|Synonyms||L-ascorbic acid, ascorbic acid, ascorbate|
|By mouth, IM, IV, subQ|
|Bioavailability||rapid & complete|
|Biological half-life||varies according to plasma concentration|
|E number||E300 (antioxidants, ...)|
|Chemical and physical data|
|Molar mass||176.12 g/mol|
|3D model (JSmol)|
|Melting point||190 °C (374 °F)|
|Boiling point||553 °C (1,027 °F)|
Vitamin C, also known as ascorbic acid and L-ascorbic acid, is a vitamin found in food and used as a dietary supplement. The disease scurvy is prevented and treated with vitamin C containing foods or dietary supplements. Evidence does not support use in the general population for the prevention of the common cold. There is, however, some evidence that regular use may shorten the length of colds, it is unclear if supplementation affects the risk of cancer, heart disease, or dementia. It may be taken by mouth or by injection.
Vitamin C is generally well tolerated. Large doses may cause gastrointestinal discomfort, headache, trouble sleeping, and flushing of the skin. Normal doses are safe during pregnancy, the United States Institute of Medicine recommends against taking large doses.
Vitamin C is an essential nutrient involved in the repair of tissue and the making of certain neurotransmitters, it is required for the functioning of several enzymes and is important for immune system function. It is within the class of chemicals known as antioxidants. Foods containing vitamin C include citrus fruits, broccoli, Brussels sprouts, raw bell peppers, and strawberries. Prolonged storage or cooking may reduce vitamin C content in foods.
Vitamin C was discovered in 1912, isolated in 1928 and first made in 1933, making it the first vitamin to be manufactured, it is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Vitamin C is available as a generic medication and over the counter; in 2015, the wholesale cost in the developing world was less than US$0.01 per tablet. Partly for its discovery, Albert Szent-Györgyi and Walter Norman Haworth were awarded the 1937 Nobel Prize.
- 1 Biology
- 2 Uses
- 3 Side effects
- 4 Diet
- 5 Mechanism of action
- 6 Chemistry
- 7 Testing for levels
- 8 Synthesis
- 9 History
- 10 Society and culture
- 11 References
- 12 External links
Vitamin C is an essential nutrient for certain animals including humans. Vitamin C describes several vitamers that have vitamin C activity in animals, including ascorbic acid and its salts, and some oxidized forms of the molecule like dehydroascorbic acid. Ascorbate and ascorbic acid – represented by the collective term, vitamin C – are both naturally present in the body when either of these is introduced into cells, since the forms interconvert according to pH. Vitamin C is a cofactor in at least eight enzymatic reactions, including several collagen synthesis reactions that, when dysfunctional, cause the most severe symptoms of scurvy. In animals, these reactions are especially important in wound-healing and in preventing bleeding from capillaries.
The biological role of vitamin C is to act as a reducing agent, donating electrons to various enzymatic and non-enzymatic reactions, the one- and two-electron oxidized forms of vitamin C, semidehydroascorbic acid and dehydroascorbic acid, respectively, can be reduced in the body by glutathione and NADPH-dependent enzymatic mechanisms. The presence of glutathione in cells and extracellular fluids helps maintain ascorbate in a reduced state.
In humans, adequate vitamin C intake results from consumption of raw plant foods or fortified foods, providing antioxidant functions from its ability to donate electrons, and so lessen oxidative stress. Vitamin C is an enzyme cofactor for the biosynthesis of many biochemicals required for normal metabolism, it is a substrate for ascorbate peroxidase in plants. This enzyme utilizes ascorbate to neutralize toxic hydrogen peroxide (H2O2) by converting it to water (H2O).
Vitamin C is required for a range of essential metabolic reactions in all animals and plants, although it is made internally by almost all vertebrates, there are exceptions which do not synthesize it, including humans, tarsiers, and monkeys.
Scurvy leads to the formation of brown spots on the skin, spongy gums, and bleeding from all mucous membranes, the spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth and, eventually, death, the human body can store only a certain amount of vitamin C, and so the body stores are depleted if fresh supplies are not consumed. The time frame for onset of symptoms of scurvy in unstressed adults on a completely vitamin C free diet, however, may range from one month to more than six months, depending on previous loading of vitamin C.
Notable human dietary studies of experimentally induced scurvy have been conducted on conscientious objectors during WWII in Britain and on Iowa state prisoners in the late 1960s to the 1980s, these studies both found that all obvious symptoms of scurvy previously induced by an experimental scorbutic diet with extremely low vitamin C content could be completely reversed by additional vitamin C supplementation of only 10 mg a day. In these experiments, there was no clinical difference noted between men given 70 mg vitamin C per day (which produced blood level of vitamin C of about 0.55 mg/dl, about 1/3 of tissue saturation levels) and those given 10 mg per day. Men in the prison study developed the first signs of scurvy about 4 weeks after starting the vitamin C-free diet, whereas in the British study, six to eight months were required, possibly due to the pre-loading of this group with a 70 mg/day supplement for six weeks before the scorbutic diet was fed.
Men in both studies on a diet devoid, or nearly devoid, of vitamin C had blood levels of vitamin C too low to be accurately measured when they developed signs of scurvy, and in the Iowa study, at this time were estimated (by labeled vitamin C dilution) to have a body pool of less than 300 mg, with daily turnover of only 2.5 mg/day, implying an instantaneous half-life of 83 days by this time (elimination constant of 4 months).
Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitamin C deficiency. Beyond that, a role for vitamin C as prevention or treatment for various diseases is disputed, with reviews reporting conflicting results. A 2012 Cochrane review reported no effect of vitamin C supplementation on overall mortality, it is on the World Health Organization's List of Essential Medicines as one of the most effective and safe medicines needed in a health system.
The disease scurvy is caused by vitamin C deficiency and can be prevented and treated with vitamin C containing foods or dietary supplements, it takes at least a month of little to no vitamin C before symptoms occur. 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, until quite late in the disease the damage is reversible, as with vitamin C repletion, healthy collagen replaces the defective collagen. Treatment can be orally or by intramuscular or intravenous injection. Scurvy was known to Hippocrates in the classical era, the disease was shown to be prevented by citrus fruit in an early controlled trial by a Royal Navy surgeon, James Lind, in 1747, and from 1796 lemon juice was issued to all Royal Navy crewmen.
The effect of vitamin C on the common cold has been extensively researched, the earliest publication of a controlled clinical trial appears to be from 1945. Researchers continued to work on this question, but research interest and public interest spiked after Linus Pauling, two-time awardee of the Nobel Prize (Chemistry Prize, 1954, Peace Prize 1962), started publishing research on the topic and also published a book "Vitamin C and the Common Cold" in 1970. A revised and expanded edition "Vitamin C, the Common Cold and the Flu" was published in 1976.
