins required for active absorption. SVCT1 and SVCT2 import the reduced form of ascorbate across plasma membranes.^[129] GLUT1 and GLUT3 are glucose transporters, and transfer only the dehydroascorbic acid (DHA) form of vitamin C.^[130] 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.^[131]

Transport [edit]

SVCTs appear to be the predominant system for vitamin C transport in the body,^[129] the notable exception being red blood cells, which lose SVCT proteins during maturation.^[132] 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.^[133] The known coenzymatic functions of ascorbic acid do not require such high concentrations, so there may be other, as yet unknown functions. Consequences of all this 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.^[133]

Excretion [edit]

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. Only when plasma concentrations are 1.4 mg/dL or higher does re-absorption decline and the excess amounts pass freely into the urine. This salvage process delays onset of deficiency.^[134] Ascorbic acid also converts (reversibly) to dehydroascorbate (DHA) and from that compound non-reversibly to 2,3-diketogluonate 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.^[135]

Chemistry [edit]

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.^{[ citation needed ]}

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.^{[136] [137]}

Testing [edit]

Simple tests are available to measure the levels of vitamin C in urine and serum.^{[27] [28]} These better reflect recent dietary intake rather than total body content.^[10] 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.^{[138] [139]}

Biosynthesis [edit]

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.^[140] In plants, this is accomplished through the conversion of mannose or galactose to ascorbic acid.^{[141] [142]} 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.^[143] 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.^{[144] [145] [146] [147]}

Animal synthesis pathway [edit]

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.^[148] A report on goats, sheep and cattle reported ranges of 100–110, 265-270 and 160-350 μmol/L, respectively.^[149]

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.^{[150] [151] [135]}

Some mammals have lost the ability to synthesize vitamin C, including simians and tarsiers, which together make up one of two major primate suborders, Haplorrhini. This group includes humans. The other more primitive primates (Strepsirrhini) have the ability to make vitamin C. Synthesis does not occur in most bats^[144] nor in species in the rodent family Caviidae, that includes guinea pigs and capybaras, but does occur in other rodents, including rats and mice.^[152]

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.^[142] 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; there is a theory that the ability was lost separately a number of times in birds.^[153] In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases.^[154] The ability to synthesize vitaminC has also been lost in about 96% of fish (the teleosts).^[153]

Most tested families of bats (order Chiroptera), including major insect and fruit-eating bat families, cannot synthesize vitamin C. A trace of gulonolactone oxidase was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested.^[155] There are at least two species of bats, frugivorous bat (Rousettus leschenaultii) and insectivorous bat (Hipposideros armiger), that retain (or regained) their ability of vitamin C production.^{[156] [157]}

Some of these species (including humans) are able to make do with the lower amounts available from their diets by recycling oxidised vitamin C.^[158]

On a milligram consumed per kilogram of body weight basis, most simian species consume the vitamin in amounts 10 to 20 times higher than what is recommended by governments for humans.^[159] This discrepancy constitutes much of the basis of the controversy on current recommended dietary allowances. It is countered by arguments that humans are very good at conserving dietary vitamin C, and are able to maintain blood levels of vitamin C comparable with simians on a far smaller dietary intake, perhaps by recycling oxidized vitamin C.^[158]

Plant pathways [edit]

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.^[144] 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.^[160] to produce ascorbic acid.^[151] l-Ascorbic acid has a negative feedback on l-galactose dehydrogenase in spinach.^[161] Ascorbic acid efflux by embryo of dicots plants is a well-established mechanism of iron reduction, and a step obligatory for iron uptake.^[a]

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.^[163] 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.^{[163] [164]} There is feedback regulation in place, in that the presence of ascorbic acid inhibits enzymes in the synthesis pathway.^[165] 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.^[164] 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.^[163]

Evolution [edit]

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.^{[166] [154]} 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 codes for L-Gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above.^[167] 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 vitaminC, natural selection would not act to preserve it.^{[168] [169]}

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.^[170] According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.^[171] 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.^{[172] [173]} 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).^[170]

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.^[174]

Industrial production [edit]

Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. The Reichstein process and the modern two-step fermentation processes use sorbitol as the starting material and convert it to sorbose using fermentation. The modern 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 feed.^[175]

In 2017, China produced about 95% of the world supply of ascorbic acid (vitamin C),^[176] which is China's most exported vitamin, having total revenue of US$880 million in 2017.^[177] Due to pressure on Chinese industry to discontinue burning coal normally used for vitamin C manufacturing, the price of vitamin C rose three-fold in 2016 alone to US$12 per kg.^[176]

History [edit]

Scurvy at sea [edit]

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.^{[178] [179]} Later, the Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, which sustained passing ships.^[180]

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.^[181] In 1734, the Dutch writer Johann Bachstrom gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens." ^{[182] [183]}

Scurvy had long been a principal killer of sailors during the long sea voyages.^[184] 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."^[185]

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.^[34] The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.^{[35] [186]}

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).^[108] 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.^[34] Captain James Cook had previously demonstrated the advantages of carrying "Sour krout" on board, by taking his crews to the Hawaiian Islands without losing any of his men to scurvy.^[187] For this, the British Admiralty awarded him a medal.

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.^[188] 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,^[189] comparable with the Estimated Average Requirement.^[10]

Discovery [edit]

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.^[190]

Vitamin C was discovered in 1912, isolated in 1928 and synthesized in 1933, making it the first vitamin to be synthesized.^[17] Shortly thereafter Tadeus Reichstein succeeded in synthesizing the vitamin in bulk by what is now called the Reichstein process.^[191] This made possible the inexpensive mass-production of vitamin C. In 1934 Hoffmann–La Roche trademarked synthetic vitamin C under the brand name Redoxon^[192] and began to market it as a dietary supplement.^[b]

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. By luck, this species did not make its own vitamin C, whereas mice and rats do.^[194] 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.^[195]

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 vitaminC and the catalysis of fumaric acid".^[21]

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.^[196] 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.^[196] In 1933, Walter Norman Haworth chemically identified the vitamin as l-hexuronic acid, proving this by synthesis in 1933.^{[197] [198] [199] [200]} 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.^{[200] [17]} 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.^[201] Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine,^[202] and Haworth shared that year's Nobel Prize in Chemistry.^[21]

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.^{[203] [204]} American biochemist Irwin Stone was the first to exploit vitamin C for its food preservative properties. He later developed the theory that humans possess a mutated form of the l-gulonolactone oxidase coding gene.^[205]

In 2008, researchers at the University of Montpellier discovered that in humans and other primates the red blood cells have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized l-dehydroascorbic acid (DHA) back into ascorbic acid for reuse by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.^[158]

Large doses [edit]

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. The theory behind 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.^[206] 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.^[207] 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 (10 days) administered intravenously and thereafter orally, would cure late-stage cancer.^[208] Mega-dosing with ascorbic acid has other champions, among them chemist Irwin Stone and the controversial Matthias Rath and Patrick Holford, who both have been accused of making unsubstantiated treatment claims for treating cancer and HIV infection.^{[ citation needed ]}

The mega-dosing theory is to a large degree discredited. Modest benefits are demonstrated for the common cold. Benefits are not superior when supplement intakes of more than 1,000 mg/day are compared to intakes between 200 and 1,000 mg/day, and so not limited to the mega-dose range.^{[209] [210]} The theory that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer is - some forty years after Pauling's seminal paper - still considered unproven and still in need of high quality research.^{[62] [63]} However, a lack of conclusive evidence has not stopped individual physicians from prescribing intravenous ascorbic acid to thousands of people with cancer.^[63]

Society and culture [edit]

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.^[211]

Brand names [edit]

Vitamin C is sold around the world as a stand-alone product and as part of a fixed-dose combination product, under many brand names.^[212]

Pharmacopoeias [edit]

• British Pharmacopoeia ^[213]
• Japanese Pharmacopoeia ^[214]

Notes [edit]

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.^[162]
2. ^ "In 1934, Hoffman-La Roche, which bought the Reichstein process patent, became the first pharmaceutical company to mass produce and market synthetic vitamin C, under the brand name Redoxon."^[193]

