Vitamin C

Vitamin C
This article is about ascorbic acid as a nutrient; for its chemical properties, see the article ascorbic acid; for other uses, see the disambiguation page.
Vitamin C
Systematic (IUPAC) name
2-Oxo-L-threo-hexono-1,4-lactone-2,3-enediol
or
(R)-3,4-dihydroxy-5-((S)- 1,2-dihydroxyethyl)furan-2(5H)-one
Clinical data
AHFS/Drugs.com Multum Consumer Information
Pregnancy cat. A
Legal status general public availability
Routes oral
Pharmacokinetic data
Bioavailability rapid & complete
Protein binding negligible
Half-life varies according to plasma concentration
Excretion renal
Identifiers
CAS number 50-81-7 YesY
ATC code A11G
PubChem CID 5785
DrugBank DB00126
ChemSpider 10189562 YesY
UNII PQ6CK8PD0R YesY
KEGG D00018 YesY
ChEBI CHEBI:29073 N
ChEMBL CHEMBL196 YesY
Synonyms L-ascorbic acid
Chemical data
Formula C6H8O6 
Mol. mass 176.12 g/mole
SMILES eMolecules & PubChem
Physical data
Density 1.694 g/cm³
Melt. point 190 °C (374 °F)
Boiling point 553 °C (1027 °F)
 N(what is this?)  C (verify)

Vitamin C or L-ascorbic acid or L-ascorbate is an essential nutrient for humans and certain other animal species. In living organisms ascorbate acts as an antioxidant by protecting the body against oxidative stress.[1] It is also a cofactor in at least eight enzymatic reactions including several collagen synthesis reactions that, when dysfunctional, cause the most severe symptoms of scurvy.[2] In animals these reactions are especially important in wound-healing and in preventing bleeding from capillaries.

Ascorbate (an ion of ascorbic acid) is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms although notable mammalian group exceptions are most or all of the order chiroptera (bats), guinea pigs, capybaras, and one of the two major primate suborders, the Anthropoidea (Haplorrhini) (tarsiers, monkeys and apes, including human beings). Ascorbic acid is also not synthesized by some species of birds and fish. All species that do not synthesize ascorbate require it in the diet. Deficiency in this vitamin causes the disease scurvy in humans.[2][3][4] It is also widely used as a food additive.

The full extent of the effects and recommended daily intake of vitamin C are matters of ongoing debate, with RDI ranging from 45mg to 400mg or more per day.


Contents

Biological significance

Further information: ascorbic acid

Vitamin C is purely the L-enantiomer of ascorbate; the opposite D-enantiomer has no physiological significance. Both forms are mirror images of the same molecular structure. When L-ascorbate, which is a strong reducing agent, carries out its reducing function, it is converted to its oxidized form, L-dehydroascorbate.[2] L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione.[5] During this process semidehydroascorbic acid radical is formed. Ascorbate free radical reacts poorly with oxygen, and thus will not create a superoxide. Instead two semidehydroascorbate radicals will react and form one ascorbate and one dehydroascorbate. With the help of glutathione, dehydroxyascorbate is converted back to ascorbate.[6] The presence of glutathione is crucial since it spares ascorbate and improves antioxidant capacity of blood.[7] Without it dehydroxyascorbate could not convert back to ascorbate.

L-Ascorbate is a weak sugar acid structurally related to glucose that naturally occurs attached either to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate.

Biosynthesis in different species

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 their own vitamin C, through a sequence of four enzyme-driven steps, which convert glucose to vitamin C.[2] The glucose needed to produce ascorbate in the liver (in mammals and perching birds) is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.[8] In reptiles and birds the biosynthesis is carried out in the kidneys.

Among the animals that have lost the ability to synthesise vitamin C are simians and tarsiers, which together make up one of two major primate suborders, the anthropoidea, also called 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). A number of species of passerine birds also do not synthesise, but not all of them, and those that don't are not clearly related; there is a theory that the ability was lost separately a number of times in birds.[9] All tested families of bats, including major insect and fruit-eating bat families, cannot synthesise vitamin C. A trace of GLO was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested.[10]

These animals all lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last step of vitamin C synthesis, because they have a differing non-synthesising gene for the enzyme (Pseudogene ΨGULO).[11] A similar non-functional gene is present in the genome of the guinea pigs and in primates, including humans.[12][13] Some of these species (including humans) are able to make do with the lower levels available from their diets by recycling oxidised vitamin C.[14]

Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans.[15] 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 other simians, on a far smaller dietary intake.

An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and the biosynthesis will increase "manyfold under stress".[16] Trauma or injury has also been demonstrated to use up large quantities of vitamin C in humans.[17] Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.[18][19]

Vitamin C in evolution

Venturi and Venturi[20][21] suggested that the antioxidant action of ascorbic acid developed first in the plant kingdom when, about 500 million years ago (mya), plants began to adapt to antioxidant-mineral-deficient fresh-waters of estuaries. Some biologists suggested that many vertebrates had developed their metabolic adaptive strategies in estuary environment.[22] In this theory, some 400–300 mya, when living plants and animals first began the move from the sea to rivers and land, environmental iodine deficiency was a challenge to the evolution of terrestrial life.[23] In plants, animals and fishes, the terrestrial diet became deficient in many essential antioxidant marine micronutrients, including iodine, selenium, zinc, copper, manganese, iron, etc. Freshwater algae and terrestrial plants, in replacement of marine antioxidants, slowly optimized the production of other endogenous antioxidants such as ascorbic acid, polyphenols, carotenoids, tocopherols etc., some of which became essential “vitamins” in the diet of terrestrial animals (vitamins C, A, E, etc.).

Ascorbic acid or vitamin C is a common enzymatic co-factor in mammals used in the synthesis of collagen. Ascorbate is a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). Freshwater teleost fishes also require dietary vitamin C in their diet or they will get scurvy. The most widely recognized symptoms of vitamin C deficiency in fishes are scoliosis, lordosis and dark skin coloration. Freshwater salmonids also show impaired collagen formation, internal/fin hemorrhage, spinal curvature and increased mortality. If these fishes are housed in seawater with algae and phytoplankton, then vitamin supplementation seems to be less important, it is presumed because of the availability of other, more ancient, antioxidants in natural marine environment.[24]

Some scientists have suggested that loss of the vitamin C biosynthesis pathway may have played a role in the theory of rapid evolutionary changes, leading to hominids and the emergence of human beings.[25][26][27] However, another theory based on the theory of evolution is that the loss of ability to make vitamin C in simians may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred rather soon after the appearance of the first primates, yet sometime after the split of early primates into its 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.[28] According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 Mya[29] Approximately three to five million years later (58 Mya), 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.[30][31] 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 Mya).

It has 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.[32]

Absorption, transport, and disposal

Ascorbic acid is absorbed in the body by both active transport and simple diffusion. Sodium-Dependent Active Transport—Sodium-Ascorbate Co-Transporters (SVCTs) and Hexose transporters (GLUTs)—are the two transporters required for absorption. SVCT1 and SVCT2 import the reduced form of ascorbate across plasma membrane.[33] GLUT1 and GLUT3 are the two glucose transporters, and transfer only dehydroascorbic acid form of Vitamin C.[34] 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.[35][36] 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,[33] the notable exception being red blood cells, which lose SVCT proteins during maturation.[37] "SVCT2 knockout" animals genetically engineered to lack this functional gene, die shortly after birth,[38] suggesting that SVCT2-mediated vitamin C transport is necessary for life.

With regular intake the absorption rate varies between 70 to 95%. However, the degree of absorption decreases as intake increases. At high intake (1.25g), fractional human absorption of ascorbic acid may be as low as 33%; at low intake (<20 mg) the absorption rate can reach up to 98%.[39] Ascorbate concentrations over renal re-absorption threshold pass freely into the urine and are excreted. At high dietary doses (corresponding to several hundred mg/day in humans) ascorbate is accumulated in the body until the plasma levels reach the renal resorption threshold, which is about 1.5 mg/dL in men and 1.3 mg/dL in women. Concentrations in the plasma larger than this value (thought to represent body saturation) are rapidly excreted in the urine with a half-life of about 30 minutes. Concentrations less than this threshold amount are actively retained by the kidneys, and the excretion half-life for the remainder of the vitamin C store in the body thus increases greatly, with the half-life lengthening as the body stores are depleted. This half-life rises until it is as long as 83 days by the onset of the first symptoms of scurvy.[40]

Although the body's maximal store of vitamin C is largely determined by the renal threshold for blood, there are many tissues that maintain vitamin C concentrations far higher than in blood. Biological tissues that accumulate over 100 times the level in blood plasma of vitamin C are the adrenal glands, pituitary, thymus, corpus luteum, and retina.[41] Those with 10 to 50 times the concentration present in blood plasma include the brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucosa, leukocytes, pancreas, kidney and salivary glands.

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

Deficiency

Main article: Scurvy

Scurvy is an avitaminosis resulting from lack of vitamin C, since without this vitamin, the synthesised collagen is too unstable to perform its function. Scurvy leads to the formation of brown spots on the skin, spongy gums, and bleeding from all mucous membranes. The spots are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds and loss of teeth and, eventually, death. The human body can store only a certain amount of vitamin C,[42] 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 switched to a completely vitamin C free diet, however, may range from one month to more than six months, depending on previous loading of vitamin C (see below).

It has been shown that smokers who have diets poor in vitamin C are at a higher risk of lung-borne diseases than those smokers who have higher concentrations of vitamin C in the blood.[43]

Nobel prize winner Linus Pauling and G. C. Willis have asserted that chronic long term low blood levels of vitamin C ("chronic scurvy") is a cause of atherosclerosis.[44]

Western societies generally consume far more than sufficient Vitamin C to prevent scurvy. In 2004, a Canadian Community health survey reported that Canadians of 19 years and above have intakes of vitamin C from food of 133 mg/d for males and 120 mg/d for females;[45] these are higher than the RDA recommendations.

Notable human dietary studies of experimentally-induced scurvy have been conducted on conscientious objectors during WW II in Britain, and on Iowa state prisoners in the late 1960s. 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.[46]

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 a instantaneous half-life of 83 days by this time (elimination constant of 4 months).[47]

Moderately higher blood levels of vitamin C measured in healthy persons have been found to be prospectively correlated with decreased risk of cardiovascular disease and ischaemic heart disease, and an increase life expectancy. The same study found an inverse relationship between blood vitamin C levels and cancer risk in men, but not in women. An increase in blood level of 20 micromol/L of vitamin C (about 0.35 mg/dL, and representing a theoretical additional 50 grams of fruit and vegetables per day) was found epidemiologically to reduce the all-cause risk of mortality, four years after measuring it, by about 20%.[48] However, because this was not an intervention study, causation could not be proven, and vitamin C blood levels acting as a proxy marker for other differences between the groups could not be ruled out. However, the four-year long and prospective nature of the study did rule out proxy effect from any vitamin C lowering effects of immediately terminal illness, or near-end-of-life poor health.