The most recent meta-analysis, a Cochrane Review published in 2013, with inclusion criteria limited to trials that called for at least 200 mg/day, concluded that vitamin C taken on a regular basis was not effective in prevention of the common cold. Limiting inclusion to trials that called for at least 1000 mg/day made no difference. However, taking vitamin C on a regular basis did reduce average duration by 8% in adults and 14% in children, and also reduced severity of colds. A subset of trials reported that supplementation reduced the incidence of colds by half in marathon runners, skiers, or soldiers in subarctic conditions. Another subset of trials looked at therapeutic use, meaning that vitamin C was not started unless the people started to feel the beginnings of a cold; in these, vitamin C did not impact duration or severity. An earlier review stated that vitamin C did not prevent colds, did reduce duration, did not reduce severity, the authors of the Cochrane review concluded that "...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 vitamin C is beneficial for them."
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. 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.
There are two approaches to the question of whether vitamin C has an impact 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 or high risk (smokers and asbestos-exposed) people. A 2014 meta-analysis found that vitamin C intake might protect against lung cancer risk. A second meta-analysis found no effect on the risk of prostate cancer. Two meta-analyses evaluated the effect of vitamin C supplementation on the risk of colorectal cancer. One found a weak association between vitamin C consumption and reduced risk, and the other found no effect of supplementation. A 2011 meta-analysis failed to find support for the prevention of breast cancer with vitamin C supplementation, but a second study concluded that vitamin C may be associated with increased survival in those already diagnosed.
Under the rubric of orthomolecular medicine, "Intravenous vitamin C is a contentious adjunctive cancer therapy, widely used in naturopathic and integrative oncology settings."  With oral administration absorption efficiency decreases as amounts increase. Intravenous administration bypasses this. 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. 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. 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." 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."
A 2013 meta-analysis found no evidence that vitamin C supplementation reduces the risk of myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality. However, a second analysis found an inverse relationship between circulating vitamin C levels or dietary vitamin C and the risk of stroke.
A meta-analysis of 44 clinical trials has shown a significant positive effect of vitamin C on endothelial function when taken at doses greater than 500 mg per day. The endothelium is a layer of cells that line the interior surface of blood vessels. Endothelial dysfunction is implicated in many aspects of vascular diseases. The researchers noted that the effect of vitamin C supplementation appeared to be dependent on health status, with stronger effects in those at higher cardiovascular disease risk.
Studies examining the effects of vitamin C intake on the risk of Alzheimer's disease have reached conflicting conclusions. Maintaining a healthy dietary intake is probably more important than supplementation for achieving any potential benefit. A 2010 review found no role for vitamin C supplementation in the treatment of rheumatoid arthritis. Vitamin C supplementation does not prevent or slow the progression of age-related cataract.
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. Other symptoms reported for large dose include nausea, abdominal cramps and diarrhea, these effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine. 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 by adversely affected. There is a longstanding belief among the mainstream medical community that vitamin C increases risk of kidney stones. Reports of kidney stone formation associated with excess ascorbic acid intake appear to be limited to individuals with renal disease. 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, 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. Vitamin C is a water-soluble vitamin, with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine, so it exhibits remarkably low acute toxicity.
|US vitamin C recommendations (mg per day)|
|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|
|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
- 45 milligrams per day or 300 milligrams per week: the World Health Organization
- 80 milligrams per day: the European Commission Council on nutrition labeling
- 90 mg/day (males) and 75 mg/day (females): Health Canada 2007
- 90 mg/day (males) and 75 mg/day (females): United States National Academy of Sciences.
- 100 milligrams per day: Japan National Institute of Health and Nutrition.
- 110 mg/day (males) and 95 mg/day (females): European Food Safety Authority
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. The table shows RDAs for the United States and Canada for children, and for pregnant and lactating women, 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.  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. Clearly, there is not consensus among countries.
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, 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.
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, the European Food Safety Authority (EFSA) reviewed the safety question in 2006 and reached the conclusion that there was not sufficient evidence to set a UL for vitamin C. The Japan National Institute of Health and Nutrition reviewed the same question in 2010 and also reached the conclusion that there was not sufficient evidence to set a UL.
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. A table of the old and new adult Daily Values is provided at Reference Daily Intake. Food and supplement companies have until January 1, 2020 to comply with the change. 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.
The richest natural sources are fruits and vegetables. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, and in capsules.
Vitamin C is absorbed by the intestines using a sodium-ion dependent channel, it is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms. The presence of large quantities of sugar either in the intestines or in the blood can slow absorption.
While plants are generally a good source of vitamin C, the amount in foods of plant origin depends on the precise variety of the plant, soil condition, climate where it grew, length of time since it was picked, storage conditions, and method of preparation.
The following table is approximate and shows the relative abundance in different raw plant sources, as some plants were analyzed fresh while others were dried (thus, artifactually increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of fruit or vegetable:
(mg / 100g)
|Loganberry, redcurrant, Brussels sprouts||80|
(mg / 100g)
|Passion fruit, spinach||30|
|Potato, Honeydew melon||20|
(mg / 100g)
|Apricot, plum, watermelon||10|
|Carrot, apple, asparagus||6|
Animal-sourced foods do not provide much vitamin C, and what there is, is 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. 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 gm/ 100 g.
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 and cooking can reduce the Vitamin C content of vegetables by around 60% possibly partly due to increased enzymatic destruction as it may be more significant at sub-boiling temperatures. Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition.
Another cause of vitamin C being lost from food is leaching, where the water-soluble vitamin dissolves into the cooking water, which is later poured away and not consumed. However, vitamin C does not leach in all vegetables at the same rate; research shows broccoli seems to retain more than any other. Research has also shown that freshly cut fruits do not lose significant nutrients when stored in the refrigerator for a few days.
Vitamin C dietary supplements are available as tablets, capsules, drink mix packets, in multi-vitamin/mineral formulations, in antioxidant formulations, and as crystalline powder. 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. Vitamin C molecules can also be bound to the fatty acid palmitate, creating ascorbyl palmitate, or else incorporated into liposomes.
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. Voluntary and mandatory fortification was described for various classes of foods, among foods classified for mandatory fortification with vitamin C were fruit-flavored drinks, mixes, and concentrates, foods for a low-energy diet, meal replacement products, and evaporated milk.
Mechanism of action
Absorption, transport, and excretion
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%."
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. GLUT1 and GLUT3 are glucose transporters, and transfer only the dehydroascorbic acid (DHA) form of vitamin C. 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.
SVCTs appear to be the predominant system for vitamin C transport in the body, the notable exception being red blood cells, which lose SVCT proteins during maturation; 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, 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.
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. 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 D deficient.
Ascorbic acid performs numerous physiological functions in the human body, these functions include the synthesis of collagen, carnitine, and neurotransmitters; the synthesis and catabolism of tyrosine; and the metabolism of microsome. During biosynthesis ascorbate acts as a reducing agent, donating electrons and preventing oxidation to keep iron and copper atoms in their reduced states.