References [edit]

1. ^ "Ascorbic Acid Injection 500mg/5ml - Summary of Product Characteristics (SmPC)". (emc). July 15, 2015. Retrieved October 12, 2020.
2. ^ "Ascorbic Acid 100mg Tablets - Summary of Product Characteristics (SmPC)". (emc). October 29, 2018. Retrieved October 12, 2020.
3. ^ "Ascor- ascorbic acid injection". DailyMed. October 2, 2020. Retrieved October 12, 2020.
4. ^ "Ascorbic Acid liquid". DailyMed. November 13, 2018. Retrieved October 12, 2020.
5. ^ "Leonas Vitamin C- ascorbic acid tablet, chewable". DailyMed. September 14, 2018. Retrieved October 12, 2020.
6. ^ Merck Index, 14th ed.
7. ^ "Vitamin C". ChemSpider. Royal Society of Chemistry. Retrieved July 25, 2020.
8. ^ ^{a b} "Ascorbic acid Use During Pregnancy". Drugs.com. Archived from the original on December 31, 2016. Retrieved December 30, 2016.
9. ^ ^{a b c d e f g h i j k l} "Ascorbic Acid". The American Society of Health-System Pharmacists. Archived from the original on December 30, 2016. Retrieved December 8, 2016.
10. ^ ^{a b c d e f g h i j k l m n o p q r s t} "Vitamin C". Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press. 2000. pp. 95–185. ISBN978-0-309-06935-9. Archived from the original on September 2, 2017. Retrieved September 1, 2017.
11. ^ ^{a b c d e f} "Vitamin C". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. July 1, 2018. Retrieved June 19, 2019.
12. ^ ^{a b c d e} "Fact Sheet for Health Professionals – Vitamin C". Office of Dietary Supplements, US National Institutes of Health. February 11, 2016. Archived from the original on July 30, 2017.
13. ^ ^{a b} World Health Organization (2009). Stuart MC, Kouimtzi M, Hill SR (eds.). WHO Model Formulary 2008. World Health Organization. hdl:10665/44053. ISBN9789241547659.
14. ^ ^{a b c d e} Hemilä H, Chalker E (January 2013). "Vitamin C for preventing and treating the common cold". The Cochrane Database of Systematic Reviews. 2013 (1): CD000980. doi:10.1002/14651858.CD000980.pub4. PMC1160577. PMID 23440782.
15. ^ ^{a b} Ye Y, Li J, Yuan Z (2013). "Effect of antioxidant vitamin supplementation on cardiovascular outcomes: a meta-analysis of randomized controlled trials". PLOS ONE. 8 (2): e56803. Bibcode:2013PLoSO...856803Y. doi:10.1371/journal.pone.0056803. PMC3577664. PMID 23437244.
16. ^ Duerbeck NB, Dowling DD, Duerbeck JM (March 2016). "Vitamin C: Promises Not Kept". Obstetrical & Gynecological Survey. 71 (3): 187–93. doi:10.1097/OGX.0000000000000289. PMID 26987583. S2CID 29429545. Antioxidant vitamin supplementation has no effect on the incidence of major cardiovascular events, myocardial infarction, stroke, total death, and cardiac death.
17. ^ ^{a b c} Squires VR (2011). The Role of Food, Agriculture, Forestry and Fisheries in Human Nutrition - Volume IV. EOLSS Publications. p. 121. ISBN9781848261952.
18. ^ ^{a b} World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
19. ^ British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 1049. ISBN9780857113382.
20. ^ "The Nobel Prize in Physiology or Medicine 1937". Nobel Media AB. Archived from the original on November 5, 2014. Retrieved November 20, 2014.
21. ^ ^{a b c} Zetterström R (May 2009). "Nobel Prize 1937 to Albert von Szent-Györgyi: identification of vitamin C as the anti-scorbutic factor". Acta Paediatrica. 98 (5): 915–9. doi:10.1111/j.1651-2227.2009.01239.x. PMID 19239412. S2CID 11077461.
22. ^ ^{a b} Marriott MP, Birt DF, Stallings VA, Yates AA, eds. (2020). "Vitamin C". Present Knowledge in Nutrition, Eleventh Edition. London, United Kingdom: Academic Press (Elsevier). pp. 155–70. ISBN978-0-323-66162-1.
23. ^ Meister A (April 1994). "Glutathione-ascorbic acid antioxidant system in animals". The Journal of Biological Chemistry. 269 (13): 9397–400. doi:10.1016/S0021-9258(17)36891-6. PMID 8144521. Archived from the original on August 11, 2015.
24. ^ Michels A, Frei B (2012). "Vitamin C". In Caudill MA, Rogers M (eds.). Biochemical, Physiological, and Molecular Aspects of Human Nutrition (3 ed.). Philadelphia: Saunders. pp. 627–654. ISBN978-1-4377-0959-9.
25. ^ ^{a b} Gropper SS, Smith JL, Grodd JL (2005). Advanced nutrition and human metabolism. Belmont, CA: Thomson Wadsworth. pp. 260–275. ISBN978-0-534-55986-1.
26. ^ Anjum NA, Umar S, Chan MT, eds. (September 13, 2010). Ascorbate-Glutathione Pathway and Stress Tolerance in Plants. Springer. p. 324. ISBN978-9-048-19403-2. Archived from the original on November 5, 2017. Retrieved August 3, 2017.
27. ^ ^{a b} Carr AC, Pullar JM, Bozonet SM, Vissers MC (June 2016). "Marginal Ascorbate Status (Hypovitaminosis C) Results in an Attenuated Response to Vitamin C Supplementation". Nutrients. 8 (6): 341. doi:10.3390/nu8060341. PMC4924182. PMID 27271663.
28. ^ ^{a b c d} Schleicher RL, Carroll MD, Ford ES, Lacher DA (November 2009). "Serum vitamin C and the prevalence of vitamin C deficiency in the United States: 2003-2004 National Health and Nutrition Examination Survey (NHANES)". Am. J. Clin. Nutr. 90 (5): 1252–63. doi:10.3945/ajcn.2008.27016. PMID 19675106.
29. ^ Magiorkinis E, Beloukas A, Diamantis A (April 2011). "Scurvy: past, present and future". The European Journal of Internal Medicine. 22 (2): 147–52. doi:10.1016/j.ejim.2010.10.006. PMID 21402244.
30. ^ ^{a b} Hodges RE, Baker EM, Hood J, Sauberlich HE, March SC (May 1969). "Experimental scurvy in man". The American Journal of Clinical Nutrition. 22 (5): 535–48. doi:10.1093/ajcn/22.5.535. PMID 4977512.
31. ^ Pemberton J (June 2006). "Medical experiments carried out in Sheffield on conscientious objectors to military service during the 1939-45 war". International Journal of Epidemiology. 35 (3): 556–8. doi:10.1093/ije/dyl020. PMID 16510534.
32. ^ Belsky, Justin B.; Wira, Charles R.; Jacob, Vinitha; Sather, John E.; Lee, Patty J. (December 2018). "A review of micronutrients in sepsis: the role of thiamine, l-carnitine, vitamin C, selenium and vitamin D". Nutrition Research Reviews. 31 (2): 281–290. doi:10.1017/S0954422418000124. PMID 29984680. S2CID 51599526.
33. ^ Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (March 2012). "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". The Cochrane Database of Systematic Reviews. 2012 (3): CD007176. doi:10.1002/14651858.CD007176.pub2. hdl:10138/136201. PMC8407395. PMID 22419320.
34. ^ ^{a b c d e} Baron JH (June 2009). "Sailors' scurvy before and after James Lind--a reassessment". Nutrition Reviews. 67 (6): 315–32. doi:10.1111/j.1753-4887.2009.00205.x. PMID 19519673. S2CID 20435128.
35. ^ ^{a b} Lind J (1753). A Treatise of the Scurvy. London: A. Millar. In the 1757 edition of his work, Lind discusses his experiment starting on page 149. Archived March 20, 2016, at the Wayback Machine