Studies with much higher doses of vitamin C, usually between 200 and 6000 mg/day, for the treatment of infections and wounds have shown inconsistent results.[49] Combinations of antioxidants seem to improve wound healing.[50]

Physiological function in mammals

In humans, vitamin C is essential to a healthy diet as well as being a highly effective antioxidant, acting to lessen oxidative stress; a substrate for ascorbate peroxidase in plants (APX is plant specific enzyme);[4] and an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for important enzymes:[51]

Collagen, carnitine, and tyrosine synthesis, and microsomal metabolism

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.[7] 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 different enzymes:[51]

  • Two enzymes are necessary for synthesis of carnitine.[55][56] Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.

Antioxidant

Ascorbic acid is well known for its antioxidant activity, acting as a reducing agent to reverse oxidation in liquids. When there are more free radicals (reactive oxygen species, ROS) in the human body than antioxidants, the condition is called oxidative stress,[63] and has an impact on cardiovascular disease, hypertension, chronic inflammatory diseases, diabetes[64][65][66][67] as well as on critically ill patients and individuals with severe burns.[63] Individuals experiencing oxidative stress have ascorbate blood levels lower than 45 µmol/L, compared to healthy individual who range between 61.4-80 µmol/L.[68]

It is not yet certain whether vitamin C and antioxidants in general prevent oxidative stress-related diseases and promote health. Clinical studies regarding the effects of vitamin C supplementation on lipoproteins and cholesterol have found that vitamin C supplementation does not improve disease markers in the blood.[69][70] Vitamin C may contribute to decreased risk of cardiovascular disease and strokes through a small reduction in systolic blood pressure,[71] and was also found to both increase ascorbic acid levels and reduce levels of resistin serum,[72] another likely determinant of oxidative stress and cardiovascular risk. However, so far there is no consensus that vitamin C intake has an impact on cardiovascular risks in general, and an array of studies found negative results.[73] Meta-analysis of a large number of studies on antioxidants, including vitamin C supplementation, found no relationship between vitamin C and mortality. [74]

Pro-oxidant

Ascorbic acid behaves not only as an antioxidant but also as a pro-oxidant.[63] Ascorbic acid has been shown to reduce transition metals, such as cupric ions (Cu2+), to cuprous (Cu1+), and ferric ions (Fe3+) to ferrous (Fe2+) during conversion from ascorbate to dehydroascorbate in vitro.[75] This reaction can generate superoxide and other ROS. However, in the body, free transition elements are unlikely to be present while iron and copper are bound to diverse proteins[63] and the intravenous use of vitamin C does not appear to increase pro-oxidant activity.[76] Thus, ascorbate as a pro-oxidant is unlikely to convert metals to create ROS in vivo. However, vitamin C supplementation has been associated with increased DNA damage in the lymphocytes of healthy volunteers.[77]

Immune system

Vitamin C is found in high concentrations in immune cells, and is consumed quickly during infections. It is not certain how vitamin C interacts with the immune system; it has been hypothesized to modulate the activities of phagocytes, the production of cytokines and lymphocytes, and the number of cell adhesion molecules in monocytes.[78]

Antihistamine

Vitamin C is a natural antihistamine. It both prevents histamine release and increases the detoxification of histamine. A 1992 study found that taking 2 grams vitamin C daily lowered blood histamine levels 38 percent in healthy adults in just one week.[79] It has also been noted that low concentrations of serum vitamin C has been correlated with increased serum histamine levels.[citation needed]

Physiologic function in plants

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.[80]

Daily requirements

The North American Dietary Reference Intake recommends 90 milligrams per day and no more than 2 grams (2,000 milligrams) per day.[81] Other related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this reference intake.[82] There is continuing debate within the scientific community over the best dose schedule (the amount and frequency of intake) of vitamin C for maintaining optimal health in humans.[83] It is generally agreed that a balanced diet[clarification needed] without supplementation contains enough vitamin C to prevent scurvy in an average healthy adult, while those who are pregnant, smoke tobacco, or are under stress require slightly more.[81] However, the amount of Vitamin C necessary to prevent scurvy is less than the amount required for optimal health, as there are a number of other chronic diseases whose risk are increased by a low vitamin C intake, including cancer, heart disease, and cataracts. A 1999 review suggested a dose of 90–100 mg Vitamin C daily is required to optimally protect against these diseases, in contrast to the lower 45 mg daily required to prevent scurvy.[84]

High doses (thousands of milligrams) may result in diarrhea in healthy adults, as a result of the osmotic water-retaining effect of the unabsorbed portion in the gastrointestinal tract (similar to cathartic osmotic laxatives). Proponents of orthomolecular medicine[85] claim the onset of diarrhea to be an indication of where the body’s true vitamin C requirement lies, though this has not been clinically verified.

United States vitamin C recommendations[81]
Recommended Dietary Allowance (adult male) 90 mg per day
Recommended Dietary Allowance (adult female) 75 mg per day
Tolerable Upper Intake Level (adult male) 2,000 mg per day
Tolerable Upper Intake Level (adult female) 2,000 mg per day

Government recommended intakes

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

The United States defined Tolerable Upper Intake Level for a 25-year-old male is 2,000 milligrams per day.

Therapeutic uses

Further information: Vitamin C and the common cold

Vitamin C functions as an antioxidant and is necessary for the treatment and prevention of scurvy, though in nearly all cases dietary intake is adequate to prevent deficiency and supplementation is not necessary.[88][89][90][91][92][93] Though vitamin C has been promoted as useful in the treatment of a variety of conditions, most of these uses are poorly supported by the evidence and sometimes contraindicated.[94][95][96][97] Vitamin C may be useful in lowering serum uric acid levels, resulting in a correspondingly lower incidence of gout.[98] Neither prophylactic nor therapeutic use is supported in the prevention or treatment of pneumonia.[99] People with a the highest levels of ascorbic acid in their blood stream seem to be at a significantly reduced risk of having a stroke and low ascorbic acid has been suggested as a way of identifying those at high risk of stroke. [100]

Vitamin C's effect on the common cold has been extensively researched. It has not been shown effective in prevention or treatment of the common cold, except in limited circumstances (specifically, individuals exercising vigorously in cold environments).[101][102][103] Routine vitamin C supplementation does not reduce the incidence or severity of the common cold in the general population, though it may reduce the duration of illness.[101][104][105]

Vitamin C megadosage

Main article: Vitamin C megadosage

Several individuals and organizations advocate large doses of vitamin C in excess of 10–100 times RDI in the form of oral or intravenous therapy.[106] Large, randomized clinical trials on the effects of high doses on the general population have never taken place. Arguments for megadosage are based on the diets of closely related apes, the hypothesized diet of prehistoric humans, and that most mammals synthesize vitamin C rather than relying on dietary intake. Linus Pauling spent much of the later part of his life advocating for the use of megadose vitamin C and believed the established RDA was sufficient to prevent scurvy, but not necessarily the dosage for optimal health.[107] Megadoses have been promoted for the treatment or prevention of various conditions, including cancer,[108][109][110][111] the common cold,[101] and coronary disease.[112] These uses are not supported by clinical evidence, and in some cases harm may result.[101][108][109][110][111][112]

Testing for ascorbate levels in the body

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.[2] 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.[113][114]

Adverse effects

Common side-effects

Relatively large doses of ascorbic acid 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.[115] When taken in large doses, ascorbic acid causes diarrhea in healthy subjects. In one trial in 1936, doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes.[116]

Possible side-effects

As vitamin C enhances iron absorption,[117] iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD) can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C.[118]

There is a longstanding belief among the mainstream medical community that vitamin C causes kidney stones, which is based on little science.[119] Although recent studies have found a relationship,[120] a clear link between excess ascorbic acid intake and kidney stone formation has not been generally established.[121] Some case reports exist for a link between patients with oxalate deposits and a history of high-dose vitamin C usage.[122]

In a study conducted on rats, during the first month of pregnancy, high doses of vitamin C may suppress the production of progesterone from the corpus luteum.[123] Progesterone, necessary for the maintenance of a pregnancy, is produced by the corpus luteum for the first few weeks, until the placenta is developed enough to produce its own source. By blocking this function of the corpus luteum, high doses of vitamin C (1000+ mg) are theorized to induce an early miscarriage. In a group of spontaneously aborting women at the end of the first trimester, the mean values of vitamin C were significantly higher in the aborting group. However, the authors do state: 'This could not be interpreted as an evidence of causal association.'[124] However, in a previous study of 79 women with threatened, previous spontaneous, or habitual abortion, Javert and Stander (1943) had 91% success with 33 patients who received vitamin C together with bioflavonoids and vitamin K (only three abortions), whereas all of the 46 patients who did not receive the vitamins aborted.[125]

A study in rats and humans suggested that adding Vitamin C supplements to an exercise training program lowered the expected effect of training on VO2 Max. Although the results in humans were not statistically significant, this study is often cited as evidence that high doses of Vitamin C have an adverse effect on exercise performance. In rats, it was shown that the additional Vitamin C resulted in lowered mitochondria production.[126] Since rats are able to produce all of their needed Vitamin C, however, it is questionable whether they offer a relevant model of human physiological processes in this regard.

A cancer-causing mechanism of hexavalent chromium may be triggered by vitamin C.[127]

Chance of overdose

Vitamin C is water soluble, with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine. It exhibits remarkably low toxicity. The LD50 (the dose that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per kilogram of body weight when given by forced gavage (orally). The mechanism of death from such doses (1.2% of body weight, or 1.8 lbs for a 150 lb human) is unknown, but may be more mechanical than chemical.[128] The LD50 in humans remains unknown, given lack of any accidental or intentional poisoning death data. However, as with all substances tested in this way, the rat LD50 is taken as a guide to its toxicity in humans.

Dietary sources

Rose hips are a particularly rich source of vitamin C

The richest natural sources are fruits and vegetables, and of those, the Kakadu plum and the camu camu fruit contain the highest concentration of the vitamin. It is also present in some cuts of meat, especially liver. Vitamin C is the most widely taken nutritional supplement and is available in a variety of forms, including tablets, drink mixes, crystals in capsules or naked crystals.