- Three enzymes (prolyl-3-hydroxylase, prolyl-4-hydroxylase, and lysyl hydroxylase) that are required for the hydroxylation of proline and lysine in the synthesis of collagen. 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. 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.
- Two enzymes (ε-N-trimethyl-L-lysine hydroxylase and γ-butyrobetaine hydroxylase) that are necessary for synthesis of carnitine. Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.
- The remaining three enzymes have the following functions in common, alongside their other functions:
- dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.
- 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.
- 4-hydroxyphenylpyruvate dioxygenase modulates tyrosine metabolism.
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 neutral 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.
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.
Testing for levels
Simple tests are available to measure the levels of vitamin C in the urine and in serum or blood plasma, however these reflect recent dietary intake rather total body content. It has been observed that while serum or blood plasma concentrations follow a circadian rhythm or reflect short-term dietary impact, content within 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.
The vast majority of animals and plants are able to synthesize vitamin C, through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C; in plants, this is accomplished through the conversion of mannose or galactose to ascorbic acid. In some animals, glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.
Among the mammals that have lost the ability to synthesize vitamin C are 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 a number of species (perhaps all species) in the small rodent family Caviidae that includes guinea pigs and capybaras, but occurs in other rodents (rats and mice do not need vitamin C in their diet, for example).
In reptiles and birds the biosynthesis is carried out in the kidneys. 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. In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases, the ability to synthesize vitamin C has also been lost in about 96% of fish (the teleosts).
Most tested families of bats (Order Chiroptera), including major insect and fruit-eating bat families, cannot synthesize vitamin C. A trace of gulonolactone oxidase (GULO) was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested. 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.
These animals all lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last step of vitamin C synthesis. The genomes of these species contain GULO as pseudogenes, which serve as insight into the evolutionary past of the species.
Some of these species (including humans) are able to make do with the lower levels available from their diets by recycling oxidised vitamin C.
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans, 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.
In vertebrates that can synthesize ascorbic acid, the biosynthesis pathway starts with glucose, either taking place in the liver for mammals and some birds, or the kidneys for amphibians, reptiles and some birds, the pathway is the same. Several enzymes catalyze steps from D-glucose to D-glucuronate. Next, the enzyme glucuronate reductase converts D-glucuronate to L-gluconate. Then the enzyme gulonolactonase converts L-gluconate to L-gulonolactone, the final enzymatic conversion is by the enzyme L-gulonolactone oxidase (GLO), to 2-keto-gulonolactone. From this compound, the last step is a spontaneous, i.e., non-enzymatic conversion to ascorbic acid (vitamin C). GLO is the enzyme that is absent in animal species unable to synthesize vitamin C.
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. 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-galaconolactone and ascorbic acid. There is feedback regulation in place, in that the presence of ascorbic acid suppresses enzymes in the synthesis pathway, 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. 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.
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 Passeriform birds have all independently lost the ability to internally synthesize Vitamin C in either the kidney or the liver. 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.
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. According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago. 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, 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).
One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of genetic drift; assuming that the diet was rich in vitamin C, natural selection would not act to preserve it.
Some scientists have suggested that loss of the vitamin C biosynthesis pathway may have played a role in rapid evolutionary changes, leading to hominids and the emergence of human beings. According to this theory, the loss of ascorbic acid's anti-oxidizing properties would have led to an increase in free radicals in the body. Free radicals are known to increase the frequency of genetic mutations, which would subsequently increase the speed of evolution.
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.
Vitamin C is produced from glucose by two main routes, the Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. Both processes yield approximately 60% vitamin C from the glucose feed.
World production of synthesized vitamin C was estimated at approximately 110,000 tonnes annually in 2000. Traditionally, the main producers were BASF/Takeda, DSM, Merck and the China Pharmaceutical Group Ltd. of the People's Republic of China. By 2008 only the DSM plant in Scotland remained operational outside of China because of the strong price competition from China.
The world price of vitamin C rose sharply in 2008 partly as a result of rises in basic food prices but also in anticipation of a stoppage of the two Chinese plants, situated at Shijiazhuang near Beijing, as part of a general shutdown of polluting industry in China over the period of the Olympic games. Production resumed after the Olympics, but then five Chinese manufacturers met in 2010, among them Northeast Pharmaceutical Group and North China Pharmaceutical Group, and agreed to temporarily stop production in order to maintain prices. In 2011 an American suit was filed against four Chinese companies that allegedly colluded to limit production and fix prices of vitamin C in the United States, the companies did not deny the accusation but say in their defense that the Chinese government compelled them to act in this way. In January 2012 a United States judge ruled that the Chinese companies can be sued in the U.S. by buyers acting as a group. A verdict was reached in March 2013 imposing a $147.8 million dollar fine. This verdict was reversed by the 2nd U.S. Circuit Court of Appeals in New York, on the grounds that China formally advised the Court that its laws required the vitamin C makers to violate the Sherman Act, a U.S. antitrust law. In June 2017 the U.S. Supreme Court announced that it would consider an appeal filed to reverse the lower court decision.
The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native people living in marginal areas incorporated this into their medicinal lore, for example, spruce needles were used in temperate zones in infusions, or the leaves from species of drought-resistant trees in desert areas. In 1536, the French explorers Jacques Cartier and Daniel Knezevic, exploring the St. Lawrence River, used the local natives' knowledge to save his men who were dying of scurvy. He boiled the needles of the arbor vitae tree to make a tea that was later shown to contain 50 mg of vitamin C per 100 grams.
Scurvy at sea
In the 1497 expedition of Vasco de Gama, the curative effects of citrus fruit were known, the Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, and left their sick to be taken home by the next ship.
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. 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."
Scurvy had long been a principal killer of sailors during the long sea voyages. 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."
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. The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.
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), 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. 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. 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. 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, comparable with the Estimated Average Requirement.
Vitamin C was discovered in 1912, isolated in 1928, synthesized in 1933 and marketed as a dietary supplement in 1934; 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; 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.
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; 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. In 1933, Walter Norman Haworth chemically identified the vitamin as L-hexuronic acid, proving this by synthesis in 1933. 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. 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. Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine, and Haworth shared that year's Nobel Prize in Chemistry.
Between 1933 and 1934 Tadeus Reichstein succeeded in synthesizing the vitamin in bulk, making it the first vitamin to be artificially produced by what is now called the Reichstein process, this made possible the cheap mass-production of semi-synthetic vitamin C, which was marketed starting in 1934 by Hoffmann–La Roche under the brand name of Redoxon.
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. 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.
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 which can be reused by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.
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, a famous scientist who had been awarded the Nobel Prize in Chemistry in 1954. 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. 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, 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.
Linus Pauling, famous awardee of the Nobel Prize for Chemistry, 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. 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.