36. ^ Vorilhon P, Arpajou B, Vaillant Roussel H, Merlin É, Pereira B, Cabaillot A (March 2019). "Efficacy of vitamin C for the prevention and treatment of upper respiratory tract infection. A meta-analysis in children". Eur. J. Clin. Pharmacol. 75 (3): 303–11. doi:10.1007/s00228-018-2601-7. PMID 30465062. S2CID 53718830.
37. ^ Heimer KA, Hart AM, Martin LG, Rubio-Wallace S (May 2009). "Examining the evidence for the use of vitamin C in the prophylaxis and treatment of the common cold". Journal of the American Academy of Nurse Practitioners. 21 (5): 295–300. doi:10.1111/j.1745-7599.2009.00409.x. PMC7166744. PMID 19432914.
38. ^ Wintergerst ES, Maggini S, Hornig DH (2006). "Immune-enhancing role of vitamin C and zinc and effect on clinical conditions" (PDF). Annals of Nutrition & Metabolism. 50 (2): 85–94. doi:10.1159/000090495. PMID 16373990. S2CID 21756498.
39. ^ EFSA Panel on Dietetic Products, Nutrition and Allergies (2009). "Scientific Opinion on the substantiation of health claims related to vitamin C and protection of DNA, proteins and lipids from oxidative damage (ID 129, 138, 143, 148), antioxidant function of lutein (ID 146), maintenance of vision (ID 141, 142), collagen formation (ID 130, 131, 136, 137, 149), function of the nervous system (ID 133), function of the immune system (ID 134), function of the immune system during and after extreme physical exercise (ID 144), non-haem iron absorption (ID 132, 147), energy-yielding metabolism (ID 135), and relief in case of irritation in the upper respiratory tract (ID 1714, 1715) pursuant to Article 13(1) of Regulation (EC) No 1924/2006". EFSA Journal. 7 (9): 1226. doi:10.2903/j.efsa.2009.1226.
40. ^ EFSA Panel on Dietetic Products, Nutrition and Allergies (2015). "Vitamin C and contribution to the normal function of the immune system: evaluation of a health claim pursuant to Article 14 of Regulation (EC) No 1924/2006". EFSA Journal. 13 (11): 4298. doi:10.2903/j.efsa.2015.4298.
41. ^ Gorton, H. C.; Jarvis, K. (October 1999). "The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections". Journal of Manipulative and Physiological Therapeutics. 22 (8): 530–533. doi:10.1016/s0161-4754(99)70005-9. ISSN 0161-4754. PMID 10543583.
42. ^ MURATA, Akira; OYADOMARI, Reiko; OHASHI, Tadashi; KITAGAWA, Kazuko (1975). "Mechanism of inactivation of bacteriophage deltaA containing single-stranded DNA by ascorbic acid". Journal of Nutritional Science and Vitaminology. 21 (4): 261–269. doi:10.3177/jnsv.21.261. ISSN 0301-4800. PMID 1214179.
43. ^ Harakeh, S; Jariwalla, R J; Pauling, L (1990). "Suppression of human immunodeficiency virus replication by ascorbate in chronically and acutely infected cells". Proceedings of the National Academy of Sciences. 87 (18): 7245–7249. doi:10.1073/pnas.87.18.7245. ISSN 0027-8424. PMC54720. PMID 1698293.
44. ^ Madhusudana, Shampur Narayan; Shamsundar, Ranjini; Seetharaman, Saraswati (January 2004). "In vitro inactivation of the rabies virus by ascorbic acid". International Journal of Infectious Diseases: IJID: Official Publication of the International Society for Infectious Diseases. 8 (1): 21–25. doi:10.1016/j.ijid.2003.09.002. ISSN 1201-9712. PMID 14690777.
45. ^ Schwerdt, P. R.; Schwerdt, C. E. (April 1975). "Effect of ascorbic acid on rhinovirus replication in WI-38 cells". Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.). 148 (4): 1237–1243. doi:10.3181/00379727-148-38724. ISSN 0037-9727. PMID 165544. S2CID 37968271.
46. ^ Ayami Furuya, Misao Uozaki, Hisashi Yamasaki, Tsutomu Arakawa, Mikio Arita, A Hajime Koyama (January 1, 1998). "Antiviral effects of ascorbic and dehydroascorbic acids in vitro". International Journal of Molecular Medicine. 22 (4). doi:10.3892/ijmm_00000053. ISSN 1107-3756. CS1 maint: multiple names: authors list (link)
47. ^ Kim, Yejin; Kim, Hyemin; Bae, Seyeon; Choi, Jiwon; Lim, Sun Young; Lee, Naeun; Kong, Joo Myung; Hwang, Young-Il; Kang, Jae Seung; Lee, Wang Jae (April 2013). "Vitamin C Is an Essential Factor on the Anti-viral Immune Responses through the Production of Interferon-α/β at the Initial Stage of Influenza A Virus (H3N2) Infection". Immune Network. 13 (2): 70–74. doi:10.4110/in.2013.13.2.70. ISSN 1598-2629. PMC3659258. PMID 23700397.
48. ^ Abobaker A, Alzwi A, Alraied AH (December 2020). "Overview of the possible role of vitamin C in management of COVID-19". Pharmacological Reports. 72 (6): 1517–28. doi:10.1007/s43440-020-00176-1. PMC7592143. PMID 33113146.
49. ^ "Search of: vitamin C | Recruiting, Completed Studies | COVID-19". clinicaltrials.gov . Retrieved February 27, 2021.
50. ^ Rawat D, Roy A, Maitra S, Gulati A, Khanna P, Baidya DK (October 2021). "Vitamin C and COVID-19 treatment: A systematic review and meta-analysis of randomized controlled trials". Diabetes & Metabolic Syndrome. 15 (6): 102324. doi:10.1016/j.dsx.2021.102324. PMC8552785. PMID 34739908.
51. ^ Bramstedt KA (October 2020). "Unicorn Poo and Blessed Waters: COVID-19 Quackery and FDA Warning Letters". Ther Innov Regul Sci. 55 (1): 239–244. doi:10.1007/s43441-020-00224-1. PMC7528445. PMID 33001378.
52. ^ "Vitamin C". COVID-19 Treatment Guidelines.
53. ^ Cortés-Jofré M, Rueda JR, Asenjo-Lobos C, Madrid E, Bonfill Cosp X (March 2020). "Drugs for preventing lung cancer in healthy people". The Cochrane Database of Systematic Reviews. 2020 (3): CD002141. doi:10.1002/14651858.CD002141.pub3. PMC7059884. PMID 32130738.
54. ^ Stratton J, Godwin M (June 2011). "The effect of supplemental vitamins and minerals on the development of prostate cancer: a systematic review and meta-analysis". Family Practice. 28 (3): 243–52. doi:10.1093/fampra/cmq115. PMID 21273283.
55. ^ Xu X, Yu E, Liu L, Zhang W, Wei X, Gao X, et al. (November 2013). "Dietary intake of vitamins A, C, and E and the risk of colorectal adenoma: a meta-analysis of observational studies". European Journal of Cancer Prevention. 22 (6): 529–39. doi:10.1097/CEJ.0b013e328364f1eb. PMID 24064545. S2CID 36958552.
56. ^ Papaioannou D, Cooper KL, Carroll C, Hind D, Squires H, Tappenden P, Logan RF (October 2011). "Antioxidants in the chemoprevention of colorectal cancer and colorectal adenomas in the general population: a systematic review and meta-analysis". Colorectal Disease. 13 (10): 1085–99. doi:10.1111/j.1463-1318.2010.02289.x. PMID 20412095. S2CID 7380783.
57. ^ Fulan H, Changxing J, Baina WY, Wencui Z, Chunqing L, Fan W, et al. (October 2011). "Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression". Cancer Causes & Control. 22 (10): 1383–96. doi:10.1007/s10552-011-9811-y. PMID 21761132. S2CID 24867472.
58. ^ Harris HR, Orsini N, Wolk A (May 2014). "Vitamin C and survival among women with breast cancer: a meta-analysis". European Journal of Cancer. 50 (7): 1223–31. doi:10.1016/j.ejca.2014.02.013. PMID 24613622.