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.[129]

Plant sources

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.[130]

The following table is approximate and shows the relative abundance in different raw plant sources.[131][132][133] As some plants were analyzed fresh while others were dried (thus, artifactually increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of fruit or vegetable and is a rounded average from multiple authoritative sources:

Plant source Amount
(mg / 100g)
Kakadu plum 3100-5000
Camu Camu 2800
Rose hip 2000
Acerola 1600
Seabuckthorn 695
Mica Muro 500
Indian gooseberry 445
Baobab 400
Chili pepper (green) 244
Guava (common, raw) 228.3[s 1]
Blackcurrant 200
Red pepper 190
Chili pepper (red) 144
Parsley 130
Kiwifruit 90
Broccoli 90
Loganberry 80
Redcurrant 80
Brussels sprouts 80
Wolfberry (Goji) 73 †
Lychee 70
Persimmon (native, raw) 66.0[s 2]
Cloudberry 60
Elderberry 60

† average of 3 sources; dried

Plant source Amount
(mg / 100g)
Papaya 60
Strawberry 60
Orange 50
Kale 41
Lemon 40
Melon, cantaloupe 40
Cauliflower 40
Garlic 31
Grapefruit 30
Raspberry 30
Tangerine 30
Mandarin orange 30
Passion fruit 30
Spinach 30
Cabbage raw green 30
Lime 30
Mango 28
Blackberry 21
Potato 20
Melon, honeydew 20
Cranberry 13
Tomato 10
Blueberry 10
Pineapple 10
Pawpaw 10
Plant source Amount
(mg / 100g)
Grape 10
Apricot 10
Plum 10
Watermelon 10
Banana 9
Carrot 9
Avocado 8
Crabapple 8
Persimmon (Japanese, fresh) 7.5[s 3]
Cherry 7
Peach 7
Apple 6
Asparagus 6
Horned melon 5.3[s 4]
Beetroot 5
Chokecherry 5
Pear 4
Lettuce 4
Cucumber 3
Eggplant 2
Raisin 2
Fig 2
Bilberry 1
Medlar 0.3


Plant sources notes

  1. ^ USDA Guava, common, raw
  2. ^ USDA Persimmons, native, raw
  3. ^ USDA Persimmon, japanese, raw
  4. ^ USDA Horned melon

Animal sources

Goats, like almost all animals, 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.[134][135]

The overwhelming majority of species of animals and plants synthesise their own vitamin C.[136] Therefore, some animal products can be used as sources of dietary vitamin C.

Vitamin C is most present in the liver and least present in the muscle. Since muscle provides the majority of meat consumed in the western human diet, animal products are not a reliable source of the vitamin. Vitamin C is present in mother's milk but, not present in raw cow's milk.[137] All excess vitamin C is disposed of through the urinary system.

The following table shows the relative abundance of vitamin C in various foods of animal origin, given in milligram of vitamin C per 100 grams of food:

Animal Source Amount
(mg / 100g)
Calf liver (raw) 36
Beef liver (raw) 31
Oysters (raw) 30
Cod roe (fried) 26
Pork liver (raw) 23
Lamb brain (boiled) 17
Chicken liver (fried) 13
Animal Source Amount
(mg / 100g)
Lamb liver (fried) 12
Calf adrenals (raw) 11[138]
Lamb heart (roast) 11
Lamb tongue (stewed) 6
Human milk (fresh) 4
Goat milk (fresh) 2
Camel milk (fresh) 5[139]
Cow milk (fresh) 2


Food preparation

Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Vitamin C concentrations in various food substances decrease with time in proportion to the temperature they are stored at[140] 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.[141] Longer cooking times also add to this effect, as will copper food vessels, which catalyse the decomposition.[128]

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.[142] Research has also shown that fresh-cut fruits do not lose significant nutrients when stored in the refrigerator for a few days.[143]

Vitamin C supplements

Vitamin C is widely available in the form of tablets and powders. The Redoxon brand, launched in 1934 by Hoffmann-La Roche, was the first mass-produced synthetic vitamin C.

Vitamin C is the most widely taken dietary supplement.[144] It is available in caplets, tablets, capsules, drink mix packets, in multi-vitamin formulations, in multiple antioxidant formulations, and as crystalline powder. Timed release versions are available, as are formulations containing bioflavonoids such as quercetin, hesperidin, and rutin. Tablet and capsule sizes range from 25 mg to 1500 mg. Vitamin C (as ascorbic acid) crystals are typically available in bottles containing 300 g to 1 kg of powder (a 5 ml teaspoon of vitamin C crystals equals 5,000 mg).

Industrial synthesis

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.[145]

Research is underway at the Scottish Crop Research Institute in the interest of creating a strain of yeast that can synthesise vitamin C in a single fermentation step from galactose, a technology expected to reduce manufacturing costs considerably.[18]

World production of synthesised vitamin C is currently estimated at approximately 110,000 tonnes annually. 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.[146] 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.[147] 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.[148] In 2011 a case was filed in a US court against 4 Chinese companies that they 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 do not deny the accusation but say in their defense that the Chinese government compelled them to act in this way.[149]

Food fortification

In 2005, Health Canada evaluated the effect of fortification of foods with ascorbate in the guidance document, Addition of Vitamins and Minerals to Food.[150] Abscorbate was categorized as a ‘Risk Category A nutrients’, meaning it is a nutrient for which an upper limit for intake is set but allows a wide margin of intake that has a narrow margin of safety but non-serious critical adverse effects. Health Canada recommended a minimum of 3 mg or 5% of RDI for the food to claim to be a source of Vitamin C, and maximum fortification of 12 mg (20% of RDI) to claim "Excellent Source".[150]

Compendial status


History

James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented the disease of scurvy in what was the first recorded controlled experiment.

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.[153][154]

Throughout history, the benefit of plant food to survive long sea voyages has been occasionally recommended by authorities. John Woodall, the first appointed surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his book, The Surgeon's Mate, in 1617. The Dutch writer, Johann Bachstrom, in 1734, gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens, which is alone the primary cause of the disease."[155]

Scurvy had long been a principal killer of sailors during the long sea voyages.[156] 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."[157]

While the earliest documented case of scurvy was described by Hippocrates around the year 400 BC, the first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the British Royal Navy, James Lind. Scurvy was common among those with poor access to fresh fruit and vegetables, such as remote, isolated sailors and soldiers. 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 the history of science, this is considered to be the first occurrence of a controlled experiment. The results conclusively showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.[158]

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

Lind's work was slow to be noticed, partly because his Treatise was not published until six years after his study, and also because he recommended a lemon juice extract known as rob.[159] Fresh fruit was very expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles).[128] Ship captains concluded wrongly that Lind's other suggestions were ineffective because those juices failed to prevent or cure scurvy.

It was 1795 before the British navy adopted lemons or lime as standard issue at sea. Limes were more popular, as they could be found in British West Indian Colonies, unlike lemons, which were not found in British Dominions, and were therefore more expensive. This practice led to the American use of the nickname "limey" to refer to the British. Captain James Cook had previously demonstrated and proven the principle of the advantages of carrying "Sour krout" on board, by taking his crews to the Hawaiian Islands and beyond without losing any of his men to scurvy.[160] For this otherwise unheard of feat, the British Admiralty awarded him a medal.

The name antiscorbutic was used in the eighteenth and nineteenth centuries as general term for those foods known to prevent scurvy, even though there was no understanding of the reason for this. These foods included but were not limited to: lemons, limes, and oranges; sauerkraut, cabbage,malt, and portable soup.[161]

Even before the antiscorbutic substance was identified, there were indications that it was present in amounts sufficient to prevent scurvy, in nearly all fresh (uncooked and uncured) foods, including raw animal-derived foods. In 1928, the Arctic anthropologist Vilhjalmur Stefansson attempted to prove his theory of how the Eskimos are able to avoid scurvy with almost no plant food in their diet, despite the disease's striking European Arctic explorers living on similar high cooked-meat diets. Stefansson theorised that the natives get their vitamin C from fresh meat that is minimally cooked. Starting in February 1928, for one year he and a colleague lived on an exclusively minimally-cooked meat diet while under medical supervision; they remained healthy. Later studies done after vitamin C could be quantified in mostly-raw traditional food diets of the Yukon, Inuit, and Métís of the Northern Canada, showed that their daily intake of vitamin C averaged between 52 and 62 mg/day, an amount approximately the dietary reference intake (DRI), even at times of the year when little plant-based food was eaten.[162]

Discovery

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".

In 1907, the needed biological-assay model to isolate and identify the antiscorbutic factor was discovered. Axel Holst and Theodor Frølich, two Norwegian physicians studying shipboard beriberi in the Norwegian fishing fleet, wanted a small test mammal to substitute for the pigeons then used in beriberi research. They fed guinea pigs their test diet of grains and flour, which had earlier produced beriberi in their pigeons, and were surprised when classic scurvy resulted instead. This was a serendipitous choice of model. Until that time, scurvy had not been observed in any organism apart from humans, and had been considered an exclusively human disease. (Pigeons, as seed-eating birds, were also later found to make their own vitamin C.) Holst and Frølich found they could cure the disease in guinea pigs with the addition of various fresh foods and extracts. This discovery of a clean animal experimental model for scurvy, made even before the essential idea of vitamins in foods had even been put forward, has been called the single most important piece of vitamin C research.[163]

In 1912, the Polish American biochemist Casimir Funk, while researching beriberi in pigeons, developed the concept of vitamins to refer to the non-mineral micronutrients that are essential to health. The name is a blend of "vital", due to the vital biochemical role they play, and "amines" because Funk thought that all these materials were chemical amines. Although the "e" was dropped after skepticism that all these compounds were amines, the word vitamin remained as a generic name for them. One of the vitamins was thought to be the anti-scorbutic factor in foods discovered by Holst and Frølich. In 1928, this vitamin was referred to as "water-soluble C," although its chemical structure had still not been determined. [164]

From 1928 to 1932, the Hungarian research team of Albert Szent-Györgyi and Joseph L. Svirbely, as well as the American team led by Charles Glen King in Pittsburgh, first identified the anti-scorbutic factor. Szent-Györgyi had isolated the chemical hexuronic acid from animal adrenal glands at the Mayo clinic, and suspected it to be the antiscorbutic factor, but could not prove it without a biological assay. At the same time, for five years, King's laboratory at the University of Pittsburgh had been trying to isolate the antiscorbutic factor in lemon juice, using the original 1907 model of scorbutic guinea pigs, which developed scurvy when not fed fresh foods, but were cured by lemon juice. They had also considered hexuronic acid, but had been put off the trail when a coworker made the explicit (and mistaken) experimental claim that this substance was not the antiscorbutic substance.[citation needed]

Finally, in late 1931, Szent-Györgyi gave Svirbely, formerly of King's lab, the last of this 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, leading to a bitter dispute over priority claims (in reality it had taken a team effort by both groups, since Szent-Györgyi was unwilling to do the difficult and messy animal studies).[citation needed]

Meanwhile, by 1932, Szent-Györgyi had moved to Hungary and his group had discovered that paprika peppers, a common spice in the Hungarian diet, was a rich source of hexuronic acid, the antiscorbutic factor. With a new and plentiful source of the vitamin, Szent-Györgyi sent a sample to noted British sugar chemist Walter Norman Haworth, who chemically identified it and proved the identification by synthesis in 1933.{{Time fact{{ Haworth and Szent-Györgyi now proposed that the substance be called a-scorbic acid, and chemically L-ascorbic acid, in honor of its activity against scurvy.[165]Ascorbic acid turned out not to be an amine, nor even to contain any nitrogen.