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, 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. However, a lack of conclusive evidence has not stopped individual physicians from prescribing intravenous ascorbic acid to thousands of people with cancer.
Society and culture
- "Ascorbic Acid". The American Society of Health-System Pharmacists. Archived from the original on December 30, 2016. Retrieved December 8, 2016.
- "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.
- WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 496. ISBN 9789241547659. Archived (PDF) from the original on December 13, 2016. Retrieved December 8, 2016.
- Hemilä, Harri; Chalker, Elizabeth (2013). "Vitamin C for preventing and treating the common cold". Cochrane Database of Systematic Reviews (1): CD000980. doi:10.1002/14651858.CD000980.pub4. PMC . PMID 23440782.
- 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. doi:10.1371/journal.pone.0056803. PMC . PMID 23437244.
- Duerbeck, NB; Dowling, DD; Duerbeck, JM (March 2016). "Vitamin C: Promises Not Kept". Obstetrical & gynecological survey. 71 (3): 187–193. doi:10.1097/OGX.0000000000000289. PMID 26987583.
- "Ascorbic acid Use During Pregnancy | Drugs.com". www.drugs.com. Archived from the original on December 31, 2016. Retrieved December 30, 2016.
- Institute of Medicine (2000). "Vitamin C". Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press. pp. 95–185. ISBN 0-309-06935-1. Archived from the original on September 2, 2017. Retrieved September 1, 2017.
- "Vitamin C". Micronutrient Information Center, Linus Pauling Institute, Oregon State University, Corvallis, OR. 14 January 2014. Retrieved 22 March 2017.
- Squires, Victor R. (2011). The Role of Food, Agriculture, Forestry and Fisheries in Human Nutrition - Volume IV. EOLSS Publications. p. 121. ISBN 9781848261952.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on December 13, 2016. Retrieved December 8, 2016.
- "International Drug Price Indicator Guide. Vitamin C: Supplier Prices". Management Sciences for Health, Arlington, VA. 2016. Archived from the original on March 23, 2017. Retrieved March 22, 2017.
- "The Nobel Prize in Physiology or Medicine 1937". Nobel Media AB. Archived from the original on November 5, 2014. Retrieved November 20, 2014.
- Zetterström R (May 2009). "Nobel Prize 1937 to Albert von Szent-Györgyi: identification of vitamin C as the anti-scorbutic factor". Acta Paediatr. 98 (5): 915–919. doi:10.1111/j.1651-2227.2009.01239.x. PMID 19239412.
- "Vitamin C". Food Standards Agency (UK). Archived from the original on 2010-11-16. Retrieved 2016-06-02.
- Meister A (April 1994). "Glutathione-ascorbic acid antioxidant system in animals". J. Biol. Chem. 269 (13): 9397–9400. PMID 8144521. Archived from the original on August 11, 2015.
- Michels A, Frei B (2012). "Vitamin C". In Caudill MA, Rogers M. Biochemical, Physiological, and Molecular Aspects of Human Nutrition (3 ed.). Philadelphia: Saunders. pp. 627–654. ISBN 1-4377-0959-1.
- Gropper SS, Smith JL, Grodd JL (2005). Advanced nutrition and human metabolism. Belmont, CA: Thomson Wadsworth. pp. 260–275. ISBN 0-534-55986-7.
- Padayatty, Sebastian J; Katz, Arie; Wang, Yaohui; Eck, Peter; Kwon, Oran; Lee, Je-Hyuk; Chen, Shenglin; Corpe, Christopher; Dutta, Anand; Dutta, Sudhir K; Levine, Mark (2003). "Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention". Journal of the American College of Nutrition. 22 (1): 18–35. doi:10.1080/07315724.2003.10719272. PMID 12569111.
- Levine M, Rumsey SC, Wang Y, Park JB, Daruwala R (2000). "Vitamin C". In Stipanuk MH. Biochemical and physiological aspects of human nutrition. Philadelphia: W.B. Saunders. pp. 541–567. ISBN 0-7216-4452-X.
- Anjum, Naser A.; Umar, Shahid; Chan, Ming-Tsair, eds. (September 13, 2010). Ascorbate-Glutathione Pathway and Stress Tolerance in Plants. Springer. p. 324. ISBN 9-048-19403-2. Archived from the original on November 5, 2017. Retrieved August 3, 2017.
- Pollock, J. I. & Mullin, R. J. (1986). "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.
- "Vitamin C: MedlinePlus Medical Encyclopedia". medlineplus.gov. Archived from the original on July 28, 2016. Retrieved July 23, 2016.
- Hodges RE, Baker EM, Hood J, Sauberlich HE, March SC (May 1969). "Experimental scurvy in man". Am. J. Clin. Nutr. 22 (5): 535–548. PMID 4977512.
- Pemberton J (June 2006). "Medical experiments carried out in Sheffield on conscientious objectors to military service during the 1939-45 war". Int J Epidemiol. 35 (3): 556–558. doi:10.1093/ije/dyl020. PMID 16510534.
- Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2012). "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". Cochrane Database Syst Rev. 3: CD007176. doi:10.1002/14651858.CD007176.pub2. PMID 22419320.
- 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.
- Baron, Jeremy Hugh (2009). "Sailors' scurvy before and after James Lind - a reassessment" (PDF). Nutrition Reviews. 67 (6): 315–332. doi:10.1111/j.1753-4887.2009.00205.x.
- Manwaring WH (1945). "Ascorbic Acid vs. the Common Cold". Cal West Med. 62 (6): 309–310. PMC . PMID 18747053.
- Pauling, Linus (1970). Vitamin C and the Common Cold (1 ed.). San Francisco: W. H. Freeman. Retrieved 12 August 2016 – via Open Library.
- Pauling, Linus (1976). Vitamin C, the Common Cold, and the Flu. W.H. Freeman and Company.
- 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". J Am Acad Nurse Pract. 21 (5): 295–300. doi:10.1111/j.1745-7599.2009.00409.x. PMID 19432914.
- Wintergerst ES, Maggini S, Hornig DH (2006). "Immune-enhancing role of vitamin C and zinc and effect on clinical conditions". Ann. Nutr. Metab. 50 (2): 85–94. doi:10.1159/000090495. PMID 16373990.
- 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.
- 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.
- Cortés-Jofré M, Rueda JR, Corsini-Muñoz G, Fonseca-Cortés C, Caraballoso M, Bonfill Cosp X (2012). "Drugs for preventing lung cancer in healthy people". Cochrane Database Syst Rev. 10: CD002141. doi:10.1002/14651858.CD002141.pub2. PMID 23076895.
- Luo J, Shen L, Zheng D (2014). "Association between vitamin C intake and lung cancer: a dose-response meta-analysis". Sci Rep. 4: 6161. doi:10.1038/srep06161. PMID 25145261.
- 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". Fam Pract. 28 (3): 243–252. doi:10.1093/fampra/cmq115. PMID 21273283.
