Vitamin C

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Vitamin C
Natta projection of structural formula for L-ascorbic acid
Ball-and-stick model of L-ascorbic acid
Clinical data
Synonyms L-ascorbic acid, ascorbic acid, ascorbate
AHFS/Drugs.com Monograph
MedlinePlus a682583
Pregnancy
category
  • A (to RDA), C (above RDA)
Routes of
administration
by mouth, IM, IV, subQ
ATC code
Legal status
Legal status
  • AU: Unscheduled
  • US: OTC
  • general public availability
Pharmacokinetic data
Bioavailability rapid & complete
Protein binding negligible
Biological half-life varies according to plasma concentration
Excretion kidney
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
NIAID ChemDB
E number E300 (antioxidants, ...)
ECHA InfoCard 100.000.061
Chemical and physical data
Formula C6H8O6
Molar mass 176.12 g/mol
3D model (JSmol)
Density 1.694 g/cm3
Melting point 190 °C (374 °F)
Boiling point 553 °C (1,027 °F)
  (verify)

Vitamin C, also known as ascorbic acid and L-ascorbic acid, is a vitamin found in food and used as a dietary supplement.[1] The disease scurvy is prevented and treated with vitamin C containing foods or dietary supplements.[1] Evidence does not support use in the general population for the prevention of the common cold,[2][3] it may be taken by mouth or by injection.[1]

Vitamin C is generally well tolerated.[1] Large doses may cause gastrointestinal discomfort, headache, trouble sleeping, and flushing of the skin.[1][3] Normal doses are safe during pregnancy.[4] Vitamin C is an essential nutrient involved in the repair of tissue.[1] Foods containing vitamin C include citrus fruits, broccoli, Brussels sprouts, raw bell peppers, and strawberries.[2] Prolonged storage or cooking may reduce vitamin C content in foods.[2]

Vitamin C was discovered in 1912, isolated in 1928, and first made in 1933,[5] it is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.[6] Vitamin C is available as a generic medication and over the counter;[1] in 2015, the wholesale cost in the developing world was about 0.003 to 0.007 USD per tablet.[7] In some countries, ascorbic acid may be added to foods such as breakfast cereal.[2]

Biological significance[edit]

Vitamin C is an essential nutrient for certain animals including humans.[8] 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.[8][9] In animals, these reactions are especially important in wound-healing and in preventing bleeding from capillaries.[8]

The biological role of vitamin C is to act as a reducing agent, donating electrons to various enzymatic and non-enzymatic reactions,[8] 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.[10][11] The presence of glutathione in cells and extracellular fluids helps maintain ascorbate in a reduced state.[12]

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.[8][13] Vitamin C is an enzyme cofactor for the biosynthesis of many biochemicals required for normal metabolism,[8][14] 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).[15]

Vitamin C is required for a range of essential metabolic reactions in all animals and plants,[16] although it is made internally by almost all vertebrates, there are exceptions which do not synthesize it, including humans,[8] tarsiers, and monkeys.[citation needed] All vertabrate species that do not make vitamin C require it in the diet.[citation needed]

Deficiency[edit]

Scurvy is an avitaminosis resulting from lack of vitamin C, since without this vitamin, collagen made by the body is too unstable to perform its function.[15]

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,[17] 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.[18][19]

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.[18][19]

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).[18]

Uses[edit]

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

Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitamin C deficiency. Beyond that, a role for vitamin C as prevention or treatment for various diseases is contentious, with individual clinical trials and even reviews, systemic reviews and meta-analyses reporting conflicting results. A 2012 Cochrane review compiled the results of 29 human trials, average length two years, and reported no effect of vitamin C supplementation on overall mortality,[20] 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.[6]

Scurvy[edit]

The disease scurvy is caused by vitamin C deficiency and can be prevented and treated with vitamin C containing foods or dietary supplements,[1][8] it takes at least a month of little to no vitamin C before symptoms occur.[18] 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,[1] 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.[1]

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.[21][22]

Common cold[edit]

The Nobel prizewinner Linus Pauling advocated taking vitamin C for the common cold in a 1970 book.

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.[23] 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.[24] A revised and expanded edition "Vitamin C, the Common Cold and the Flu" was published in 1976.[25]

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.[26] A subset of trials reported that supplementation reduced the incidence of colds by half in marathon runners, skiers, or soldiers in subarctic conditions.[26] 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.[26] An earlier review stated that vitamin C did not prevent colds, did reduce duration, did not reduce severity,[27] 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."[26]

Cancer[edit]

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.[28] A 2014 meta-analysis found that vitamin C intake might protect against lung cancer risk.[29] A second meta-analysis found no effect on the risk of prostate cancer.[30] 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.[31][32] A 2011 meta-analysis failed to find support for the prevention of breast cancer with vitamin C supplementation,[33] but a second study concluded that vitamin C may be associated with increased survival in those already diagnosed.[34] 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."[35]

Cardiovascular disease[edit]