In part, in recognition of his accomplishment with vitamin C, Szent-Györgyi was awarded the unshared 1937 Nobel Prize in Medicine.[166] Haworth also shared that year's Nobel Prize in Chemistry, in part for his vitamin C synthetic work.

Between 1933 and 1934, not only Haworth and fellow British chemist (later Sir) Edmund Hirst had synthesized vitamin C, but also, independently, the Polish chemist Tadeus Reichstein, succeeded in synthesizing the vitamin in bulk, making it the first vitamin to be artificially produced.[chronology citation needed] The latter process made possible the cheap mass-production of semi-synthetic vitamin C, which was quickly marketed. Only Haworth was awarded the 1937 Nobel Prize in Chemistry in part for this work, but the Reichstein process, a combined chemical and bacterial fermentation sequence still used today to produce vitamin C, retained Reichstein's name.[167][168] In 1934 Hoffmann–La Roche, which bought the Reichstein process patent, became the first pharmaceutical company to mass produce and market synthetic vitamin C, under the brand name of Redoxon.[169]

In 1957, the American J.J. Burns showed that the reason some mammals are susceptible to scurvy is the inability of their liver to produce the active enzyme L-gulonolactone oxidase, which is the last of the chain of four enzymes that synthesize vitamin C.[170][171] 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.[172]

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.[14]

Society and culture

  • In February 2011 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. Swiss chemist Tadeus Reichstein synthesised the vitamin for the first time in 1933.[173]