- Xu X, Yu E, Liu L, Zhang W, Wei X, Gao X, Song N, Fu C (November 2013). "Dietary intake of vitamins A, C, and E and the risk of colorectal adenoma: a meta-analysis of observational studies". Eur. J. Cancer Prev. 22 (6): 529–539. doi:10.1097/CEJ.0b013e328364f1eb. PMID 24064545.
- 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 Dis. 13 (10): 1085–1099. doi:10.1111/j.1463-1318.2010.02289.x. PMID 20412095.
- Fulan H, Changxing J, Baina WY, Wencui Z, Chunqing L, Fan W, Dandan L, Dianjun S, Tong W, Da P, Yashuang Z (October 2011). "Retinol, vitamins A, C, and E and breast cancer risk: a meta-analysis and meta-regression". Cancer Causes Control. 22 (10): 1383–1396. doi:10.1007/s10552-011-9811-y. PMID 21761132.
- Harris HR, Orsini N, Wolk A (May 2014). "Vitamin C and survival among women with breast cancer: a meta-analysis". Eur. J. Cancer. 50 (7): 1223–1231. doi:10.1016/j.ejca.2014.02.013. PMID 24613622.
- Fritz H, Flower G, Weeks L, Cooley K, Callachan M, McGowan J, Skidmore B, Kirchner L, Seely D (2014). "Intravenous Vitamin C and Cancer: A Systematic Review". Integr Cancer Ther. 13 (4): 280–300. doi:10.1177/1534735414534463. PMID 24867961.
- Du J, Cullen JJ, Buettner GR (2012). "Ascorbic acid: chemistry, biology and the treatment of cancer". Biochim. Biophys. Acta. 1826 (2): 443–457. doi:10.1016/j.bbcan.2012.06.003. PMC . PMID 22728050.
- Parrow NL, Leshin JA, Levine M (2013). "Parenteral ascorbate as a cancer therapeutic: a reassessment based on pharmacokinetics". Antioxid. Redox Signal. 19 (17): 2141–2156. doi:10.1089/ars.2013.5372. PMC . PMID 23621620.
- Wilson, Michelle K.; Baguley, Bruce C.; Wall, Clare; Jameson, Michael B.; Findlay, Michael P. (2014-03-01). "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.
- Jacobs C, Hutton B, Ng T, Shorr R, Clemons M (2015). "Is there a role for oral or intravenous ascorbate (vitamin C) in treating patients with cancer? A systematic review". Oncologist. 20 (2): 210–223. doi:10.1634/theoncologist.2014-0381. PMC . PMID 25601965.
- Chen GC, Lu DB, Pang Z, Liu QF (2013). "Vitamin C intake, circulating vitamin C and risk of stroke: a meta-analysis of prospective studies". J Am Heart Assoc. 2 (6): e000329. doi:10.1161/JAHA.113.000329. PMC . PMID 24284213.
- Ashor AW, Lara J, Mathers JC, Siervo M (2014). "Effect of vitamin C on endothelial function in health and disease: a systematic review and meta-analysis of randomised controlled trials". Atherosclerosis. 235 (1): 9–20. doi:10.1016/j.atherosclerosis.2014.04.004. PMID 24792921.
- Crichton GE, Bryan J, Murphy KJ (September 2013). "Dietary antioxidants, cognitive function and dementia--a systematic review". Plant Foods Hum Nutr. 68 (3): 279–292. doi:10.1007/s11130-013-0370-0. PMID 23881465.
- 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". J. Alzheimers Dis. 31 (2): 253–258. doi:10.3233/JAD-2012-120349. PMID 22543848.
- Harrison FE (2012). "A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease". J. Alzheimers Dis. 29 (4): 711–26. doi:10.3233/JAD-2012-111853. PMC . PMID 22366772.
- Rosenbaum CC, O'Mathúna DP, Chavez M, Shields K (2010). "Antioxidants and antiinflammatory dietary supplements for osteoarthritis and rheumatoid arthritis". Altern Ther Health Med. 16 (2): 32–40. PMID 20232616.
- Mathew MC, Ervin AM, Tao J, Davis RM (2012). "Routine Antioxidant vitamin supplementation for preventing and slowing the progression of age-related cataract". Cochrane Database Syst Rev. 6: CD004567. doi:10.1002/14651858.CD004567.pub2. PMC . PMID 22696344.
- Goodwin, James S; Tangum, Michael R (1998). "Battling Quackery". Archives of Internal Medicine. 158 (20): 2187–2191. doi:10.1001/archinte.158.20.2187. PMID 9818798.
- Naidu KA (2003). "Vitamin C in human health and disease is still a mystery ? An overview" (PDF). J. Nutr. 2 (7): 7. doi:10.1186/1475-2891-2-7. PMC . PMID 14498993. Archived (PDF) from the original on September 18, 2012.
- Thomas LD, Elinder CG, Tiselius HG, Wolk A, Akesson A (2013). "Ascorbic Acid Supplements and Kidney Stone Incidence Among Men: A Prospective Study". JAMA Intern. Med. 173 (5): 1–2. doi:10.1001/jamainternmed.2013.2296. PMID 23381591.
- "Nutrient Requirements and Recommended Dietary Allowances for Indians: A Report of the Expert Group of the Indian Council of Medical Research. pp.283-295 (2009)" (PDF). Archived (PDF) from the original on June 15, 2016.
- World Health Organization (2004). "Chapter 7: Vitamin C" (PDF). Vitamin and Mineral Requirements in Human Nutrition, Second Edition. Geneva: World Health Organization. ISBN 92-4-154612-3. Archived (PDF) from the original on November 29, 2007. Retrieved February 20, 2007.
- "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. Archived from the original on October 2, 2016.
- "Vitamin C". Natural Health Product Monograph. Health Canada. Archived from the original on April 3, 2013.
- Dietary Reference Intakes for Japanese 2010: Water-Soluble Vitamins Journal of Nutritional Science and Vitaminology 2013(59):S67-S82.
- "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.
- "TABLE 1: Nutrient Intakes from Food and Beverages" Archived February 24, 2017, at the Wayback Machine. What We Eat In America, NHANES 2012-2014
- "TABLE 37: Nutrient Intakes from Dietary Supplements" Archived October 6, 2017, at the Wayback Machine. What We Eat In America, NHANES 2012-2014
- "Tolerable Upper Intake Levels For Vitamins And Minerals" (PDF). European Food Safety Authority. 2006. Archived (PDF) from the original on March 16, 2016.
- "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.
- "Changes to the Nutrition Facts Panel - Compliance Date" Archived March 12, 2017, at the Wayback Machine.
- REGULATION (EU) No 1169/2011 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL Official Journal of the European Union. page 304/61. (2009).
- Wilson JX (2005). "Regulation of vitamin C transport". Annu. Rev. Nutr. 25: 105–125. doi:10.1146/annurev.nutr.25.050304.092647. PMID 16011461.