59. ^ ^{a b} Fritz H, Flower G, Weeks L, Cooley K, Callachan M, McGowan J, Skidmore B, Kirchner L, Seely D (July 2014). "Intravenous Vitamin C and Cancer: A Systematic Review". Integrative Cancer Therapies. 13 (4): 280–300. doi:10.1177/1534735414534463. PMID 24867961.
60. ^ ^{a b} Du J, Cullen JJ, Buettner GR (December 2012). "Ascorbic acid: chemistry, biology and the treatment of cancer". Biochimica et Biophysica Acta (BBA) - Reviews on Cancer. 1826 (2): 443–57. doi:10.1016/j.bbcan.2012.06.003. PMC3608474. PMID 22728050.
61. ^ Parrow NL, Leshin JA, Levine M (December 2013). "Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics". Antioxidants & Redox Signaling. 19 (17): 2141–56. doi:10.1089/ars.2013.5372. PMC3869468. PMID 23621620.
62. ^ ^{a b} Wilson MK, Baguley BC, Wall C, Jameson MB, Findlay MP (March 2014). "Review of high-dose intravenous vitamin C as an anticancer agent". Asia-Pacific Journal of Clinical Oncology. 10 (1): 22–37. doi:10.1111/ajco.12173. PMID 24571058. S2CID 206983069.
63. ^ ^{a b c} Jacobs C, Hutton B, Ng T, Shorr R, Clemons M (February 2015). "Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review". The Oncologist. 20 (2): 210–23. doi:10.1634/theoncologist.2014-0381. PMC4319640. PMID 25601965.
64. ^ Al-Khudairy L, Flowers N, Wheelhouse R, Ghannam O, Hartley L, Stranges S, Rees K (March 2017). "Vitamin C supplementation for the primary prevention of cardiovascular disease". The Cochrane Database of Systematic Reviews. 2017 (3): CD011114. doi:10.1002/14651858.CD011114.pub2. PMC6464316. PMID 28301692.
65. ^ Chen GC, Lu DB, Pang Z, Liu QF (November 2013). "Vitamin C intake, circulating vitamin C and risk of stroke: a meta-analysis of prospective studies". Journal of the American Heart Association. 2 (6): e000329. doi:10.1161/JAHA.113.000329. PMC3886767. PMID 24284213.
66. ^
67. ^ ^{a b} Travica N, Ried K, Sali A, Scholey A, Hudson I, Pipingas A (August 30, 2017). "Vitamin C status and cognitive function: A systematic review". Nutrients. 9 (9): E960. doi:10.3390/nu9090960. PMC5622720. PMID 28867798.
68. ^ Lopes da Silva S, Vellas B, Elemans S, Luchsinger J, Kamphuis P, Yaffe K, Sijben J, Groenendijk M, Stijnen T (2014). "Plasma nutrient status of patients with Alzheimer's disease: Systematic review and meta-analysis". Alzheimer's and Dementia. 10 (4): 485–502. doi:10.1016/j.jalz.2013.05.1771. PMID 24144963.
69. ^ Crichton GE, Bryan J, Murphy KJ (September 2013). "Dietary antioxidants, cognitive function and dementia--a systematic review". Plant Foods for Human Nutrition. 68 (3): 279–92. doi:10.1007/s11130-013-0370-0. PMID 23881465. S2CID 26065398.
70. ^ Li FJ, Shen L, Ji HF (2012). "Dietary intakes of vitamin E, vitamin C, and β-carotene and risk of Alzheimer's disease: a meta-analysis". Journal of Alzheimer's Disease. 31 (2): 253–8. doi:10.3233/JAD-2012-120349. PMID 22543848.
71. ^ Harrison FE (2012). "A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease". Journal of Alzheimer's Disease. 29 (4): 711–26. doi:10.3233/JAD-2012-111853. PMC3727637. PMID 22366772.
72. ^ Rosenbaum CC, O'Mathúna DP, Chavez M, Shields K (2010). "Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis". Alternative Therapies in Health and Medicine. 16 (2): 32–40. PMID 20232616.
73. ^ Mathew MC, Ervin AM, Tao J, Davis RM (June 2012). "Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract". The Cochrane Database of Systematic Reviews. 6 (6): CD004567. doi:10.1002/14651858.CD004567.pub2. PMC4410744. PMID 22696344.
74. ^ Tada, A; Miura, H (July 2019). "The Relationship between Vitamin C and Periodontal Diseases: A Systematic Review". Int J Environ Res Public Health. 16 (14): 2472. doi:10.3390/ijerph16142472. PMC6679374. PMID 31337635.
75. ^ ^{a b} "Vitamin C: MedlinePlus Medical Encyclopedia". medlineplus.gov. Archived from the original on July 28, 2016. Retrieved July 23, 2016.
76. ^ Pauling L (1976). Vitamin C, the Common Cold, and the Flu. W.H. Freeman and Company.
77. ^ Goodwin JS, Tangum MR (November 1998). "Battling quackery: attitudes about micronutrient supplements in American academic medicine". Archives of Internal Medicine. 158 (20): 2187–91. doi:10.1001/archinte.158.20.2187. PMID 9818798.
78. ^ Naidu KA (August 2003). "Vitamin C in human health and disease is still a mystery? An overview" (PDF). Nutrition Journal. 2 (7): 7. doi:10.1186/1475-2891-2-7. PMC201008. PMID 14498993. Archived (PDF) from the original on September 18, 2012.
79. ^ Thomas LD, Elinder CG, Tiselius HG, Wolk A, Akesson A (March 2013). "Ascorbic acid supplements and kidney stone incidence among men: a prospective study". JAMA Internal Medicine. 173 (5): 386–8. doi:10.1001/jamainternmed.2013.2296. PMID 23381591.
80. ^ ^{a b} "Dietary Guidelines for Indians" (PDF). National Institute of Nutrition, India. 2011. Archived from the original (PDF) on December 22, 2018. Retrieved February 10, 2019.
81. ^ World Health Organization (2005). "Chapter 7: Vitamin C". Vitamin and Mineral Requirements in Human Nutrition (2nd ed.). Geneva: World Health Organization. hdl:10665/42716. ISBN978-92-4-154612-6.
82. ^ "Commission Directive 2008/100/EC of 28 October 2008 amending Council Directive 90/496/EEC on nutrition labelling for foodstuffs as regards recommended daily allowances, energy conversion factors and definitions". The Commission of the European Communities. October 29, 2008. Archived from the original on October 2, 2016.
83. ^ "Vitamin C". Natural Health Product Monograph. Health Canada. Archived from the original on April 3, 2013.
84. ^ ^{a b} "Overview of Dietary Reference Intakes for Japanese" (PDF). Ministry of Health, Labour and Welfare (Japan). 2015. Retrieved August 19, 2021.
85. ^ ^{a b} "Overview on Dietary Reference Values for the EU population as derived by the EFSA Panel on Dietetic Products, Nutrition and Allergies" (PDF). 2017. Archived (PDF) from the original on August 28, 2017.
86. ^ Luo J, Shen L, Zheng D (2014). "Association between vitamin C intake and lung cancer: a dose-response meta-analysis". Scientific Reports. 4: 6161. Bibcode:2014NatSR...4E6161L. doi:10.1038/srep06161. PMC5381428. PMID 25145261.
87. ^ "TABLE 1: Nutrient Intakes from Food and Beverages" Archived February 24, 2017, at the Wayback Machine What We Eat In America, NHANES 2012-2014
88. ^ "TABLE 37: Nutrient Intakes from Dietary Supplements" Archived October 6, 2017, at the Wayback Machine What We Eat In America, NHANES 2012-2014
89. ^ "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006. Archived (PDF) from the original on March 16, 2016.
90. ^ "Federal Register May 27, 2016 Food Labeling: Revision of the Nutrition and Supplement Facts Labels. FR page 33982" (PDF). Archived (PDF) from the original on August 8, 2016.
91. ^ "Daily Value Reference of the Dietary Supplement Label Database (DSLD)". Dietary Supplement Label Database (DSLD). Archived from the original on April 7, 2020. Retrieved May 16, 2020.