References

  1. ^ Padayatty, Sebastian J.; Katz, Arie; Wang, Yaohui; Eck, Peter; Kwon, Oran; Lee, Je-Hyuk; Chen, Shenglin; Corpe, Christopher et al. (2003). "Vitamin C as an antioxidant: evaluation of its role in disease prevention". Journal of the American College of Nutrition 22 (1): 18–35. PMID 12569111. http://www.jacn.org/cgi/content/full/22/1/18. 
  2. ^ a b c d e f "Vitamin C". Food Standards Agency (UK). http://www.eatwell.gov.uk/healthydiet/nutritionessentials/vitaminsandminerals/vitaminc/. Retrieved 2007-02-19. 
  3. ^ "Vitamin C". University of Maryland Medical Center. January 2007. http://www.umm.edu/ency/article//002404.htm. Retrieved 2008-03-31. 
  4. ^ a b Higdon, Jane, Ph.D. (2006-01-31). "Vitamin C". Oregon State University, Micronutrient Information Center. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminC/. Retrieved 2007-03-07. 
  5. ^ Meister, Alton (1994). "Glutathione-ascorbic acid antioxidant system in animals". The Journal of biological chemistry 269 (13): 9397–400. PMID 8144521. http://www.jbc.org/content/269/13/9397.full.pdf+html. 
  6. ^ , Nualart FJ, Rivas CI, Montecinos VP, et al. Recycling of vitamin C by a bystander effect. J Biol Chem 2003; 278:10128–10133.
  7. ^ a b Gropper SS, Smith JL, Grodd JL (2004). Advanced Nutrition and Human Metabolism (4th ed.). Belmont, CA. USA: Thomson Wadsworth. pp. 260–275. 
  8. ^ Bánhegyi, Gábor; Mandl, JóZsef (2001). "The hepatic glycogenoreticular system". Pathology & Oncology Research 7 (2): 107–110. doi:10.1007/BF03032575. 
  9. ^ Martinez del Rio, Carlos (July 1997). "Can passerines synthesize vitamin C?". The Auk 114 (3): 513–16. JSTOR 4089257. http://findarticles.com/p/articles/mi_qa3793/is_199707/ai_n8765385. Retrieved 2 May 2011. 
  10. ^ Jenness, R; Birney, E; Ayaz, K (1980). "Variation of l-gulonolactone oxidase activity in placental mammals". Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology 67 (2): 195–204. doi:10.1016/0305-0491(80)90131-5.  Earlier reports of only fruit bats lacking synthesisng ability were based on smaller samples.
  11. ^ Harris, James W. (1996). Ascorbic acid: biochemistry and biomedical cell biology. New York: Plenum Press. p. 35. ISBN 0-306-45148-4. 
  12. ^ Nishikimi, M; Kawai, T; Yagi, K (October 1992). "Guinea pigs possess a markedly different gene for L-gulono-gamma-lactone oxidase, the key enzyme for L-ascorbic acid biosynthesis missing in this species". The Journal of biological chemistry 267 (30): 21967–72. PMID 1400507. 
  13. ^ Ohta, Y; Nishikimi, M (October 1999). "Random nucleotide substitutions in primate nonfunctional gene for L-gulono-gamma-lactone oxidase, the missing enzyme in L-ascorbic acid biosynthesis". Biochimica et biophysica acta 1472 (1–2): 408–11. doi:10.1016/S0304-4165(99)00123-3. PMID 10572964. 
  14. ^ a b Montelhagen, A; Kinet, S; Manel, N; Mongellaz, C; Prohaska, R; Battini, JL; Delaunay, J; Sitbon, M et al. (2008). "Erythrocyte Glut1 Triggers Dehydroascorbic Acid Uptake in Mammals Unable to Synthesize Vitamin C". Cell 132 (6): 1039–48. doi:10.1016/j.cell.2008.01.042. PMID 18358815. Lay summary – Science Daily (March 21, 2008). 
  15. ^ Milton, K (1999). "Nutritional characteristics of wild primate foods: do the diets of similar organisms have lessons for us?". Nutrition 15 (6): 488–98. doi:10.1016/S0899-9007(99)00078-7. PMID 10378206. 
  16. ^ Stone, Irwin (July 16, 1978). "Eight Decades of Scurvy. The Case History of a Misleading Dietary Hypothesis". http://www.seanet.com/~alexs/ascorbate/197x/stone-i-orthomol_psych-1979-v8-n2-p58.htm. Retrieved 2007-04-06. "Biochemical research in the 1950s showed that the lesion in scurvy is the absence of the enzyme, L-Gulonolactone oxidase (GLO) in the human liver (Burns, 1959). This enzyme is the last enzyme in a series of four that convert blood sugar, glucose, into ascorbate in the mammalian liver. This liver metabolite, ascorbate, is produced in an unstressed goat, for instance, at the rate of about 13,000 mg per day per 150 pounds body weight (Chatterjee, 1973). A mammalian feedback mechanism increases this daily ascorbate production many fold under stress (Subramanian et al., 1973)" 
  17. ^ Long, C; Maull, KI; Krishnan, RS; Laws, HL; Geiger, JW; Borghesi, L; Franks, W; Lawson, TC et al. (2003). "Ascorbic acid dynamics in the seriously ill and injured". Journal of Surgical Research 109 (2): 144–8. doi:10.1016/S0022-4804(02)00083-5. PMID 12643856. 
  18. ^ a b R.D. Hancock & R. Viola. "Ascorbic acid biosynthesis in higher plants and microorganisms" (PDF). Scottish Crop Research Institute. http://www.scri.ac.uk/scri/file/individualreports/2002/20Ascorb.pdf. Retrieved 2007-02-20. 
  19. ^ Hancock, Robert D.; Galpin, John R.; Viola, Roberto (2000). "Biosynthesis of L-ascorbic acid (vitamin C) by Saccharomyces cerevisiae". FEMS Microbiology Letters 186 (2): 245–50. doi:10.1111/j.1574-6968.2000.tb09112.x. PMID 10802179. 
  20. ^ Venturi S, Venturi M. Evolution of Dietary Antioxidant Defences. European EPI-Marker. 2007, 11, 3 :1–7. http://www.icb-asbl.com/en/pdf/epimarker/epimarker_3_07.pdf
  21. ^ Venturi, S; Donati, FM; Venturi, A; Venturi, M (2000). "Environmental iodine deficiency: A challenge to the evolution of terrestrial life?". Thyroid : official journal of the American Thyroid Association 10 (8): 727–9. doi:10.1089/10507250050137851. PMID 11014322. 
  22. ^ Purves WK, Sadava D, Orians GH, Heller HC. 1998. Life.The Science of Biology. Part 4: The Evolution of Diversity. Chapter 30[page needed]
  23. ^ Venturi, S; Venturi, M (1999). "Iodide, thyroid and stomach carcinogenesis: evolutionary story of a primitive antioxidant?". European Journal of Endocrinology 140 (4): 371–2. doi:10.1530/eje.0.1400371. PMID 10097259. 
  24. ^ Hardie, L.J.; Fletcher, T.C.; Secombes, C.J. (1991). "The effect of dietary vitamin C on the immune response of the Atlantic salmon (Salmo salar L.)". Aquaculture 95 (3–4): 201–14. doi:10.1016/0044-8486(91)90087-N. 
  25. ^ Challem, J; Taylor, EW (1998). "Retroviruses, Ascorbate, and Mutations, in the Evolution of Homo sapiens". Free Radical Biology and Medicine 25 (1): 130–2. doi:10.1016/S0891-5849(98)00034-3. PMID 9655531. 
  26. ^ Bánhegyi, G; Braun, L; Csala, M; Puskás, F; Mandl, J (1997). "Ascorbate Metabolism and Its Regulation in Animals". Free Radical Biology and Medicine 23 (5): 793–803. doi:10.1016/S0891-5849(97)00062-2. PMID 9296457. 
  27. ^ Stone, I (1979). "Homo sapiens ascorbicus, a biochemically corrected robust human mutant". Medical Hypotheses 5 (6): 711–21. doi:10.1016/0306-9877(79)90093-8. PMID 491997. 
  28. ^ Pollock, J. I.; Mullin, R. J. (1987). "Vitamin C biosynthesis in prosimians: Evidence for the anthropoid affinity ofTarsius". American Journal of Physical Anthropology 73 (1): 65–70. doi:10.1002/ajpa.1330730106. PMID 3113259. 
  29. ^ Poux, C.; Douzery, E.J.P. (2004). "Primate phylogeny, evolutionary rate variations,and divergence times: a contribution from the nuclear gene IRBP". American Journal of Physical Anthropology 124 (1): 1–16. doi:10.1002/ajpa.10322. PMID 15085543. 
  30. ^ Goodman, M.; Porter, C.A.; Czelusniak, J.; Page, S.L.; Schneider, H.; Shoshani, J.; Gunnell, G.; Groves, C.P. (1998). "Toward a phylogenetic classification of primates based on DNA evidence complemented by fossil evidence". Molecular Phylogenetics and Evolution 9 (3): 585–598. doi:10.1006/mpev.1998.0495. PMID 9668008. 
  31. ^ Porter, C.A., Page, S.L., Czelusniak, J., Schneider, H., Schneider, M.P.C., Sampaio, I. and Goodman, M., 1997. Phylogeny and evolution of selected primates as determined by sequences of the ?-globin locus and 5’flanking regions. International Journal of Primatology, 18: 261–295. Refs Poux, Porter and Goodman preceding, as quoted in [1]
  32. ^ Proctor P (1970). "Similar functions of uric acid and ascorbate in man?". Nature 228 (5274): 868. doi:10.1038/228868a0. PMID 5477017. 
  33. ^ a b Savini, I.; Rossi, A.; Pierro, C.; Avigliano, L.; Catani, M. V. (2007). "SVCT1 and SVCT2: key proteins for vitamin C uptake". Amino Acids 34 (3): 347–55. doi:10.1007/s00726-007-0555-7. PMID 17541511. 
  34. ^ Rumsey, SC; Kwon, O; Xu, GW; Burant, CF; Simpson, I; Levine, M (1997). "Glucose transporter isoforms GLUT1 and GLUT3 transport dehydroascorbic acid". The Journal of biological chemistry 272 (30): 18982–9. doi:10.1074/jbc.272.30.18982. PMID 9228080. 
  35. ^ May, J; Qu, Zhi-Chao; Neel, Dustin R.; Li, Xia (2003). "Recycling of vitamin C from its oxidized forms by human endothelial cells". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 1640 (2–3): 153–61. doi:10.1016/S0167-4889(03)00043-0. 
  36. ^ Packer, L. (1997) Vitamin C and redox cycling antioxidants. In: Packer L, F. J. (ed). Vitamin C in health and disease, Marcel Dekker Inc, New York[page needed]
  37. ^ May, JM; Qu, ZC; Qiao, H; Koury, MJ (2007). "Maturational Loss of the Vitamin C Transporter in Erythrocytes". Biochemical and biophysical research communications 360 (1): 295–8. doi:10.1016/j.bbrc.2007.06.072. PMC 1964531. PMID 17586466. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1964531. 
  38. ^ Sotiriou, S; Gispert, S; Cheng, J; Wang, Y; Chen, A; Hoogstraten-Miller, S; Miller, GF; Kwon, O et al. (2002). "Ascorbic-acid transporter Slc23a1 is essential for vitamin C transport into the brain and for perinatal survival". Nature medicine 8 (5): 514–7. doi:10.1038/0502-514. PMID 11984597. 
  39. ^ Levine, M; Conry-Cantilena, C; Wang, Y; Welch, RW; Washko, PW; Dhariwal, KR; Park, JB; Lazarev, A et al. (1996). "Vitamin C pharmacokinetics in healthy volunteers: evidence for a recommended dietary allowance". Proceedings of the National Academy of Sciences of the United States of America 93 (8): 3704–9. doi:10.1073/pnas.93.8.3704. PMC 39676. PMID 8623000. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=39676. 
  40. ^ Oreopoulos, DG; Lindeman, RD; Vanderjagt, DJ; Tzamaloukas, AH; Bhagavan, HN; Garry, PJ (1993). "Renal excretion of ascorbic acid: effect of age and sex". Journal of the American College of Nutrition 12 (5): 537–42. PMID 8263270. 
  41. ^ Hediger, Matthias A. (2002). "New view at C". Nature Medicine 8 (5): 445–6. doi:10.1038/nm0502-445. PMID 11984580. 
  42. ^ a b MedlinePlus Encyclopedia Ascorbic acid
  43. ^ "The influence of smoking on Vitamin C status in adults". BBC news and Cambridge University. 2000-09-31. http://news.bbc.co.uk/2/hi/health/901196.stm. Retrieved 2007-12-12. 
  44. ^ Rath, M; Pauling, L. (1990). "Immunological evidence for the accumulation of lipoprotein(a) in the atherosclerotic lesion of the hypoascorbemic guinea pig". Proceedings of the National Academy of Sciences 87 (23): 9388–9390. doi:10.1073/pnas.87.23.9388. PMC 55170. PMID 2147514. http://www.pnas.org/content/87/23/9388.full.pdf. 
  45. ^ Statistics Canada, Canadian Community Health Survey, Cycle 2.2, Nutrition (2004)
  46. ^ J Pemberton. Medical experiments carried out in Sheffield on conscientious objectors to military service during the 1939–45 war. International Journal of Epidemiology 2006 35(3):556–558; doi:10.1093/ije/dyl020 full text.
  47. ^ Hodges, R. E.; Baker, E. M.; Hood, J.; Sauberlich, H. E.; March, S. C. (1969). "Experimental Scurvy in Man". American Journal of Clinical Nutrition 22 (5): 535–548. PMID 4977512. 
  48. ^ Khaw, Kay-Tee; Bingham, Sheila ; Welch, Ailsa ; Luben, Robert; Wareham, Nicholas; Day, Nicholas (March 2001). "Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition". Lancet 357 (9257): 657–63. doi:10.1016/S0140-6736(00)04128-3. PMID 11247548. 
  49. ^ Hemil, Harri (15 October 2007). "The Role of Vitamin C in the Treatment of the Common Cold". Americal Family Physician. http://www.aafp.org/afp/2007/1015/p1111a.html. 
  50. ^ Barbosa, Eliana; Faintuch, Joel; Machado Moreira, Emilia Addison; Gonçalves da Silva, Viviane Rodrigues; Lopes Pereima, Maurício José; Martins Fagundes, Regina Lúcia; Filho, Danilo Wilhelm (2009). "Supplementation of vitamin E, vitamin C, and zinc attenuates oxidative stress in burned children: a randomized, double-blind, placebo-controlled pilot study". J Burn Care Res 30 (5): 859–66. doi:10.1097/BCR.0b013e3181b487a8. PMID 19692922. http://journals.lww.com/burncareresearch/Abstract/2009/09000/Supplementation_of_Vitamin_E,_Vitamin_C,_and_Zinc.15.aspx. 
  51. ^ a b 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. 541–67. ISBN 0-7216-4452-X. 
  52. ^ Prockop DJ, Kivirikko KI (1995). "Collagens: molecular biology, diseases, and potentials for therapy". Annu Rev Biochem. 64: 403–34. doi:10.1146/annurev.bi.64.070195.002155. PMID 7574488. 
  53. ^ Peterkofsky B (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. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=1720597. 
  54. ^ Kivirikko KI, Myllylä R (1985). "Post-translational processing of procollagens". Annals of the New York Academy of Sciences 460: 187–201. doi:10.1111/j.1749-6632.1985.tb51167.x. PMID 3008623. 