- "The vitamin and mineral content is stable". Danish Veterinary and Food Administration. Archived from the original on October 14, 2011. Retrieved November 20, 2014.
- "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.
- "Natural food-Fruit Vitamin C Content". The Natural Food Hub. Archived from the original on March 7, 2007. Retrieved March 7, 2007.
- USDA Food Composition Databases United States Department of Agriculture, Agricultural Research Service. Release 28 (2015).
- 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.
- 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". Arch Latinoam Nutr. 50 (4): 405–8. PMID 11464674.
- 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.
- Poole KE, Loveridge N, Barker PJ, Halsall DJ, Rose C, Reeve J, Warburton EA (January 2006). "Reduced vitamin D in acute stroke". Stroke. 37 (1): 243–5. doi:10.1161/01.STR.0000195184.24297.c1. PMID 16322500.
- "09038, Avocados, raw, California". National Nutrient Database for Standard Reference, Release 26. United States Department of Agriculture, Agricultural Research Service. Archived from the original on August 14, 2014. Retrieved August 14, 2014.
- "Nutrient data: Onion". National Nutrient Database for Standard Reference Release 25. United States Department of Agriculture. Archived from the original on March 9, 2016.
- Chatterjee, IB (1973). "Evolution and the Biosynthesis of Ascorbic Acid". Science. 182 (4118): 1271–1272. Bibcode:1973Sci...182.1271C. doi:10.1126/science.182.4118.1271. PMID 4752221.
- USDA Food Composition Databases United States Department of Agriculture, Agricultural Research Service. Release 28 (2015).
- 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.
- 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". Int J Food Sci Nutr. 46 (2): 107–15. doi:10.3109/09637489509012538. PMID 7621082.
- Allen MA, Burgess SG (1950). "The losses of ascorbic acid during the large-scale cooking of green vegetables by different methods". Br. J. Nutr. 4 (2–3): 95–100. doi:10.1079/BJN19500024. PMID 14801407.
- "Safety (MSDS) data for ascorbic acid". Oxford University. October 9, 2005. Archived from the original on February 9, 2007. Retrieved February 21, 2007.
- Combs GF (2001). The Vitamins, Fundamental Aspects in Nutrition and Health (2nd ed.). San Diego, CA: Academic Press. pp. 245–272. ISBN 978-0-12-183492-0.
- Miranda H (June 2, 2006). "Fresh-Cut Fruit May Keep Its Vitamins". WebMD. Archived from the original on July 26, 2006. Retrieved February 25, 2007.
- 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". Nutr Metab Insights. 9: 25–30. doi:10.4137/NMI.S39764. PMC . PMID 27375360.
- "Addition of Vitamins and Minerals to Food, 2014". Canadian Food Inspection Agency, Government of Canada. Retrieved 20 November 2017.
- 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.
- Rumsey SC, Kwon O, Xu GW, Burant CF, Simpson I, Levine M (July 1997). "Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid". J. Biol. Chem. 272 (30): 18982–18989. doi:10.1074/jbc.272.30.18982. PMID 9228080.
- May JM, Qu ZC, Neel DR, Li X (May 2003). "Recycling of vitamin C from its oxidized forms by human endothelial cells". Biochim. Biophys. Acta. 1640 (2–3): 153–161. doi:10.1016/S0167-4889(03)00043-0. PMID 12729925.
- May JM, Qu ZC, Qiao H, Koury MJ (August 2007). "Maturational loss of the vitamin C transporter in erythrocytes". Biochem. Biophys. Res. Commun. 360 (1): 295–298. doi:10.1016/j.bbrc.2007.06.072. PMC . PMID 17586466.
- Padayatty SJ, Levine M (2016). "Vitamin C: the known and the unknown and Goldilocks". Oral Dis. 22 (6): 463–93. doi:10.1111/odi.12446. PMC . PMID 26808119.
- Oreopoulos DG, Lindeman RD, VanderJagt DJ, Tzamaloukas AH, Bhagavan HN, Garry PJ (October 1993). "Renal excretion of ascorbic acid: effect of age and sex". J Am Coll Nutr. 12 (5): 537–542. doi:10.1080/07315724.1993.10718349. PMID 8263270.
- Linster CL, Van Schaftingen E (2007). "Vitamin C. Biosynthesis, recycling and degradation in mammals". FEBS J. 274 (1): 1–22. doi:10.1111/j.1742-4658.2006.05607.x. PMID 17222174.
- Prockop DJ, Kivirikko KI (1995). "Collagens: molecular biology, diseases, and potentials for therapy". Annu. Rev. Biochem. 64: 403–434. doi:10.1146/annurev.bi.64.070195.002155. PMID 7574488.
- Peterkofsky B (December 1991). "Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy". Am. J. Clin. Nutr. 54 (6 Suppl): 1135S–1140S. PMID 1720597.
- Kivirikko KI, Myllylä R (1985). "Post-translational processing of procollagens". Annals of the New York Academy of Sciences. 460: 187–201. Bibcode:1985NYASA.460..187K. doi:10.1111/j.1749-6632.1985.tb51167.x. PMID 3008623.
- Rebouche CJ (December 1991). "Ascorbic acid and carnitine biosynthesis". Am. J. Clin. Nutr. 54 (6 Suppl): 1147S–1152S. PMID 1962562.
- Dunn WA, Rettura G, Seifter E, Englard S (September 1984). "Carnitine biosynthesis from gamma-butyrobetaine and from exogenous protein-bound 6-N-trimethyl-L-lysine by the perfused guinea pig liver. Effect of ascorbate deficiency on the in situ activity of gamma-butyrobetaine hydroxylase" (PDF). J. Biol. Chem. 259 (17): 10764–10770. PMID 6432788. Archived (PDF) from the original on March 20, 2009.
- 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". J. Nutr. Sci. Vitaminol. Spec No: 169–172. doi:10.3177/jnsv.38.Special_169. PMID 1297733.
- Kaufman S (1974). "Dopamine-beta-hydroxylase". J Psychiatr Res. 11: 303–316. doi:10.1016/0022-3956(74)90112-5. PMID 4461800.
- Eipper BA, Milgram SL, Husten EJ, Yun HY, Mains RE (April 1993). "Peptidylglycine alpha-amidating monooxygenase: a multifunctional protein with catalytic, processing, and routing domains". Protein Sci. 2 (4): 489–497. doi:10.1002/pro.5560020401. PMC . PMID 8518727.
- Eipper BA, Stoffers DA, Mains RE (1992). "The biosynthesis of neuropeptides: peptide alpha-amidation". Annu. Rev. Neurosci. 15: 57–85. doi:10.1146/annurev.ne.15.030192.000421. PMID 1575450.