92. ^ "Changes to the Nutrition Facts Label". U.S. Food and Drug Administration (FDA). May 27, 2016. Retrieved May 16, 2020. This article incorporates text from this source, which is in the public domain .
93. ^ "Industry Resources on the Changes to the Nutrition Facts Label". U.S. Food and Drug Administration (FDA). December 21, 2018. Retrieved May 16, 2020. This article incorporates text from this source, which is in the public domain .
94. ^ REGULATION (EU) No 1169/2011 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL Official Journal of the European Union. page 304/61. (2009).
95. ^ Duarte A, Caixeirinho D, Miguel G, Sustelo V, Nunes C, Mendes M, Marreiros A (2010). "Vitamin C Content of Citrus from Conventional versus Organic Farming Systems". Acta Horticulturae. 868 (868): 389–394. doi:10.17660/ActaHortic.2010.868.52. hdl:10400.1/1158.
96. ^ "The vitamin and mineral content is stable". Danish Veterinary and Food Administration. Archived from the original on October 14, 2011. Retrieved November 20, 2014.
97. ^ "NDL/FNIC Food Composition Database Home Page". USDA Nutrient Data Laboratory, the Food and Nutrition Information Center and Information Systems Division of the National Agricultural Library. Archived from the original on November 15, 2014. Retrieved November 20, 2014.
98. ^ ^{a b} "Natural food-Fruit Vitamin C Content". The Natural Food Hub. Archived from the original on March 7, 2007. Retrieved March 7, 2007.
99. ^ ^{a b c d} "USDA National Nutrient Database for Standard Reference Legacy: Vitamin C" (PDF). U.S. Department of Agriculture, Agricultural Research Service. 2018. Retrieved September 27, 2020.
100. ^ Brand JC, Rae C, McDonnell J, Lee A, Cherikoff V, Truswell AS (1987). "The nutritional composition of Australian aboriginal bushfoods. I". Food Technology in Australia. 35 (6): 293–296.
101. ^ Justi KC, Visentainer JV, Evelázio de Souza N, Matsushita M (December 2000). "Nutritional composition and vitamin C stability in stored camu-camu (Myrciaria dubia) pulp". Archivos Latinoamericanos de Nutricion. 50 (4): 405–8. PMID 11464674.
102. ^ Vendramini AL, Trugo LC (2000). "Chemical composition of acerola fruit (Malpighia punicifolia L.) at three stages of maturity". Food Chemistry. 71 (2): 195–198. doi:10.1016/S0308-8146(00)00152-7.
103. ^ Begum RM (2008). A Textbook of Foods, Nutrition & Dietetics. Sterling Publishers Pvt. Ltd. p. 72. ISBN978-81-207-3714-3.
104. ^ Sinha N, Sidhu J, Barta J, Wu J, Cano MP (2012). Handbook of Fruits and Fruit Processing. John Wiley & Sons. ISBN978-1-118-35263-2.
105. ^ Clark S (January 8, 2007). "Comparing Milk: Human, Cow, Goat & Commercial Infant Formula". Washington State University. Archived from the original on January 29, 2007. Retrieved February 28, 2007.
106. ^ Roig MG, Rivera ZS, Kennedy JF (May 1995). "A model study on rate of degradation of L-ascorbic acid during processing using home-produced juice concentrates". International Journal of Food Sciences and Nutrition. 46 (2): 107–15. doi:10.3109/09637489509012538. PMID 7621082.
107. ^ Allen MA, Burgess SG (1950). "The losses of ascorbic acid during the large-scale cooking of green vegetables by different methods". The British Journal of Nutrition. 4 (2–3): 95–100. doi:10.1079/BJN19500024. PMID 14801407.
108. ^ ^{a b} "Safety (MSDS) data for ascorbic acid". Oxford University. October 9, 2005. Archived from the original on February 9, 2007. Retrieved February 21, 2007.
109. ^ Combs GF (2001). The Vitamins, Fundamental Aspects in Nutrition and Health (2nd ed.). San Diego, CA: Academic Press. pp. 245–272. ISBN978-0-12-183492-0.
110. ^ Davis JL, Paris HL, Beals JW, Binns SE, Giordano GR, Scalzo RL, Schweder MM, Blair E, Bell C (2016). "Liposomal-encapsulated Ascorbic Acid: Influence on Vitamin C Bioavailability and Capacity to Protect Against Ischemia-Reperfusion Injury". Nutrition and Metabolic Insights. 9: 25–30. doi:10.4137/NMI.S39764. PMC4915787. PMID 27375360.
111. ^ ^{a b} "Addition of Vitamins and Minerals to Food, 2014". Canadian Food Inspection Agency, Government of Canada. January 16, 2014. Retrieved November 20, 2017.
112. ^ Washburn C, Jensen C (2017). "Pretreatments to prevent darkening of fruits prior to canning or dehydrating". Utah State University. Retrieved January 26, 2020.
113. ^ "Ingredients". The Federation of Bakers. Retrieved April 3, 2021.
114. ^ "Frequently Asked Questions | Why Food Additives". Food Additives and Ingredients Association UK & Ireland- Making life taste better. Archived from the original on June 1, 2019. Retrieved October 27, 2010.
115. ^ ^{a b c d e} UK Food Standards Agency: "Current EU approved additives and their E Numbers". Retrieved October 27, 2011.
116. ^ ^{a b c} U.S. Food and Drug Administration: "Listing of Food Additives Status Part I". Food and Drug Administration. Archived from the original on January 17, 2012. Retrieved October 27, 2011.
117. ^ ^{a b c d e} Australia New Zealand Food Standards Code"Standard 1.2.4 – Labelling of ingredients". Retrieved October 27, 2011.
118. ^ U.S. Food and Drug Administration: "Listing of Food Additives Status Part II". Food and Drug Administration . Retrieved October 27, 2011.
119. ^ Prockop DJ, Kivirikko KI (1995). "Collagens: molecular biology, diseases, and potentials for therapy". Annual Review of Biochemistry. 64: 403–434. doi:10.1146/annurev.bi.64.070195.002155. PMID 7574488.
120. ^ Peterkofsky B (December 1991). "Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy". The American Journal of Clinical Nutrition. 54 (6 Suppl): 1135S–1140S. doi:10.1093/ajcn/54.6.1135s. PMID 1720597.
121. ^ Kivirikko KI, Myllylä R (1985). "Post-translational processing of procollagens". Annals of the New York Academy of Sciences. 460 (1): 187–201. Bibcode:1985NYASA.460..187K. doi:10.1111/j.1749-6632.1985.tb51167.x. PMID 3008623. S2CID 36467519.
122. ^ ^{a b} Ang A, Pullar JM, Currie MJ, Vissers M (2018). "Vitamin C and immune cell function in inflammation and cancer". Biochemical Society Transactions. 46 (5): 1147–1159. doi:10.1042/BST20180169. PMC6195639. PMID 30301842.
123. ^ Metzen E (2007). "Enzyme substrate recognition in oxygen sensing: how the HIF trap snaps". The Biochemical Journal. 408 (2): e5–6. doi:10.1042/BJ20071306. PMC2267343. PMID 17990984. The HIFalpha hydroxylases belong to a superfamily of dioxygenases that require the co-substrates oxygen and 2-oxoglutarate as well as the cofactors Fe2+ and ascorbate. The regulation of enzyme turnover by the concentration of the cosubstrate oxygen constitutes the interface between tissue oxygen level and the activity of HIF. The HIFalpha prolyl hydroxylases, termed PHDs/EGLNs (prolyl hydroxylase domain proteins/EGL nine homologues), bind to a conserved Leu-Xaa-Xaa-Leu-Ala-Pro motif present in all substrates identified so far.