  55. ^ Rebouche CJ (1991). "Ascorbic acid and carnitine biosynthesis". The American Journal of Clinical Nutrition 54 (6 Suppl): 1147S–1152S. PMID 1962562. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=1962562. 
  56. ^ Dunn WA, Rettura G, Seifter E, Englard S (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): 10764–70. PMID 6432788. http://www.jbc.org/cgi/reprint/259/17/10764.pdf. 
  57. ^ Levine M, Dhariwal KR, Washko P, et al. (1992). "Ascorbic acid and reaction kinetics in situ: a new approach to vitamin requirements". J Nutr Sci Vitaminol. Spec No: 169–72. PMID 1297733. 
  58. ^ Kaufman S (1974). "Dopamine-beta-hydroxylase". J Psychiatr Res 11: 303–16. doi:10.1016/0022-3956(74)90112-5. PMID 4461800. 
  59. ^ 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): 489–97. doi:10.1002/pro.5560020401. PMC 2142366. PMID 8518727. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2142366. 
  60. ^ 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. 
  61. ^ 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. 
  62. ^ Lindblad B, Lindstedt G, Lindstedt S (1970). "The mechanism of enzymic formation of homogentisate from p-hydroxyphenylpyruvate". J Am Chem Soc. 92 (25): 7446–9. doi:10.1021/ja00728a032. PMID 5487549. 
  63. ^ a b c d McGregor, GP; Biesalski, HK (2006). "Rationale and impact of vitamin C in clinical nutrition". Current opinion in clinical nutrition and metabolic care 9 (6): 697–703. doi:10.1097/01.mco.0000247478.79779.8f. PMID 17053422. 
  64. ^ Kelly, FJ (1998). "Use of antioxidants in the prevention and treatment of disease". Journal of the International Federation of Clinical Chemistry / IFCC 10 (1): 21–3. PMID 10181011. 
  65. ^ Mayne, ST (2003). "Antioxidant nutrients and chronic disease: use of biomarkers of exposure and oxidative stress status in epidemiologic research". The Journal of nutrition 133 Suppl 3: 933S–940S. PMID 12612179. 
  66. ^ Tak, PP; Zvaifler, NJ; Green, DR; Firestein, GS (2000). "Rheumatoid arthritis and p53: how oxidative stress might alter the course of inflammatory diseases". Immunology today 21 (2): 78–82. doi:10.1016/S0167-5699(99)01552-2. PMID 10652465. 
  67. ^ Goodyear-Bruch, C; Pierce, JD (2002). "Oxidative stress in critically ill patients". American journal of critical care : an official publication, American Association of Critical-Care Nurses 11 (6): 543–51; quiz 552–3. PMID 12425405. 
  68. ^ Schorah, CJ; Downing, C; Piripitsi, A; Gallivan, L; Al-Hazaa, AH; Sanderson, MJ; Bodenham, A (1996). "Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients". The American journal of clinical nutrition 63 (5): 760–5. PMID 8615361. 
  69. ^ Jacques, Paul F.; Sulsky, Sandra I.; Perrone, Gayle E.; Jenner, Jennifer; Schaefer, Ernst J. (1995). "Effect of vitamin C supplementation on lipoprotein cholesterol, apolipoprotein, and triglyceride concentrations☆". Annals of Epidemiology 5 (1): 52–9. doi:10.1016/1047-2797(94)00041-Q. PMID 7728285. 
  70. ^ Fotherby, Martin; Williams, Julie; Forster, Louise; Craner, Paul; Ferns, Gordon (2000). "Effect of vitamin C on ambulatory blood pressure and plasma lipids in older persons". Journal of Hypertension 18 (4): 541–4. doi:10.1097/00004872-200018040-00009. PMID 10779091. 
  71. ^ Fotherby, Martin; Williams, Julie; Forster, Louise; Craner, Paul; Ferns, Gordon (2000). "Effect of vitamin C on ambulatory blood pressure and plasma lipids in older persons". Journal of Hypertension 18 (4): 411–5. doi:10.1097/00004872-200018040-00009. PMID 10779091. 
  72. ^ Bo, Simona; Ciccone, Giovannino; Durazzo, Marilena; Gambino, Roberto; Massarenti, Paola; Baldi, Ileana; Lezo, Antonela; Tiozzo, Elisa et al. (2007). "Efficacy of Antioxidant Treatment in Reducing Resistin Serum Levels: A Randomized Study". PLoS Clinical Trials 2 (5): e17. doi:10.1371/journal.pctr.0020017. PMC 1865087. PMID 17479165. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1865087. 
  73. ^ Mayer-Davis, EJ; Monaco, JH; Marshall, JA; Rushing, J; Juhaeri (1997). "Vitamin C intake and cardiovascular disease risk factors in persons with non-insulin-dependent diabetes mellitus. From the Insulin Resistance Atherosclerosis Study and the San Luis Valley Diabetes Study". Preventive medicine 26 (3): 277–83. doi:10.1006/pmed.1997.0145. PMID 9144749. 
  74. ^ Bjelakovic, G.; Nikolova, D.; Gluud, L. L.; Simonetti, R. G.; Gluud, C. (2007). "Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis". JAMA: the Journal of the American Medical Association 297 (8): 842–857. doi:10.1001/jama.297.8.842. PMID 17327526. 
  75. ^ Satoh, K; Sakagami, H (1997). "Effect of metal ions on radical intensity and cytotoxic activity of ascorbate". Anticancer research 17 (2A): 1125–9. PMID 9137459. 
  76. ^ Mühlhöfer, A; Mrosek, S; Schlegel, B; Trommer, W; Rozario, F; Böhles, H; Schremmer, D; Zoller, W G et al. (2004). "High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers". European Journal of Clinical Nutrition 58 (8): 1151–8. doi:10.1038/sj.ejcn.1601943. PMID 15054428. 
  77. ^ Podmore, Ian D.; Griffiths, Helen R.; Herbert, Karl E.; Mistry, Nalini; Mistry, Pratibha; Lunec, Joseph (1998). "Vitamin C exhibits pro-oxidant properties". Nature 392 (6676): 559. Bibcode 1998Natur.392..559P. doi:10.1038/33308. PMID 9560150. 
  78. ^ Preedy VR; Watson RR; Sherma Z (2010). Dietary Components and Immune Function (Nutrition and Health). Totowa, NJ: Humana Press. pp. 36; 52. ISBN 1-60761-060-4. 
  79. ^ Johnston, Carol S.; Martin, L. J.; Cai, X. (1992). "Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis". Am Coll Nutr 11 (2): 172–176. PMID 1578094. http://www.jacn.org/cgi/content/abstract/11/2/172. 
  80. ^ Smirnoff, N (1996). "BOTANICAL BRIEFING: The Function and Metabolism of Ascorbic Acid in Plants". Annals of Botany 78 (6): 661–9. doi:10.1006/anbo.1996.0175. 
  81. ^ a b c d "US Recommended Dietary Allowance (RDA)" (PDF). Archived from the original on 2008-05-29. http://web.archive.org/web/20080529070818/http://www.iom.edu/Object.File/Master/7/296/webtablevitamins.pdf. Retrieved 2007-02-19. 
  82. ^ Milton, K (2003). "Micronutrient intakes of wild primates: are humans different?". Comparative Biochemistry and Physiology - Part A: Molecular & Integrative Physiology 136 (1): 47–59. doi:10.1016/S1095-6433(03)00084-9. PMID 14527629. 
  83. ^ "Linus Pauling Vindicated; Researchers Claim RDA For Vitamin C is Flawed" (Press release). Knowledge of Health. July 6, 2004. http://www2.prnewswire.com/cgi-bin/stories.pl?ACCT=109&STORY=/www/story/07-06-2004/0002204911. Retrieved October 28, 2010. 
  84. ^ A.C. Carr, B. Frei, "Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans", American Journal of Clinical Nutrition, Vol. 69, No. 6, 1086-1107, June 1999.
  85. ^ Cathcart, Robert (1981). "Vitamin C, titrating to bowel tolerance, anascorbemia, and acute induced scurvy". Medical hypotheses 7 (11): 1359–76. doi:10.1016/0306-9877(81)90126-2. PMID 7321921. http://www.orthomed.com/titrate.htm. 
  86. ^ "Vitamin and mineral requirements in human nutrition, 2nd edition" (PDF). World Health Organization. 2004. http://whqlibdoc.who.int/publications/2004/9241546123_chap7.pdf. Retrieved 2007-02-20. 
  87. ^ http://www.hc-sc.gc.ca/dhp-mps/prodnatur/applications/licen-prod/monograph/mono_vitamin_c_e.html hc-sc.gc.ca
  88. ^ WHO (2001-06-04). "Area of work: nutrition. Progress report 2000" (PDF). Archived from the original on 2007-07-03. http://web.archive.org/web/20070703141441/http://www.who.int/mipfiles/2299/MIP_01_APR_SDE_3.en.pdf 
  89. ^ Olmedo JM, Yiannias JA, Windgassen EB, Gornet MK (August 2006). "Scurvy: a disease almost forgotten". Int. J. Dermatol. 45 (8): 909–13. doi:10.1111/j.1365-4632.2006.02844.x. PMID 16911372. 
  90. ^ Shenkin A (2006). "The key role of micronutrients". Clin Nutr 25 (1): 1–13. doi:10.1016/j.clnu.2005.11.006. PMID 16376462. 
  91. ^ Woodside J, McCall D, McGartland C, Young I (2005). "Micronutrients: dietary intake v. supplement use". Proc Nutr Soc 64 (4): 543–53. doi:10.1079/PNS2005464. PMID 16313697. 
  92. ^ Stanner SA, Hughes J, Kelly CN, Buttriss J (2004). "A review of the epidemiological evidence for the 'antioxidant hypothesis'". Public Health Nutr 7 (3): 407–22. doi:10.1079/PHN2003543. PMID 15153272. 
  93. ^ Rivers, Jerry M (1987). "Safety of High-level Vitamin C Ingestion". Annals of the New York Academy of Sciences 498: 445–54. doi:10.1111/j.1749-6632.1987.tb23780.x. PMID 3304071. 
  94. ^ "Vitamin C (Ascorbic acid)". MedLine Plus. National Institute of Health. 2006-08-01. http://www.nlm.nih.gov/medlineplus/druginfo/natural/patient-vitaminc.html. Retrieved 2007-08-03. 
  95. ^ Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008). Bjelakovic, Goran. ed. "Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases". Cochrane Database Syst Rev (2): CD007176. doi:10.1002/14651858.CD007176. PMID 18425980. 
  96. ^ Huang, Han-Yao; Caballero, Benjamin; Chang, Stephanie; Alberg, Anthony J.; Semba, Richard D.; Schneyer, Christine; Wilson, Renee F.; Cheng, Ting-Yuan; Prokopowicz, Gregory; Barnes, George J. II; Vassy, Jason; Bass, Eric B. (May 2006). "Multivitamin/mineral supplements and prevention of chronic disease". Evid Rep Technol Assess (Full Rep) (139): 1–117. PMID 17764205. http://www.ajcn.org/cgi/content/full/85/1/265S. 
  97. ^ Brzozowska A, Kaluza J, Knoops KT, de Groot LC (April 2008). "Supplement use and mortality: the SENECA study". Eur J Nutr 47 (3): 131–7. doi:10.1007/s00394-008-0706-y. PMID 18414768. 
  98. ^ Choi, MD, DrPH, Hyon K.; Xiang Gao, MD, PhD; Gary Curhan, MD, ScD (March 9, 2009). "Vitamin C Intake and the Risk of Gout in Men – A Prospective Study". Archives of Internal Medicine. 169 (5): 502–507. doi:10.1001/archinternmed.2008.606. PMC 2767211. PMID 19273781. http://archinte.ama-assn.org/cgi/content/abstract/169/5/502. 
  99. ^ Hemilä H, Louhiala P (2007). Hemilä, Harri. ed. "Vitamin C for preventing and treating pneumonia". Cochrane Database Syst Rev (1): CD005532. doi:10.1002/14651858.CD005532.pub2. PMID 17253561. 
  100. ^ Myint, PK; Luben RN, Welch AA, Bingham SA, Wareham NJ, Khaw KT. (2008). "Plasma vitamin C concentrations predict risk of incident stroke over 10 y in 20 649 participants of the European Prospective Investigation into Cancer Norfolk prospective population study". The American Journal of Clinical Nutrition Jan;87(1): (1): 64–9. PMID 18175738. ""...persons in the top quartiles of baseline plasma vitamin C concentrations had a 42% lower risk (relative risk: 0.58; 95% CI: 0.43, 0.78) than did those in the bottom quartile, independently of age, sex, smoking, body mass index, systolic blood pressure, cholesterol, physical activity, prevalent diabetes and myocardial infarction, social class, alcohol consumption, and any supplement use."" 
  101. ^ a b c d Hemilä, Harri; Chalker, Elizabeth; Douglas, Bob; Hemilä, Harri (2007). Hemilä, Harri. ed. "Vitamin C for preventing and treating the common cold". Cochrane database of systematic reviews (3): CD000980. doi:10.1002/14651858.CD000980.pub3. PMID 17636648. 
  102. ^ Douglas, R.; Hemilä, H.; Chalker, E.; Treacy, B. (2007). Hemilä, Harri. ed. "Vitamin C for preventing and treating the common cold". Cochrane Database of Systematic Reviews (3): CD000980. doi:10.1002/14651858.CD000980.pub3. PMID 17636648.  edit
  103. ^ Heiner, Kathryn A; Hart, Ann Marie; Martin, Linda Gore; Rubio-Wallace, Sherrie (2009). "Examining the evidence for the use of vitamin C in the prophylaxis and treatment of the common cold". Journal of the American Academy of Nurse Practitioners 21 (5): 295–300. doi:10.1111/j.1745-7599.2009.00409.x. PMID 19432914. 
  104. ^ Audera, C (2001). "Mega-dose vitamin C in treatment of the common cold: a randomised controlled trial". Medical Journal of Australia 389: 175. 
  105. ^ Sasazuki, S; Sasaki, S; Tsubono, Y; Okubo, S; Hayashi, M; Tsugane, S (2005). "Effect of vitamin C on common cold: randomized controlled trial". European Journal of Clinical Nutrition 60 (1): 9–17. doi:10.1038/sj.ejcn.1602261. PMID 16118650. 
  106. ^ Douglas, R. M.; Hemil�, H. (2005). "Vitamin C for Preventing and Treating the Common Cold". PLoS Medicine 2 (6): e168. doi:10.1371/journal.pmed.0020168. PMC 1160577. PMID 15971944. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1160577.  edit
  107. ^ Pauling, Linus (1986). How to Live Longer and Feel Better. W. H. Freeman and Company. ISBN 0-380-70289-4. OCLC 15690499 154663991 15690499. [page needed]
  108. ^ a b Cabanillas, F (2010). "Vitamin C and cancer: what can we conclude--1,609 patients and 33 years later?". Puerto Rico health sciences journal 29 (3): 215–7. PMID 20799507.  edit
  109. ^ a b Heaney, M. L.; Gardner, J. R.; Karasavvas, N.; Golde, D. W.; Scheinberg, D. A.; Smith, E. A.; O'Connor, O. A. (2008). "Vitamin C Antagonizes the Cytotoxic Effects of Antineoplastic Drugs". Cancer Research 68 (19): 8031. doi:10.1158/0008-5472.CAN-08-1490. PMID 18829561.  edit
  110. ^ a b Caraballoso, M.; Sacristan, M.; Serra, C.; Bonfill Cosp, X. (2003). "Drugs for preventing lung cancer in healthy people". Cochrane Database of Systematic Reviews (2): CD002141. doi:10.1002/14651858.CD002141. PMID 12804424.  edit