- Englard S, Seifter S (1986). "The biochemical functions of ascorbic acid". Annu. Rev. Nutr. 6: 365–406. doi:10.1146/annurev.nu.06.070186.002053. PMID 3015170.
- Lindblad B, Lindstedt G, Lindstedt S (December 1970). "The mechanism of enzymic formation of homogentisate from p-hydroxyphenylpyruvate". J. Am. Chem. Soc. 92 (25): 7446–7449. doi:10.1021/ja00728a032. PMID 5487549.
- "Testing Foods for Vitamin C (Ascorbic Acid)" (PDF). British Nutrition Foundation. 2004. Archived (PDF) from the original on November 23, 2015.
- "Measuring the Vitamin C content of foods and fruit juices". Nuffield Foundation. November 24, 2011. Archived from the original on July 21, 2015.
- Emadi-Konjin P, Verjee Z, Levin AV, Adeli K (2005). "Measurement of intracellular vitamin C levels in human lymphocytes by reverse phase high performance liquid chromatography (HPLC)". Clinical Biochemistry. 38 (5): 450–456. doi:10.1016/j.clinbiochem.2005.01.018. PMID 15820776.
- Yamada, H; Yamada, K; Waki, M; Umegaki, K (2004). "Lymphocyte and Plasma Vitamin C Levels in Type 2 Diabetic Patients with and Without Diabetes Complications". Diabetes Care. 27 (10): 2491–2492. doi:10.2337/diacare.27.10.2491. PMID 15451922.
- Wheeler GL, Jones MA, Smirnoff N (May 1998). "The biosynthetic pathway of vitamin C in higher plants". Nature. 393 (6683): 365–69. Bibcode:1998Natur.393..365W. doi:10.1038/30728. PMID 9620799.
- Bánhegyi G, Mándl J (2001). "The hepatic glycogenoreticular system". Pathol. Oncol. Res. 7 (2): 107–110. doi:10.1007/BF03032575. PMID 11458272.
- R. Eric Miller, Murray E. Fowler. Fowler's Zoo and Wild Animal Medicine, Volume 8. p. 389. Archived from the original on December 7, 2016. Retrieved June 2, 2016.
- Martinez del Rio C (July 1997). "Can passerines synthesize vitamin C?". The Auk. 114 (3): 513–516. doi:10.2307/4089257. JSTOR 4089257.
- Drouin G, Godin JR, Pagé B (2011). "The genetics of vitamin C loss in vertebrates". Curr. Genomics. 12 (5): 371–378. doi:10.2174/138920211796429736. PMC . PMID 22294879.
- 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.
- Cui J, Pan YH, Zhang Y, Jones G, Zhang S (Feb 2011). "Progressive pseudogenization: vitamin C synthesis and its loss in bats". Mol. Biol. Evol. 28 (2): 1025–1031. doi:10.1093/molbev/msq286. PMID 21037206.
- Cui J, Yuan X, Wang L, Jones G, Zhang S (Nov 2011). "Recent loss of vitamin C biosynthesis ability in bats". PLoS ONE. 6 (11): e27114. doi:10.1371/journal.pone.0027114. PMC . PMID 22069493.
- "Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis". Am J Clin Nutr. 54: 1203S–8S. 1991. PMID 1962571.
- 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". J. Biol. Chem. 267 (30): 21967–21972. PMID 1400507.
- 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". Biochim. Biophys. Acta. 1472 (1–2): 408–411. doi:10.1016/S0304-4165(99)00123-3. PMID 10572964.
- 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): 1039–1048. doi:10.1016/j.cell.2008.01.042. PMID 18358815. Lay summary – Science Daily (March 21, 2008).
- 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): 488–498. doi:10.1016/S0899-9007(99)00078-7. PMID 10378206. Archived (PDF) from the original on August 10, 2017.
- 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.
- Gallie DR (2013). "L-ascorbic Acid: a multifunctional molecule supporting plant growth and development". Scientifica (Cairo). 2013: 795964. doi:10.1155/2013/795964. PMC . PMID 24278786.
- Mellidou I, Kanellis AK (2017). "Genetic Control of Ascorbic Acid Biosynthesis and Recycling in Horticultural Crops". Front Chem. 5: 50. doi:10.3389/fchem.2017.00050. PMC . PMID 28744455.
- Bulley S, Laing W (2016). "The regulation of ascorbate biosynthesis". Curr. Opin. Plant Biol. 33: 15–22. doi:10.1016/j.pbi.2016.04.010. PMID 27179323.
- Drouin, Guy; Godin, Jean-Rémi; Pagé, Benoît (August 2011). "The genetics of vitamin C loss in vertebrates". Current Genomics. 12 (5): 371–378. doi:10.2174/138920211796429736. PMC . PMID 22294879.
- Yang, Hongwen (2013-06-01). "Conserved or Lost: Molecular Evolution of the Key Gene GULO in Vertebrate Vitamin C Biosynthesis". Biochemical Genetics. 51 (5-6): 413–425. doi:10.1007/s10528-013-9574-0.
- Pollock JI, Mullin RJ (May 1987). "Vitamin C biosynthesis in prosimians: evidence for the anthropoid affinity of Tarsius". Am. J. Phys. Anthropol. 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259.
- Poux C, Douzery EJ (May 2004). "Primate phylogeny, evolutionary rate variations, and divergence times: a contribution from the nuclear gene IRBP". Am. J. Phys. Anthropol. 124 (1): 1–16. doi:10.1002/ajpa.10322. PMID 15085543.
- Goodman M, Porter CA, Czelusniak J, Page SL, Schneider H, Shoshani J, Gunnell G, Groves CP (June 1998). "Toward a phylogenetic classification of Primates based on DNA evidence complemented by fossil evidence". Mol. Phylogenet. Evol. 9 (3): 585–598. doi:10.1006/mpev.1998.0495. PMID 9668008.
- Porter CA, Page SL, Czelusniak J, Schneider H, Schneider MP, Sampaio I, Goodman M (January 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.
- Zhang, Zhengdong D.; Frankish, Adam; Hunt, Toby; Harrow, Jennifer; Gerstein, Mark (2010-03-08). "Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates". Genome Biology. 11: R26. doi:10.1186/gb-2010-11-3-r26.
- Koshizaka, T.; Nishikimi, M.; Ozawa, T.; Yagi, K. (1988-02-05). "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): 1619–1621. PMID 3338984.
- Challem JJ, Taylor EW (July 1998). "Retroviruses, ascorbate, and mutations, in the evolution of Homo sapiens". Free Radic. Biol. Med. 25 (1): 130–132. doi:10.1016/S0891-5849(98)00034-3. PMID 9655531.
- Bánhegyi G, Braun L, Csala M, Puskás F, Mandl J (1997). "Ascorbate metabolism and its regulation in animals". Free Radic. Biol. Med. 23 (5): 793–803. doi:10.1016/S0891-5849(97)00062-2. PMID 9296457.