124. ^ Levine M, Dhariwal KR, Washko P, Welch R, Wang YH, Cantilena CC, Yu R (1992). "Ascorbic acid and reaction kinetics in situ: a new approach to vitamin requirements". Journal of Nutritional Science and Vitaminology. Spec No: 169–172. doi:10.3177/jnsv.38.Special_169. PMID 1297733.
125. ^ Kaufman S (1974). "Dopamine-beta-hydroxylase". Journal of Psychiatric Research. 11: 303–316. doi:10.1016/0022-3956(74)90112-5. PMID 4461800.
126. ^ Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE (1993). "Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains". Protein Science. 2 (4): 489–497. doi:10.1002/pro.5560020401. PMC2142366. PMID 8518727.
127. ^ Eipper BA, Stoffers DA, Mains RE (1992). "The biosynthesis of neuropeptides: peptide alpha-amidation". Annual Review of Neuroscience. 15: 57–85. doi:10.1146/annurev.ne.15.030192.000421. PMID 1575450.
128. ^ Wilson JX (2005). "Regulation of vitamin C transport". Annual Review of Nutrition. 25: 105–125. doi:10.1146/annurev.nutr.25.050304.092647. PMID 16011461.
129. ^ ^{a b} Savini I, Rossi A, Pierro C, Avigliano L, Catani MV (April 2008). "SVCT1 and SVCT2: key proteins for vitamin C uptake". Amino Acids. 34 (3): 347–355. doi:10.1007/s00726-007-0555-7. PMID 17541511. S2CID 312905.
130. ^ Rumsey SC, Kwon O, Xu GW, Burant CF, Simpson I, Levine M (July 1997). "Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid". The Journal of Biological Chemistry. 272 (30): 18982–18989. doi:10.1074/jbc.272.30.18982. PMID 9228080.
131. ^ May JM, Qu ZC, Neel DR, Li X (May 2003). "Recycling of vitamin C from its oxidized forms by human endothelial cells". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1640 (2–3): 153–161. doi:10.1016/S0167-4889(03)00043-0. PMID 12729925.
132. ^ May JM, Qu ZC, Qiao H, Koury MJ (August 2007). "Maturational loss of the vitamin C transporter in erythrocytes". Biochemical and Biophysical Research Communications. 360 (1): 295–298. doi:10.1016/j.bbrc.2007.06.072. PMC1964531. PMID 17586466.
133. ^ ^{a b} Padayatty SJ, Levine M (September 2016). "Vitamin C: the known and the unknown and Goldilocks". Oral Diseases. 22 (6): 463–493. doi:10.1111/odi.12446. PMC4959991. PMID 26808119.
134. ^ Oreopoulos DG, Lindeman RD, VanderJagt DJ, Tzamaloukas AH, Bhagavan HN, Garry PJ (October 1993). "Renal excretion of ascorbic acid: effect of age and sex". Journal of the American College of Nutrition. 12 (5): 537–542. doi:10.1080/07315724.1993.10718349. PMID 8263270.
135. ^ ^{a b} Linster CL, Van Schaftingen E (January 2007). "Vitamin C. Biosynthesis, recycling and degradation in mammals". The FEBS Journal. 274 (1): 1–22. doi:10.1111/j.1742-4658.2006.05607.x. PMID 17222174. S2CID 21345196.
136. ^ "Testing Foods for Vitamin C (Ascorbic Acid)" (PDF). British Nutrition Foundation. 2004. Archived (PDF) from the original on November 23, 2015.
137. ^ "Measuring the Vitamin C content of foods and fruit juices". Nuffield Foundation. November 24, 2011. Archived from the original on July 21, 2015.
138. ^ Emadi-Konjin P, Verjee Z, Levin AV, Adeli K (May 2005). "Measurement of intracellular vitamin C levels in human lymphocytes by reverse phase high performance liquid chromatography (HPLC)". Clinical Biochemistry. 38 (5): 450–6. doi:10.1016/j.clinbiochem.2005.01.018. PMID 15820776.
139. ^ Yamada H, Yamada K, Waki M, Umegaki K (October 2004). "Lymphocyte and plasma vitamin C levels in type 2 diabetic patients with and without diabetes complications". Diabetes Care. 27 (10): 2491–2. doi:10.2337/diacare.27.10.2491. PMID 15451922.
140. ^ Branduardi P, Fossati T, Sauer M, Pagani R, Mattanovich D, Porro D (October 2007). "Biosynthesis of vitamin C by yeast leads to increased stress resistance". PLOS ONE. 2 (10): e1092. Bibcode:2007PLoSO...2.1092B. doi:10.1371/journal.pone.0001092. PMC2034532. PMID 17971855.
141. ^ Wheeler GL, Jones MA, Smirnoff N (May 1998). "The biosynthetic pathway of vitamin C in higher plants". Nature. 393 (6683): 365–9. Bibcode:1998Natur.393..365W. doi:10.1038/30728. PMID 9620799. S2CID 4421568.
142. ^ ^{a b} Stone I (1972), The Natural History of Ascorbic Acid in the Evolution of Mammals and Primates
143. ^ Bánhegyi G, Mándl J (2001). "The hepatic glycogenoreticular system". Pathology & Oncology Research. 7 (2): 107–10. CiteSeerX10.1.1.602.5659. doi:10.1007/BF03032575. PMID 11458272. S2CID 20139913.
144. ^ ^{a b c} Valpuesta V, Botella MA (2004). "Biosynthesis of L-Ascorbic Acid in Plants: New Pathways for an Old Antioxidant" (PDF). Trends in Plant Science. 9 (12): 573–577. doi:10.1016/j.tplants.2004.10.002. PMID 15564123.
145. ^ Nishikimi M, Yagi K (December 1991). "Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis". The American Journal of Clinical Nutrition. 54 (6 Suppl): 1203S–1208S. doi:10.1093/ajcn/54.6.1203s. PMID 1962571.
146. ^ Nishikimi M, Kawai T, Yagi K (October 1992). "Guinea pigs possess a highly mutated gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species". The Journal of Biological Chemistry. 267 (30): 21967–72. doi:10.1016/S0021-9258(19)36707-9. PMID 1400507.
147. ^ Ohta Y, Nishikimi M (October 1999). "Random nucleotide substitutions in primate nonfunctional gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis". Biochimica et Biophysica Acta. 1472 (1–2): 408–11. doi:10.1016/S0304-4165(99)00123-3. PMID 10572964.
148. ^ Wang S, Berge GE, Sund RB (August 2001). "Plasma ascorbic acid concentrations in healthy dogs". Res. Vet. Sci. 71 (1): 33–5. doi:10.1053/rvsc.2001.0481. PMID 11666145.
149. ^ Ranjan R, Ranjan A, Dhaliwal GS, Patra RC (2012). "l-Ascorbic acid (vitamin C) supplementation to optimize health and reproduction in cattle". Vet Q. 32 (3–4): 145–50. doi:10.1080/01652176.2012.734640. PMID 23078207. S2CID 1674389.
150. ^ Figure 2 in The Natural History of Ascorbic Acid in the Evolution of the Mammals and Primates and Its Significance for Present Day Man Stone I. Orthomolecular Psychiatry 1972;1:82-89. Archived January 30, 2017, at the Wayback Machine
151. ^ ^{a b c} Dewick PM (2009). Medicinal Natural Products: A Biosynthetic Approach (3rd ed.). John Wiley and Sons. p. 493. ISBN978-0470741672.
152. ^ Miller RE, Fowler ME (July 31, 2014). Fowler's Zoo and Wild Animal Medicine, Volume 8. p. 389. ISBN9781455773992. Archived from the original on December 7, 2016. Retrieved June 2, 2016.
153. ^ ^{a b} Martinez del Rio C (July 1997). "Can passerines synthesize vitamin C?". The Auk. 114 (3): 513–516. doi:10.2307/4089257. JSTOR 4089257.
154. ^ ^{a b} Drouin G, Godin JR, Pagé B (August 2011). "The genetics of vitamin C loss in vertebrates". Current Genomics. 12 (5): 371–8. doi:10.2174/138920211796429736. PMC3145266. PMID 22294879.