A 2013 meta-analysis found no evidence that vitamin C supplementation reduces the risk of myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality.[36] However, a second analysis found an inverse relationship between circulating vitamin C levels or dietary vitamin C and the risk of stroke.[37]

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.[38]

Rheumatoid arthritis[edit]

A 2010 review found no role for vitamin C supplementation in the treatment of rheumatoid arthritis.[39]

Alzheimer's disease[edit]

Studies examining the effects of vitamin C intake on the risk of Alzheimer's disease have reached conflicting conclusions.[40][41] Maintaining a healthy dietary intake is probably more important than supplementation for achieving any potential benefit.[42]

Cataract[edit]

Vitamin C supplementation does not prevent or slow the progression of age-related cataract.[43]

Side effects[edit]

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.[25] 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.[8] In theory, high vitamin C intake may cause excessive absorption of iron. A summary of reviews of supplementation in healthy subjects did not report this problem, but left as untested the possibility that individuals with hereditary hemochromatosis might by adversely affected.[8] There is a longstanding belief among the mainstream medical community that vitamin C increases risk of kidney stones.[44] 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,[8][45] 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.[46] Vitamin C is a water-soluble vitamin,[17] with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine, so it exhibits remarkably low acute toxicity.

Diet[edit]

Recommended levels[edit]

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

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

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.[8] The table shows RDAs for the United States and Canada for children, and for pregnant and lactating women,[8] 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. [52] 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.[47] 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,[53] 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.[54]

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,[8] 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.[55] 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.[51]

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.[56] 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.[57] 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.[58]

Sources[edit]

Rose hips are a particularly rich source of vitamin C

The richest natural sources are fruits and vegetables.[15] Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms,[15] 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.[59]

Plant sources[edit]

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.[60]

The following table is approximate and shows the relative abundance in different raw plant sources,[61][62] 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:

Plant source[63] Amount
(mg / 100g)
Cloudberry, Elderberry 60
Papaya, Strawberry 60
Orange, Lemon 53
Pineapple, Cauliflower 48
Cantaloupe 40
Grapefruit, Raspberry 30
Passion fruit, Spinach 30
Cabbage, Lime 30
Mango 28
Blackberry 21
Potato, Honeydew melon 20
Plant source[63] Amount
(mg / 100g)
Tomato 14
Cranberry 13
Blueberry, Grape 10
Apricot, Plum, Watermelon 10
Banana 9
Avocado 8.8[68]
Onion 7.4[69]
Cherry, Peach 7
Carrot, Apple, Asparagus 6
Pear, Lettuce 4

Animal sources[edit]

Goats, like many animals but not humans, make their own vitamin C. An adult goat, weighing approx. 70 kg, will manufacture more than 13,000 mg of vitamin C per day in normal health, and levels manyfold higher when faced with stress.[70]

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.[71] 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.[72]

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[73] 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.[74] Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition.[75]

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.[76] Research has also shown that freshly cut fruits do not lose significant nutrients when stored in the refrigerator for a few days.[77]

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.[1] 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.[1] Vitamin C molecules can also be bound to the fatty acid palmitate, creating ascorbyl palmitate, or else incorporated into liposomes.[78]

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.[79] Voluntary and mandatory fortification was described for various classes of foods, among foods classified for mandatory fortification were fruit-flavored drinks, mixes, and concentrates, foods for a low-energy diet, meal replacement products, and evaporated milk.[79]

Testing for levels[edit]

Simple tests use dichlorophenolindophenol, a redox indicator, to measure the levels of vitamin C in the urine and in serum or blood plasma. However these reflect recent dietary intake rather than the level of vitamin C in body stores.[9] Reverse phase high performance liquid chromatography is used for determining the storage levels of vitamin C within lymphocytes and tissue. It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, those within tissues themselves are more stable and give a better view of the availability of ascorbate within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories.[80][81]

Biology[edit]

Biosynthesis[edit]

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

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.[82] 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.[83]

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).[84]

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.[85] In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases,[86] the ability to synthesize vitamin C has also been lost in about 96% of fish (the teleosts).[85]

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.[87] 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.[88][89]

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.[90][91][92]

Some of these species (including humans) are able to make do with the lower levels available from their diets by recycling oxidised vitamin C.[93]

Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans,[94] 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 oxidised vitamin C.[93]

Biosynthesis Routes[edit]

Vitamin C biosynthesis in vertebrates

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,[95] 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.[96]

Vitamin C biosynthesis in plants

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.[97] 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.[97][98] 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.[98] 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.[97]

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 Passeriform birds have all independently lost the ability to internally synthesize Vitamin C in either the kidney or the liver.[99] 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.[100]

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.[101] According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.[102] 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,[103][104] 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).[citation needed]

One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of semi-random genetic drift. If a function that a gene provides is redundant to an organism, it could become effectively disposable to that organism.[105] Given that a certain allele does not affect fitness, a pseudogenic version could fix in the population by random genetic drift, because there is no longer any disadvantage conveyed by a non-synonymous mutation.[106]  At the very least, natural selection might have been lessened, paving the way for genetic drift to control the fate of the gene. In the case of the L-Gulono-γ-lactone oxidase coding region, its function in organisms with a diet high in Vitamin C might have been redundant, which might subsequently allow the trait to be lost by genetic drift.

