위대한 의학혁명 '비타민의 발견 히스토리' - 비타민 C 논문 읽어야

[문형철]

BEYOND REASON

현대의학의 선배탐구자에게 감사와 존경을

비타민 발견의 역사

- 1911년 영국 런던의 레스터 연구소에서 일하던 폴란드 출신의 생화학자 '카시미르 펑크(Casimir Funk)'는 비둘기의 각기병을 예방하는 성분을 쌀겨로부터 분리해내고 이를 Vital amine으로 부르다가 나중에 비타민(vitamin)이라 부름

카지미르 풍크(폴란드어: Kazimierz Funk 카지미에시 푼크^[*], 영어: Casimir Funk 캐지머 펑크^[*], 1884년 2월 23일 ~ 1967년 11월 20일)는 폴란드 출신의 미국생화학자이다. 1912년에 비타민 가설을 주장하였고 이는 영양에 대한 연구에 큰 도움이 되었다.

생애[편집]

바르샤바 태생. 베른 대학교에서 박사 학위를 받은 후 파리의 파스퇴르 연구소, 런던의 리스터 예방의학 연구소, 베를린 등에서 연구하였다. 미국에는 1915년에서부터 1923년, 그리고 1939년부터 1967년 뉴욕에서 사망할 때까지 체류하였다.

업적[편집]

1912년 바이타민 가설을 주장하고, 영양에 있어서 비타민의 중요성에 대해 주창하였다. 그는 각기병, 괴혈병, 펠라그라, 구루병 등이 특정한 필수 영양소의 부족으로 인한 것이라고 주장하였다. 그는 각기병 예방물질(바이타민 B₁)을 완전하게 분리해 내지는 못하였으나 그것이 유기염기나 아민의 일종이라는 것은 알 수 있었고 따라서 다른 필수 영양소들도 마찬가지라고 생각하여 그것에 바이타민(vitamine, '생사에 관련된'이란 뜻을 가진 vita-와 아민의 합성어)이라는 이름을 붙였다. 그 후의 연구에 의해서 비타민 B₁를 제외한 나머지 비타민이 아민을 함유하고 있지는 않다는 것이 밝혀졌지만, 바이타민(vitamin, 모든 바이타민이 아민은 아니었기 때문에 vitamine에서 e를 제외함)이라는 말은 오늘날까지 계속 쓰이고 있다.

1912년 그는 니코틴산(비타민 B₃) 역시 분리해 냈지만, 그것이 펠라그라 예방물질이라는 사실은 알지 못하였다. 그는 이후 암과 성 호르몬에 의한 연구도 하였고, 의약품 생산에 있어서 좀 더 효과적인 방법을 고안하기도 하였다.

- 1913년 미국의 맥컬럼(E.V. McCollum)은 특정지방에 섞여있는 비타민 '지용성 비타민 A'를 발견함. 

-  1915년 밀과 계란 노른자의 수분추출물에서 수용성 비타민 B발견

Nutritional Biochemistry and the Discovery of Vitamins: the Work of Elmer Verner McCollum

1. Robert D. Simoni, 
2. Robert L. Hill and 
3. Martha Vaughan

 

Next Section

The “Vitamine” Hypothesis and Deficiency Diseases
(McCollum, E. V., and Pitz, W. (1917) J. Biol. Chem. 31, 229–253)

Studies on Experimental Rickets. XXI. An Experimental Demonstration of the Existence of a Vitamin Which Promotes Calcium Deposition
(McCollum, E. V., Simmonds, N., Becker, J. E., and Shipley, P. G. (1922) J. Biol. Chem. 53, 293–312)

The Effect of Additions of Fluorine to the Diet of the Rat on the Quality of the Teeth
(McCollum, E. V., Simmonds, N., Becker, J. E., and Bunting, R. W. (1925) J. Biol. Chem. 63, 553–562)

Elmer Verner McCollum was one of the giants of nutritional biochemistry. He was born and raised in Kansas and attended the University of Kansas. His studies were initially directed toward medicine, but he eventually decided that chemistry better captured his interests, and he completed his work for a Masters degree in chemistry at Kansas. He was accepted into the Ph.D. program at the Sheffield Scientific School at Yale. One of his classmates at Yale was Stanley R. Benedict, the subject of a previous JBC Classic (1).

McCollum completed his Ph.D. work in 2 years and, given the lack of university positions, stayed at Yale for another year working with T. B. Osborne and Lafayette B. Mendel on problems of plant protein composition and diet. This work was influential to McCollum's career, and Mendel helped McCollum secure a faculty position at the University of Wisconsin. (The work of Osborne and Mendel was the subject of a previous installment of JBC Classics (2).)

On arrival at Wisconsin, McCollum was assigned to the famous heifer project. Three groups of heifers were fed restricted diets from single plant sources: wheat, corn, and oat. A fourth group of animals was fed all three plants. The animals fed all three plants did remarkably better, but there was no satisfactory explanation for the difference. McCollum decided that“ the most important problem in nutrition was to discover what was lacking in such diets” (3).

He decided that nutritional studies would benefit from using small animals with short lifespans. He started with a colony of wild rats he had captured himself, but these quickly proved unsatisfactory, and he persuaded his Dean to allow him to purchase 12 albino rats even though the purchase was with his own funds. This colony of rats was the first established in the United States for nutritional studies (3).