- Proctor P (November 1970). "Similar functions of uric acid and ascorbate in man?". Nature. 228 (5274): 868. Bibcode:1970Natur.228..868P. doi:10.1038/228868a0. PMID 5477017.
- "The production of vitamin C" (PDF). Competition Commission. 2001. Archived from the original (PDF) on 2012-01-19. Retrieved February 20, 2007.
- Starling S (June 26, 2008). "DSM vitamin plant gains green thumbs-up". Decision News Media SAS. Archived from the original on March 14, 2012. Retrieved February 25, 2010.
- "Vitamin C: Distruptions to Production in China to Maintain Firm Market". Flexnews. June 30, 2008. Archived from the original on October 2, 2013. Retrieved February 25, 2010.
- "Bizbites October 11". Global Times. October 11, 2010. Archived from the original on October 13, 2010. Retrieved October 15, 2010.
- Longstreth, Andrew U.S. courts confront China's involvement in price fixing Archived September 24, 2015, at the Wayback Machine., Reuters.com, March 11, 2011; accessed July 22, 2017.
- Vitamin C Makers Can Be Sued by Buyers Acting as Group, BusinessWeek.com, January 27, 2012; accessed January 2012 Archived June 4, 2013, at the Wayback Machine.
- China Vitamin C price-fixing verdict voided by U.S. appeals court Jonathan Stempel, Reuters, September 20, 2016.
- Supreme Court Considers Vitamin C Price Fixing Lawsuit Patterson Belknap Webb & Tyler LLP, June 29, 2017.
- "Jacques Cartier's Second Voyage - 1535 - Winter & Scurvy". Archived from the original on February 12, 2007. Retrieved February 25, 2007.
- Martini E (June 2002). "Jacques Cartier witnesses a treatment for scurvy". Vesalius. 8 (1): 2–6. PMID 12422875.
- Cegłowski, Maciej (March 7, 2010). "Scott and Scurvy". Archived from the original on March 10, 2010.
- 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
- 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
- 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; … "
- 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.
- 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, … )
- 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.
- Lamb J (2001). Preserving the self in the south seas, 1680–1840. University of Chicago Press. p. 117. ISBN 0-226-46849-6. Archived from the original on April 30, 2016.
- Singh S; Edzard Ernst (2008). Trick of Treatment: The Undeniable Facts about Alternative Medicine. WW Norton & Company. pp. 15–18. ISBN 978-0-393-06661-6.
- Beaglehole JH, Cook JD, Edwards PR (1999). The journals of Captain Cook. Harmondsworth [Eng.]: Penguin. ISBN 0-14-043647-2.
- 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. ISBN 1-74114-200-8.
- Kuhnlein HV, Receveur O, Soueida R, Egeland GM (June 2004). "Arctic indigenous peoples experience the nutrition transition with changing dietary patterns and obesity". J. Nutr. 134 (6): 1447–1453. PMID 15173410. Archived from the original on March 17, 2010.
- Bächi B (2008). "[Natural or synthetic vitamin C? A new substance's precarious status behind the scenes of World War II]". NTM (in German). 16 (4): 445–470. doi:10.1007/s00048-008-0309-y. PMID 19579835.
- Norum KR, Grav HJ (June 2002). "[Axel Holst and Theodor Frolich--pioneers in the combat of scurvy]". Tidsskr. Nor. Laegeforen. (in Norwegian). 122 (17): 1686–1687. PMID 12555613.
- Rosenfeld L (April 1997). "Vitamine--vitamin. The early years of discovery". Clin. Chem. 43 (4): 680–685. PMID 9105273.
- Svirbely JL, Szent-Györgyi A (1932). "The chemical nature of vitamin C". Biochem. J. 26 (3): 865–70. Bibcode:1932Sci....75..357K. doi:10.1126/science.75.1944.357-a. PMC . PMID 16744896.
- Juhász-Nagy S (March 2002). "[Albert Szent-Györgyi--biography of a free genius]". Orv Hetil (in Hungarian). 143 (12): 611–614. PMID 11963399.
- Kenéz J (December 1973). "[Eventful life of a scientist. 80th birthday of Nobel prize winner Albert Szent-Györgyi]". Munch Med Wochenschr (in German). 115 (51): 2324–2326. PMID 4589872.
- Szállási A (December 1974). "[2 interesting early articles by Albert Szent-Györgyi]". Orv Hetil (in Hungarian). 115 (52): 3118–3119. PMID 4612454.
- "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.
- "Scurvy". Online Entymology Dictionary. Retrieved 19 November 2017.
- "The Nobel Prize in Physiology or Medicine 1937". Nobel Media AB. Archived from the original on November 5, 2014. Retrieved November 20, 2014.
- Stacey M, Manners DJ (1978). "Edmund Langley Hirst. 1898-1975". Adv Carbohydr Chem Biochem. Advances in Carbohydrate Chemistry and Biochemistry. 35: 1–29. doi:10.1016/S0065-2318(08)60217-6. ISBN 9780120072354. PMID 356548.
- Burns JJ, Evans C (December 1956). "The synthesis of L-ascorbic acid in the rat from D-glucuronolactone and L-gulonolactone". J. Biol. Chem. 223 (2): 897–905. PMID 13385237.
- Burns JJ, Moltz A, Peyser P (December 1956). "Missing step in guinea pigs required for the biosynthesis of L-ascorbic acid". Science. 124 (3232): 1148–1149. Bibcode:1956Sci...124.1148B. doi:10.1126/science.124.3232.1148-a. PMID 13380431.
- Henson DE, Block G, Levine M (April 1991). "Ascorbic acid: biologic functions and relation to cancer". J. Natl. Cancer Inst. 83 (8): 547–550. doi:10.1093/jnci/83.8.547. PMID 1672383.
- Pauling L (1970). "Evolution and the need for ascorbic acid". Proc. Natl. Acad. Sci. USA. 67 (4): 1643–1648. Bibcode:1970PNAS...67.1643P. doi:10.1073/pnas.67.4.1643. PMC . PMID 5275366.
- Mandl J, Szarka A, Bánhegyi G (2009). "Vitamin C: update on physiology and pharmacology". Br. J. Pharmacol. 157 (7): 1097–1110. doi:10.1111/j.1476-5381.2009.00282.x. PMC . PMID 19508394.
- Cameron E, Pauling L (1976). "Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer". Proc. Natl. Acad. Sci. U.S.A. 73 (10): 3685–3689. PMC . PMID 1068480.
- "Vitamin C: Common cold". Corvallis, OR: Micronutrient Information Center, Linus Pauling Institute, Oregon State University. 14 January 2014. Retrieved 3 May 2017.
- Hemilä H (2009) Vitamins and minerals. In:"Common cold" (Eccles R, Weber O, eds.) Birkhauser Verlag, pp. 275-307
- 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.
|Wikimedia Commons has media related to Ascorbic acid.|