155. ^ Jenness R, Birney E, Ayaz K (1980). "Variation of l-gulonolactone oxidase activity in placental mammals". Comparative Biochemistry and Physiology B. 67 (2): 195–204. doi:10.1016/0305-0491(80)90131-5.
156. ^ Cui J, Pan YH, Zhang Y, Jones G, Zhang S (February 2011). "Progressive pseudogenization: vitamin C synthesis and its loss in bats". Molecular Biology and Evolution. 28 (2): 1025–31. doi:10.1093/molbev/msq286. PMID 21037206.
157. ^ Cui J, Yuan X, Wang L, Jones G, Zhang S (November 2011). "Recent loss of vitamin C biosynthesis ability in bats". PLOS ONE. 6 (11): e27114. Bibcode:2011PLoSO...627114C. doi:10.1371/journal.pone.0027114. PMC3206078. PMID 22069493.
158. ^ ^{a b c} Montel-Hagen A, Kinet S, Manel N, Mongellaz C, Prohaska R, Battini JL, Delaunay J, Sitbon M, Taylor N (March 2008). "Erythrocyte Glut1 triggers dehydroascorbic acid uptake in mammals unable to synthesize vitamin C". Cell. 132 (6): 1039–48. doi:10.1016/j.cell.2008.01.042. PMID 18358815. S2CID 18128118. Lay summary – Science Daily (March 21, 2008).
159. ^ Milton K (June 1999). "Nutritional characteristics of wild primate foods: do the diets of our closest living relatives have lessons for us?" (PDF). Nutrition. 15 (6): 488–98. CiteSeerX10.1.1.564.1533. doi:10.1016/S0899-9007(99)00078-7. PMID 10378206. Archived (PDF) from the original on August 10, 2017.
160. ^ Leferink NG, van den Berg WA, van Berkel WJ (February 2008). "l-Galactono-gamma-lactone dehydrogenase from Arabidopsis thaliana, a flavoprotein involved in vitamin C biosynthesis". The FEBS Journal. 275 (4): 713–26. doi:10.1111/j.1742-4658.2007.06233.x. PMID 18190525. S2CID 25096297.
161. ^ Mieda T, Yabuta Y, Rapolu M, Motoki T, Takeda T, Yoshimura K, et al. (September 2004). "Feedback inhibition of spinach L-galactose dehydrogenase by L-ascorbate". Plant & Cell Physiology. 45 (9): 1271–9. doi:10.1093/pcp/pch152. PMID 15509850.
162. ^ Grillet L, Ouerdane L, Flis P, Hoang MT, Isaure MP, Lobinski R, et al. (January 2014). "Ascorbate efflux as a new strategy for iron reduction and transport in plants". The Journal of Biological Chemistry. 289 (5): 2515–25. doi:10.1074/jbc.M113.514828. PMC3908387. PMID 24347170.
163. ^ ^{a b c} Gallie DR (2013). "L-ascorbic Acid: a multifunctional molecule supporting plant growth and development". Scientifica. 2013: 1–24. doi:10.1155/2013/795964. PMC3820358. PMID 24278786.
164. ^ ^{a b} Mellidou I, Kanellis AK (2017). "Genetic Control of Ascorbic Acid Biosynthesis and Recycling in Horticultural Crops". Frontiers in Chemistry. 5: 50. Bibcode:2017FrCh....5...50M. doi:10.3389/fchem.2017.00050. PMC5504230. PMID 28744455.
165. ^ Bulley S, Laing W (October 2016). "The regulation of ascorbate biosynthesis". Current Opinion in Plant Biology. 33: 15–22. doi:10.1016/j.pbi.2016.04.010. PMID 27179323.
166. ^ Lachapelle MY, Drouin G (February 2011). "Inactivation dates of the human and guinea pig vitamin C genes". Genetica. 139 (2): 199–207. doi:10.1007/s10709-010-9537-x. PMID 21140195. S2CID 7747147.
167. ^ Yang H (June 2013). "Conserved or lost: molecular evolution of the key gene GULO in vertebrate vitamin C biosynthesis". Biochemical Genetics. 51 (5–6): 413–25. doi:10.1007/s10528-013-9574-0. PMID 23404229. S2CID 14393449.
168. ^ Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M (2010). "Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates". Genome Biology. 11 (3): R26. doi:10.1186/gb-2010-11-3-r26. PMC2864566. PMID 20210993.
169. ^ Koshizaka T, Nishikimi M, Ozawa T, Yagi K (February 1988). "Isolation and sequence analysis of a complementary DNA encoding rat liver L-gulono-gamma-lactone oxidase, a key enzyme for L-ascorbic acid biosynthesis". The Journal of Biological Chemistry. 263 (4): 1619–21. doi:10.1016/S0021-9258(19)77923-X. PMID 3338984.
170. ^ ^{a b} Pollock JI, Mullin RJ (1987). "Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius". American Journal of Physical Anthropology. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259.
171. ^ Poux C, Douzery EJ (2004). "Primate phylogeny, evolutionary rate variations, and divergence times: a contribution from the nuclear gene IRBP". American Journal of Physical Anthropology. 124 (1): 01–16. doi:10.1002/ajpa.10322. PMID 15085543.
172. ^ Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP (1998). "Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence". Molecular Phylogenetics and Evolution. 9 (3): 585–598. doi:10.1006/mpev.1998.0495. PMID 9668008.
173. ^ Porter CA, Page SL, Czelusniak J, Schneider H, Schneider MP, Sampaio I, Goodman M (1997). "Phylogeny and Evolution of Selected Primates as Determined by Sequences of the ε-Globin Locus and 5′ Flanking Regions". International Journal of Primatology. 18 (2): 261–295. doi:10.1023/A:1026328804319. hdl:2027.42/44561. S2CID 1851788.
174. ^ Proctor P (1970). "Similar functions of uric acid and ascorbate in man?". Nature. 228 (5274): 868. Bibcode:1970Natur.228..868P. doi:10.1038/228868a0. PMID 5477017. S2CID 4146946.
175. ^ "The production of vitamin C" (PDF). Competition Commission. 2001. Archived from the original (PDF) on January 19, 2012. Retrieved February 20, 2007.
176. ^ ^{a b} Gelski J (November 6, 2017). "Vitamin C prices triple in a year's time". FoodBusiness News. Retrieved August 15, 2019.
177. ^ Koe T (August 28, 2018). "'China-free' vitamin C: Industry defends standards against 'marketing claims'". NutraIngredients-Asia.com, William Reed Business Media, Ltd. Retrieved August 15, 2019.
178. ^ Cegłowski M (March 7, 2010). "Scott and Scurvy". Archived from the original on March 10, 2010.
179. ^ As they sailed farther up the east coast of Africa, they met local traders, who traded them fresh oranges. Within six days of eating the oranges, da Gama's crew recovered fully and he noted, "It pleased God in his mercy that ... all our sick recovered their health for the air of the place is very good." Infantile Scurvy: A Historical Perspective Archived September 4, 2015, at the Wayback Machine, Kumaravel Rajakumar
180. ^ On returning, Lopes' ship had left him on St Helena, where with admirable sagacity and industry he planted vegetables and nurseries with which passing ships were marvellously sustained. [...] There were 'wild groves' of oranges, lemons and other fruits that ripened all the year round, large pomegranates and figs. Santa Helena, A Forgotten Portuguese Discovery Archived May 29, 2011, at the Wayback Machine, Harold Livermore - Estudos em Homenagem a Luis Antonio de Oliveira Ramos, Faculdade de Letras da Universidade do Porto, 2004, pp. 630-631
181. ^ John Woodall, The Surgions Mate … (London, England : Edward Griffin, 1617), p. 89. From page 89: Archived April 11, 2016, at the Wayback Machine "Succus Limonum, or juice of Lemons … [is] the most precious help that ever was discovered against the Scurvy[;] to be drunk at all times; … "