  111. ^ a b Bjelakovic, G.; Nikolova, D.; Simonetti, R. G.; Gluud, C. (2008). "Antioxidant supplements for preventing gastrointestinal cancers". Cochrane Database of Systematic Reviews (3): CD004183. doi:10.1002/14651858.CD004183.pub3. PMID 18677777.  edit
  112. ^ a b Houston, M. C. (2010). "The role of cellular micronutrient analysis, nutraceuticals, vitamins, antioxidants and minerals in the prevention and treatment of hypertension and cardiovascular disease". Therapeutic Advances in Cardiovascular Disease 4 (3): 165. doi:10.1177/1753944710368205. PMID 20400494.  edit
  113. ^ Emadi-Konjin P, Verjee Z, Levin A, Adeli K (2005). "Measurement of intracellular vitamin C levels in human lymphocytes by reverse phase high performance liquid chromatography (HPLC)" (PDF). Clinical Biochemistry 38 (5): 450–6. doi:10.1016/j.clinbiochem.2005.01.018. PMID 15820776. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B6TDD-4FMHSY9-2-1&_cdi=5196&_user=308069&_orig=search&_coverDate=05%2F31%2F2005&_sk=999619994&view=c&wchp=dGLzVzz-zSkWW&md5=05a80321d3767c0cdfd386ef7121a781&ie=/sdarticle.pdf. 
  114. ^ 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" (PDF). Diabetes Care 27 (10): 2491–2. doi:10.2337/diacare.27.10.2491. PMID 15451922. http://care.diabetesjournals.org/cgi/reprint/27/10/2491.pdf. 
  115. ^ Pauling, Linus. (1976). Vitamin C, the Common Cold, and the Flu. San Francisco, CA: W.H. Freeman and Company.
  116. ^ "Toxicological evaluation of some food additives including anticaking agents, antimicrobials, antioxidants, emulsifiers and thickening agents". World Health Organization. 4 July 1973. http://www.inchem.org/documents/jecfa/jecmono/v05je20.htm. Retrieved 2007-04-13. 
  117. ^ Fleming DJ, Tucker KL, Jacques PF, Dallal GE, Wilson PW, Wood RJ (December 2002). "Dietary factors associated with the risk of high iron stores in the elderly Framingham Heart Study cohort". The American Journal of Clinical Nutrition 76 (6): 1375–84. PMID 12450906. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=12450906. 
  118. ^ Cook JD, Reddy MB (January 2001). "Effect of ascorbic acid intake on nonheme-iron absorption from a complete diet". The American Journal of Clinical Nutrition 73 (1): 93–8. PMID 11124756. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=11124756. 
  119. ^ Goodwin JS, Tangum MR (November 1998). "Battling quackery: attitudes about micronutrient supplements in American academic medicine". Archives of Internal Medicine 158 (20): 2187–91. doi:10.1001/archinte.158.20.2187. PMID 9818798. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=9818798. 
  120. ^ Massey LK, Liebman M, Kynast-Gales SA (July 2005). "Ascorbate increases human oxaluria and kidney stone risk". The Journal of Nutrition 135 (7): 1673–7. PMID 15987848. http://jn.nutrition.org/cgi/pmidlookup?view=long&pmid=15987848. 
  121. ^ 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 201008. PMID 14498993. http://www.nutritionj.com/content/pdf/1475-2891-2-7.pdf. 
  122. ^ Mashour S, Turner JF, Merrell R (August 2000). "Acute renal failure, oxalosis, and vitamin C supplementation: a case report and review of the literature". Chest 118 (2): 561–3. doi:10.1378/chest.118.2.561. PMID 10936161. 
  123. ^ Ovcharov R, Todorov S (1974). "[The effect of vitamin C on the estrus cycle and embryogenesis of rats]" (in Bulgarian). Akusherstvo I Ginekologii͡a 13 (3): 191–5. PMID 4467736. 
  124. ^ Vobecky JS, Vobecky J, Shapcott D, Cloutier D, Lafond R, Blanchard R (1976). "Vitamins C and E in spontaneous abortion". International Journal for Vitamin and Nutrition Research 46 (3): 291–6. PMID 988001. 
  125. ^ Javert CT, Stander HJ (1943). "Plasma Vitamin C and Prothrombin Concentration in Pregnancy and in Threatened, Spontaneous, and Habitual Abortion". Surgery, Gynecology, and Obstetrics 76: 115–122. 
  126. ^ Gomez-Cabrera MC, Domenech E, Romagnoli M, et al. (January 2008). "Oral administration of vitamin C decreases muscle mitochondrial biogenesis and hampers training-induced adaptations in endurance performance". The American Journal of Clinical Nutrition 87 (1): 142–9. PMID 18175748. http://www.ajcn.org/cgi/pmidlookup?view=long&pmid=18175748. 
  127. ^ "Cancer-Causing Compound Can Be Triggered By Vitamin C". 2007-03-13. http://www.sciencedaily.com/releases/2007/03/070312151951.htm. Retrieved 2009-12-26. 
  128. ^ a b c "Safety (MSDS) data for ascorbic acid". Oxford University. 2005-10-09. http://physchem.ox.ac.uk/MSDS/AS/ascorbic_acid.html. Retrieved 2007-02-21. 
  129. ^ Wilson JX (2005). "Regulation of vitamin C transport". Annu. Rev. Nutr. 25: 105–25. doi:10.1146/annurev.nutr.25.050304.092647. PMID 16011461. 
  130. ^ "The vitamin and mineral content is stable". Danish Veterinary and Food Administration. http://www.uk.foedevarestyrelsen.dk/Nutrition/Vitamin_mineral_content_is_stable/forside.htm. Retrieved 2010-02-26. 
  131. ^ "National Nutrient Database". Nutrient Data Laboratory of the US Agricultural Research Service. http://www.nal.usda.gov/fnic/foodcomp/search/. Retrieved 2007-03-07. 
  132. ^ "Vitamin C Food Data Chart". Healthy Eating Club. http://www.healthyeatingclub.com/info/books-phds/books/foodfacts/html/data/data4i.html. Retrieved 2007-03-07. 
  133. ^ "Natural food-Fruit Vitamin C Content". The Natural Food Hub. http://www.naturalhub.com/natural_food_guide_fruit_vitamin_c.htm. Retrieved 2007-03-07. 
  134. ^ Chatterjee, IB (1973). "Evolution and the Biosynthesis of Ascorbic Acid". Science 182 (4118): 1271–1272. doi:10.1126/science.182.4118.1271. PMID 4752221. 
  135. ^ Irwin Stone, PC-A (1979). "Eight Decades of Scurvy". Orthomolecular Psychiatry 8 (2): 58–62. http://www.seanet.com/~alexs/ascorbate/197x/stone-i-orthomol_psych-1979-v8-n2-p58.htm. 
  136. ^ Elwood, McCluskey. "Which Vertebrates Make Vitamin C?". http://www.grisda.org/origins/12096.htm. 
  137. ^ Clark, Stephanie, Ph. D (8 January 2007). "Comparing Milk: Human, Cow, Goat & Commercial Infant Formula". Washington State University. Archived from the original on 2007-01-29. http://web.archive.org/web/20070129024619/http://www.saanendoah.com/compare.html. Retrieved 2007-02-28. 
  138. ^ Toutain, P. L.; D. Béchu, and M. Hidiroglou (November 1997). "Ascorbic acid disposition kinetics in the plasma and tissues of calves". Am J Physiol Regul Integr Comp Physiol 273 (5): R1585–R1597. PMID 9374798. http://ajpregu.physiology.org/cgi/content/full/273/5/R1585. 
  139. ^ Mal. G. (2000) Indian Veterinary Journal; 77: 695–696
  140. ^ Roig, M. G.; Rivera, Z. S.; Kennedy, J. F. (1995). "A model study on rate of degradation of L-ascorbic acid during processing using home-produced juice concentrates". International Journal of Food Sciences and Nutrition 46 (2): 107–115. doi:10.3109/09637489509012538. PMID 7621082. 
  141. ^ Allen, MA,; Burgess, S. G. (1950). "The Losses of Ascorbic Acid during the Large-scale Cooking of Green Vegetables by Different Methods". British Journal of Nutrition 4 (2–3): 95–100. doi:10.1079/BJN19500024. PMID 14801407. 
  142. ^ G. F., Combs (2001). The Vitamins, Fundamental Aspects in Nutrition and Health (2nd ed.). San Diego, CA: Academic Press. pp. 245–272. ISBN 9780121834920. 
  143. ^ Hitti, Miranda (2 June 2006). "Fresh-Cut Fruit May Keep Its Vitamins". WebMD. http://www.webmd.com/content/article/123/115022.htm. Retrieved 2007-02-25. 
  144. ^ The Diet Channel Vitamin C is historically the first marketed pure single vitamin supplements, and remains perhaps the most widely known.
  145. ^ "The production of vitamin C" (PDF). Competition Commission. 2001. http://www.competition-commission.org.uk/rep_pub/reports/2001/fulltext/456a4.2.pdf. Retrieved 2007-02-20. 
  146. ^ Starling, Shane (2008-06-26). "DSM vitamin plant gains green thumbs-up". Decision News Media SAS. http://www.nutraingredients.com/news/ng.asp?n=86166-dsm-carbon-foot-printing-quali-c. Retrieved 2010-02-25. [dead link]
  147. ^ "Vitamin C: Distruptions to Production in China to Maintain Firm Market". Flexnews. 2008-06-30. http://www.flex-news-food.com/pages/17441/China/Vitamin/vitamin-distruptions-production-china-maintain-firm-market.html. Retrieved 2010-02-25. [dead link]
  148. ^ "Bizbites October 11". Global Times. October 11, 2010. http://www.globaltimes.cn/www/english/metro-beijing/update/business/2010-10/580763.html. Retrieved 15 October 2010. 
  149. ^ U.S. courts confront China's involvement in price fixing Andrew Longstreth , Reuters, Mar 11, 2011. Accessed March 2011
  150. ^ a b "Addition of Vitamins and Minerals to Food, 2005". Health Canada. http://www.hc-sc.gc.ca/fn-an/nutrition/vitamin/fortification_final_doc_1-eng.php. Retrieved 2010-02-25. 
  151. ^ British Pharmacopoeia Commission Secretariat (2009). "Index, BP 2009". http://www.pharmacopoeia.co.uk/pdf/2009_index.pdf. Retrieved 4 February 2010. 
  152. ^ "Japanese Pharmacopoeia, Fifteenth Edition". 2006. http://jpdb.nihs.go.jp/jp15e/JP15.pdf. Retrieved 4 Februally 2010. 
  153. ^ "Jacques Cartier's Second Voyage - 1535 - Winter & Scurvy". http://www3.sympatico.ca/goweezer/canada/z00cartier3.htm. Retrieved 2007-02-25. 
  154. ^ Martini E. (June 2002). "Jacques Cartier witnesses a treatment for scurvy". Vesalius 8 (1): 2–6. PMID 12422875. 
  155. ^ Armstrong, Alexander (1858). "Observation on Navel Hygiene and Scarvy, more particularly as the later appeared during the Polar Voyaje". British and foreign medico-chirurgical review: or, Quarterly journal of practical medicine and surgery 22: 295–305. http://books.google.com/?id=7VJYAAAAMAAJ&pg=PA295. 
  156. ^ "Captain Cook and the Scourge of Scurvy". BBC –History.
  157. ^ Lamb, Jonathan (2001). Preserving the self in the south seas, 1680–1840. University of Chicago Press. p. 117. ISBN 0226468496. http://books.google.com/books?id=hSoj1DR4ZSMC&pg=&dq#v=onepage&q=&f=false. 
  158. ^ Lind, James (1753). A Treatise of the Scurvy. London: A. Millar. 
  159. ^ Singh, Simon; Edzard Ernst (2008). Trick of Treatment: The Undeniable Facts about Alternative Medicine. WW Norton & Company. pp. 15–18. ISBN 9780393066616. 
  160. ^ Cook, James; Philip Edwards (1999). The Journals of Captain Cook. Penguin Books. p. 38. ISBN 0140436472. OCLC 42445907. 
  161. ^ Stevens, David; Reeve, John (2006). "Cook'sVpyages 1768–1780". Navy and the nation: the influence of the navy on modern Australia. Allen & Unwin. p. 74. ISBN 9781741142006. http://books.google.com/?id=BGs6__kbqKIC&pg=PA74. 
  162. ^ Kuhnlein HV, Receveur O, Soueida R, Egeland GM (1 June 2004). "Arctic indigenous peoples experience the nutrition transition with changing dietary patterns and obesity". J Nutr. 134 (6): 1447–53. PMID 15173410. http://jn.nutrition.org/cgi/content/full/134/6/1447. 
  163. ^ PMID 12555613 Tidsskr Nor Laegeforen. 2002 June 30;122(17):1686–7. [Axel Holst and Theodor Frolich--pioneers in the combat of scurvy][Article in Norwegian] Norum KR, Grav HJ.
  164. ^ PMID 9105273 L Rosenfeld. Vitamine--vitamin. The early years of discovery. Clin Chem. 1997 April;43(4):680–5.
  165. ^ Story of Vitamin C's chemical discovery. Accessed Jan 21, 2010
  166. ^ "Pitt History - 1932: Charles Glen King". University of Pittsburgh. http://www.pitt.edu/history/1932.html. Retrieved 2007-02-21. "In recognition of this medical breakthrough, some scientists believe that King also deserved Nobel Prize recognition." 
  167. ^ Boudrant J (May 1990). "Microbial processes for ascorbic acid biosynthesis: a review". Enzyme and Microbial Technology 12 (5): 322–9. doi:10.1016/0141-0229(90)90159-N. PMID 1366548. 
  168. ^ Bremus, Christoph; Herrmann, Ute; Bringer-Meyera, Stephanie; Sahma, Hermann (June 2006). "The use of microorganisms in L-ascorbic acid production". Journal of Biotechnology 124 (1): 196–205. doi:10.1016/j.jbiotec.2006.01.010. PMID 16516325. 
  169. ^ Bächi, Beat (2008). "Natürliches oder künstliches Vitamin C?: Der prekäre Status eines neuen Stoffes im Schatten des Zweiten Weltkriegs [Natural or synthetic vitamin C? A new substance's precarious status behind the scenes of World War II]" (in German). NTM 16 (4): 445–70. doi:10.1007/s00048-008-0309-y. PMID 19579835. 
  170. ^ BURNS JJ, EVANS C (1 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. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=13385237. 
  171. ^ Burns JJ, Moltz A, Peyser P (December 1956). "Missing step in guinea pigs required for the biosynthesis of L-ascorbic acid". Science 124 (3232): 1148–9. doi:10.1126/science.124.3232.1148-a. PMID 13380431. 
  172. ^ Henson DE, Block G, Levine M (April 1991). "Ascorbic acid: biologic functions and relation to cancer". Journal of the National Cancer Institute 83 (8): 547–50. doi:10.1093/jnci/83.8.547. PMID 1672383. 
  173. ^ Stephens, Thomas (Feb 17, 2011). "Let the chemical games begin!". Swiss Info. Swiss Broadcasting Corporation. http://www.swissinfo.ch/eng/Specials/International_year_of_chemistry/Background/Let_the_chemical_games_begin!.html?cid=29513206. Retrieved 2011-02-23. 