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.[107][108]

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.[109]

Absorption, transport, and excretion[edit]

From the U.S. National Institutes of Health: "Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1000 mg/day, absorption falls to less than 50%. Absorbed, unmetabolized ascorbic acid is excreted in the urine."[2]

Ascorbic acid is absorbed in the body by both active transport and simple diffusion. Sodium-Dependent Active Transport—Sodium-Ascorbate Co-Transporters (SVCTs) and Hexose transporters (GLUTs)—are the two transporters required for active absorption. SVCT1 and SVCT2 import the reduced form of ascorbate across plasma membranes.[110] GLUT1 and GLUT3 are glucose transporters, and transfer only the dehydroascorbic acid form of Vitamin C.[111] 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.[112] Thus, SVCTs appear to be the predominant system for vitamin C transport in the body. SVCT2 is involved in vitamin C transport in almost every tissue,[110] the notable exception being red blood cells, which lose SVCT proteins during maturation.[113] "SVCT2 knockout" animals genetically engineered to lack this functional gene, die shortly after birth,[114] suggesting that SVCT2-mediated vitamin C transport is necessary for life.

Excretion is via urine, having passed through kidneys, with low dietary intake, vitamin C is reabsorbed by the kidneys; above a certain threshold, triggered by plasma concentrations of about 1.4 mg/dL or higher, re-absorption declines and excess amounts passes freely into the urine and are excreted. Concentrations less than this threshold amount are actively retained by the kidneys, and the excretion half-life for the remainder of the vitamin C store in the body thus increases greatly, with the half-life lengthening as the body stores are depleted, this half-life rises until it is as long as 83 days by the onset of the first symptoms of scurvy.[115]

Enzymatic cofactor[edit]

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.[12] 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 acts as an electron donor for eight enzymes:[14]

Immune system[edit]

Soluble in cellular water compartments, 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.[127] 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.[128][129]

Role in plants[edit]

Ascorbic acid is associated with chloroplasts and apparently plays a role in ameliorating the oxidative stress of photosynthesis; in addition, it has a number of other roles in cell division and protein modification. Plants appear to be able to make ascorbate by at least one other biochemical route that is different from the major route in animals, although precise details remain unknown.[130]

Industrial synthesis[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. Both processes yield approximately 60% vitamin C from the glucose feed.[131]

World production of synthesized vitamin C is currently estimated at approximately 110,000 tonnes annually, the main producers have been 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 the strong price competition from China.[132]

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.[133] 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.[134] 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. According to the plaintiffs, after the agreement was made spot prices for vitamin C shot to as high as $7 per kilogram in December 2002 from $2.50 per kilogram in December 2001. The companies did not deny the accusation but say in their defense that the Chinese government compelled them to act in this way;[135] 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.[136]

Chemistry[edit]

The name "vitamin C" always refers to the L-enantiomer of ascorbic acid and its oxidized forms. Therefore, unless written otherwise, "ascorbate" and "ascorbic acid" refer in the nutritional literature to L-ascorbate and L-ascorbic acid respectively. This notation will be followed in this article. Similarly, their oxidized derivatives (dehydroascorbate, etc., see below) are all L-enantiomers and also need not be written with full stereochemical notation here.

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.[137][138]

History[edit]

Folk medicine[edit]

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.[139][140]

Scurvy at sea[edit]

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

In the 1497 expedition of Vasco de Gama, the curative effects of citrus fruit were known,[141][142] 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.[143]

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.[144] 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."[145][146]

Scurvy had long been a principal killer of sailors during the long sea voyages.[147] 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."[148]

James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented the disease of scurvy in one of the first recorded controlled experiments.[22]

Scurvy was first described by Hippocrates around 400 BC. 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.[22] The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.[21][149]

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).[75]

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.[22] 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.[150] 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.[151]

In 1928, the Canadian Arctic anthropologist Vilhjalmur Stefansson showed that the Inuit avoid scurvy on a diet of largely raw meat. Later studies in mostly raw 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,[152] comparable with the Estimated Average Requirement.[8]

Discovery[edit]

Albert Szent-Györgyi, pictured here in 1948, was awarded the 1937 Nobel Prize in Medicine "for his discoveries in connection with the biological combustion processes, with special reference to vitamin C and the catalysis of fumaric acid".[153]

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;[154] 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.[155]

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;[156] 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.[156] In 1933, Walter Norman Haworth chemically identified the vitamin as L-hexuronic acid, proving this by synthesis in 1933.[157][158][159][160] 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.[160][161] 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.[162] Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine,[163] and Haworth shared that year's Nobel Prize in Chemistry.[153]

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,[164] this made possible the cheap mass-production of semi-synthetic vitamin C, which was quickly marketed,[165][166] and from 1934 produced by Hoffmann–La Roche under the brand name of Redoxon.[167]

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.[168][169] 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.[170]

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.[93]

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.[171]

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