182. ^ Armstrong A (1858). "Observation on Naval Hygiene and Scurvy, more particularly as the later appeared during the Polar Voyage". British and Foreign Medico-chirurgical Review: Or, Quarterly Journal of Practical Medicine and Surgery. 22: 295–305.
183. ^ Johann Friedrich Bachstrom, Observationes circa scorbutum [Observations on scurvy] (Leiden ("Lugdunum Batavorum"), Netherlands: Conrad Wishof, 1734) p. 16. From page 16: Archived January 1, 2016, at the Wayback Machine " … sed ex nostra causa optime explicatur, quae est absentia, carentia & abstinentia a vegetabilibus recentibus, … " ( … but [this misfortune] is explained very well by our [supposed] cause, which is the absence of, lack of, and abstinence from fresh vegetables, … )
184. ^ Lamb J (February 17, 2011). "Captain Cook and the Scourge of Scurvy". British History in depth. BBC. Archived from the original on February 21, 2011.
185. ^ Lamb J (2001). Preserving the self in the south seas, 1680–1840. University of Chicago Press. p. 117. ISBN978-0-226-46849-5. Archived from the original on April 30, 2016.
186. ^ Singh S, Ernst E (2008). Trick or Treatment: The Undeniable Facts about Alternative Medicine. WW Norton & Company. pp. 15–18. ISBN978-0-393-06661-6.
187. ^ Beaglehole JH, Cook JD, Edwards PR (1999). The journals of Captain Cook. Harmondsworth [Eng.]: Penguin. ISBN978-0-14-043647-1.
188. ^ Reeve J, Stevens DA (2006). "Cook's Voyages 1768–1780". Navy and the Nation: The Influence of the Navy on Modern Australia. Allen & Unwin Academic. p. 74. ISBN978-1-74114-200-6.
189. ^ Kuhnlein HV, Receveur O, Soueida R, Egeland GM (June 2004). "Arctic indigenous peoples experience the nutrition transition with changing dietary patterns and obesity". The Journal of Nutrition. 134 (6): 1447–53. doi:10.1093/jn/134.6.1447. PMID 15173410.
190. ^ Szent-Gyoergyi A (June 1963). "Lost in the Twentieth Century". Annual Review of Biochemistry. 32 (1): 1–14. doi:10.1146/annurev.bi.32.070163.000245. PMID 14140702.
191. ^ Stacey M, Manners DJ (1978). Edmund Langley Hirst. 1898-1975. Advances in Carbohydrate Chemistry and Biochemistry. 35. pp. 1–29. doi:10.1016/S0065-2318(08)60217-6. ISBN9780120072354. PMID 356548.
192. ^ "Redoxon trademark information by Hoffman-la Roche, Inc. (1934)". Retrieved December 25, 2017.
193. ^ Wang W, Xu H (2016). "Industrial fermentation of Vitamin C". In Vandamme EJ, Revuelta JI (eds.). Industrial Biotechnology of Vitamins, Biopigments, and Antioxidants. Wiley-VCH Verlag GmbH & Co. KGaA. p. 161. ISBN9783527337347.
194. ^ Norum KR, Grav HJ (June 2002). "[Axel Holst and Theodor Frolich--pioneers in the combat of scurvy]". Tidsskrift for den Norske Laegeforening (in Norwegian). 122 (17): 1686–7. PMID 12555613.
195. ^ Rosenfeld L (April 1997). "Vitamine--vitamin. The early years of discovery". Clinical Chemistry. 43 (4): 680–5. doi:10.1093/clinchem/43.4.680. PMID 9105273.
196. ^ ^{a b} Svirbely JL, Szent-Györgyi A (1932). "The chemical nature of vitamin C". The Biochemical Journal. 26 (3): 865–70. Bibcode:1932Sci....75..357K. doi:10.1126/science.75.1944.357-a. PMC1260981. PMID 16744896.
197. ^ Juhász-Nagy S (March 2002). "[Albert Szent-Györgyi--biography of a free genius]". Orvosi Hetilap (in Hungarian). 143 (12): 611–4. PMID 11963399.
198. ^ Kenéz J (December 1973). "[Eventful life of a scientist. 80th birthday of Nobel prize winner Albert Szent-Györgyi]". Munchener Medizinische Wochenschrift (in German). 115 (51): 2324–6. PMID 4589872.
199. ^ Szállási A (December 1974). "[2 interesting early articles by Albert Szent-Györgyi]". Orvosi Hetilap (in Hungarian). 115 (52): 3118–9. PMID 4612454.
200. ^ ^{a b} "The Albert Szent-Gyorgyi Papers: Szeged, 1931-1947: Vitamin C, Muscles, and WWII". Profiles in Science. United States National Library of Medicine. Archived from the original on May 5, 2009.
201. ^ "Scurvy". Online Entymology Dictionary. Retrieved November 19, 2017.
202. ^ "The Nobel Prize in Physiology or Medicine 1937". Nobel Media AB. Archived from the original on November 5, 2014. Retrieved November 20, 2014.
203. ^ Burns JJ, Evans C (December 1956). "The synthesis of L-ascorbic acid in the rat from D-glucuronolactone and L-gulonolactone". The Journal of Biological Chemistry. 223 (2): 897–905. doi:10.1016/S0021-9258(18)65088-4. PMID 13385237. ^{[ permanent dead link ]}
204. ^ Burns JJ, Moltz A, Peyser P (December 1956). "Missing step in guinea pigs required for the biosynthesis of L-ascorbic acid". Science. 124 (3232): 1148–9. Bibcode:1956Sci...124.1148B. doi:10.1126/science.124.3232.1148-a. PMID 13380431.
205. ^ Henson DE, Block G, Levine M (April 1991). "Ascorbic acid: biologic functions and relation to cancer". Journal of the National Cancer Institute. 83 (8): 547–50. doi:10.1093/jnci/83.8.547. PMID 1672383.
206. ^ Pauling L (December 1970). "Evolution and the need for ascorbic acid". Proceedings of the National Academy of Sciences of the United States of America. 67 (4): 1643–8. Bibcode:1970PNAS...67.1643P. doi:10.1073/pnas.67.4.1643. PMC283405. PMID 5275366.
207. ^ Mandl J, Szarka A, Bánhegyi G (August 2009). "Vitamin C: update on physiology and pharmacology". British Journal of Pharmacology. 157 (7): 1097–110. doi:10.1111/j.1476-5381.2009.00282.x. PMC2743829. PMID 19508394.
208. ^ Cameron E, Pauling L (October 1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proceedings of the National Academy of Sciences of the United States of America. 73 (10): 3685–9. Bibcode:1976PNAS...73.3685C. doi:10.1073/pnas.73.10.3685. PMC431183. PMID 1068480.
209. ^ "Vitamin C: Common cold". Corvallis, OR: Micronutrient Information Center, Linus Pauling Institute, Oregon State University. January 14, 2014. Retrieved May 3, 2017.
210. ^ Hemilä H (2009). "Vitamins and minerals". Commond Cold. pp. 275–307. doi:10.1007/978-3-7643-9912-2_13. hdl:10138/228060. ISBN978-3-7643-9894-1.
211. ^ Stephens T (February 17, 2011). "Let the chemical games begin!". Swiss Info. Swiss Broadcasting Corporation. Archived from the original on August 31, 2011. Retrieved February 23, 2011.
212. ^ "Ascorbic Acid Uses". Drugs.com. November 11, 2019. Retrieved October 12, 2020.
213. ^ British Pharmacopoeia Commission Secretariat (2009). "Index, BP 2009" (PDF). Archived from the original (PDF) on April 11, 2009. Retrieved February 4, 2010.
214. ^ "Japanese Pharmacopoeia, Fifteenth Edition" (PDF). 2006. Archived from the original (PDF) on July 22, 2011. Retrieved February 4, 2010.

External links [edit]

Look up vitamin C in Wiktionary, the free dictionary.

Look up vitamin c in Wiktionary, the free dictionary.

• "Vitamin C Fact Sheet". U.S. National Institutes of Health.
• "Ascorbic acid". Drug Information Portal. U.S. National Library of Medicine.

Kreb C Vitamins

Source: https://en.wikipedia.org/wiki/Vitamin_C