External links

Portal icon Food portal
Portal icon Health and fitness portal
Portal icon Medicine portal
Portal icon Pharmacy and Pharmacology portal
v · d · eVitamins (A11)
Fat soluble
Tocopherol (Alpha, Beta, Gamma, Delta) · Tocotrienol (Alpha, Beta, Gamma, Delta)  · Tocofersolan
Water soluble
C
Combinations

M: NUT

cof, enz, met

noco, nuvi, sysi/epon, met

drug(A8/11/12)


Wikimedia Foundation. 2010.

Игры ⚽ Нужен реферат?

Look at other dictionaries:

  • Vitamin K — has also been used as a slang term for ketamine, an unrelated anaesthetic. Vitamin K1 (phylloquinone). Both forms of the vitamin contain a functional naphthoquinone ring and an aliphatic side chain. Phylloquinone has a phytyl side chain …   Wikipedia

  • Vitamin D — is a group of fat soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol).cite web|url=http://dietary supplements.info.nih.gov/factsheets/vitamind.asp|title=Dietary Supplement Fact… …   Wikipedia

  • Vitamin A — Systematic (IUPAC) name (2E,4E,6E,8E) 3,7 Dimethyl …   Wikipedia

  • Vitamin B6 — is a water soluble vitamin. Pyridoxal phosphate (PLP) is the active form and is a cofactor in many reactions of amino acid metabolism, including transamination, deamination, and decarboxylation. PLP also is necessary for the enzymatic reaction… …   Wikipedia

  • Vitamin-B — ist eine Vitamin Gruppe, in der acht wasserlösliche Vitamine zusammengefasst sind, die alle als Vorstufen für Koenzyme dienen. Die Nummerierung ist nicht durchgehend, weil sich bei vielen Substanzen, die ursprünglich als Vitamine galten, der… …   Deutsch Wikipedia

  • Vitamin B — ist eine Vitamin Gruppe, in der acht Vitamine zusammengefasst sind, die alle als Vorstufen für Koenzyme dienen. Die Nummerierung ist nicht durchgehend, weil sich bei vielen Substanzen, die ursprünglich als Vitamine galten, der Vitamin Charakter… …   Deutsch Wikipedia

  • vitamin K — n. a fat soluble vitamin, synthesized constantly by intestinal bacteria in mammals and occurring in certain green vegetables, fish meal, etc., that promotes blood clotting and is required for the synthesis of prothrombin by the liver: the two… …   Universalium

  • Vitamin A — is retinol. Carotene compounds (found, for example, in egg yolk, butter and cream) are gradually converted by the body to vitamin A (retinol). A form of vitamin A called retinal is responsible for transmitting light sensation in the retina of the …   Medical dictionary

  • Vitamin B1 — is thiamine. Vitamin B1 acts as a coenzyme in the metabolism of the body. Deficiency of thiamine leads to beriberi, a disease of the heart and nervous system. The word vitamin was coined in 1911 by the Warsaw born biochemist Casimir Funk (1884… …   Medical dictionary

  • Vitamin de — Beschreibung Deutschlernerzeitschrift Verlag NP PRESS.DE Erstausgabe 2002 Erscheinungsweise …   Deutsch Wikipedia

  • vitamin de — Beschreibung Zeitschrift für junge Deutschlerner Verlag Verein vitamin de , NP PRESS.DE Erstausgabe 2002 …   Deutsch Wikipedia

Share the article and excerpts

Direct link
… Do a right-click on the link above
and select “Copy Link”