McCollum first proposed that the nutritive failure of certain diets was due to a lack of “palatability.” He proposed that if a diet could be made to taste good with flavor additives and the animals induced to eat larger quantities, the diets would be adequate. This hypothesis, and the supporting data, were criticized by Osborne and Mendel who demonstrated that plant protein diets were not adequate unless protein-free milk was added as a supplement. In some of their papers, Mendel and Osborne suggested that McCollum had been careless in some of his experiments (3). This criticism was no doubt painful especially coming form his mentors at Yale. McCollum acknowledged this error and rededicated himself to more careful analyses including an analysis of the growth-promoting factor(s) in protein-free milk, which then led to the isolation of the first known fat-soluble vitamin, later to be called vitamin A.⇓

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Elmer V. McCollum. Photo courtesy of the National Library of Medicine.

In 1916 McCollum and C. Kennedy, concerned with the growing confusion about nomenclature for dietary factors, proposed an alphabetical designation preceded by a notation of the solubility of the factor, thus fat-soluble A and water-soluble B. This was the beginning of the common nomenclature for vitamins.

In 1917, McCollum accepted the position of professor and head of the Department of Chemical Hygiene, later Biochemistry, in the newly formed School of Hygiene and Public Health at Johns Hopkins University. He had a distinguished research career supplemented by great public service including service on many government boards and panels and international nutrition organizations. Through his research and public service, McCollum, probably more than anyone, influenced human dietary policy and practices. In a commentary on his life, Time magazine stated, “He has done more than any other man to put vitamins back in the nation's bread and milk, to put fruit on American breakfast tables, fresh vegetables and salad greens in the daily diet” (3).

McCollum was involved in many policy debates including one over the best strategy to fortify bread. He had shown, and publicized, that white bread was nutritionally deficient. With the development of synthetic vitamins, it was proposed that bread and flour be enriched with thiamin, niacin, and iron. This effort was lead by the Food and Nutrition Board of the National Research Council. McCollum was a member of the Board but disagreed and was strongly critical of the recommendation because supplementation with such nutrients failed to make up for all the losses suffered during milling wheat. As a result of his disagreement with the other members of the Board, his Board colleagues changed his status from Board member to panel member. As a panel member he was not invited to any of the Board meetings (3).

The McCollum papers reprinted in this installment of JBC Classics are intended to represent a career. The first paper describes the controversy of the time about the “vitamine hypothesis” and also presents the kind of data characteristic of nutritional studies for many years. The second paper details the discovery of a growth substance distinct from vitamin A, later known as vitamin D, and necessary for bone formation. The third paper describes the role of fluoride in preventing tooth decay and eventually led to the widespread addition of fluoride to water supplies and toothpaste and a dramatic reduction in the frequency of dental caries in the United States.¹

McCollum was a member of the Journal of Biological Chemistry (JBC) Editorial Board and, in 1927 and 1928, President of the American Society of Biological Chemists (ASBC).

Previous SectionNext Section

- 1918년 영국의 에드워드 멜란비(Edward Mellanby)는 구루병이 생긴 강아지에게 생선간유 형태의 지용성 A를 먹여 완치시킴. 

- 그는 지용성 A안에 구루병을 막아주는 물질을 비타민 D라고 명명하고 정상적인 성장의 필수요소를 비타민 A라고 부름.

- 1928년 헝가리 생화학자 쉔트조오지 알버트는 과일이 공기중에서 산화되어 갈색으로 변화하는 것을 막아주는 물질을 찾다가 비타민 C를 발견함. 

- 1937년 쉔트 조오지는 괴혈병 치료제 비타민  C 발견의 공로로 노벨상을 받음

Vitamin C

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For other uses, see vitamin C (disambiguation).

Vitamin C

Clinical data
Other names	l-ascorbic acid, ascorbic acid, ascorbate
AHFS/Drugs.com	Monograph
MedlinePlus	a682583
Pregnancy category	A (to RDA), C (above RDA)
Routes of administration	By mouth, IM, IV, subQ
ATC code	A11G (WHO)
Legal status
Legal status	OTC (when used by mouth); prescription (for injectable form)
Pharmacokinetic data
Bioavailability	rapid & complete
Protein binding	negligible
Elimination half-life	varies according to plasma concentration
Excretion	kidney
Identifiers
IUPAC name[show]
CAS Number	50-81-7
PubChem CID	54670067
IUPHAR/BPS	4781
DrugBank	DB00126
ChemSpider	10189562
UNII	PQ6CK8PD0R
KEGG	D00018
ChEBI	CHEBI:29073
ChEMBL	ChEMBL196
NIAID ChemDB	002072
E number	E300 (antioxidants, ...)
CompTox Dashboard (EPA)	DTXSID5020106
ECHA InfoCard	100.000.061
Chemical and physical data
Formula	C6H8O6
Molar mass	176.12 g·mol−1
3D model (JSmol)	Interactive image
Density	1.694 g/cm3
Melting point	190–192 °C (374–378 °F) (some decomposition)[1]
Boiling point	553 °C (1,027 °F)[citation needed]
SMILES[show]
InChI[show]
(verify)

Vitamin C, also known as ascorbic acid and ascorbate, is a vitamin found in various foods and sold as a dietary supplement.^[2] It is used to prevent and treat scurvy.^[2] Vitamin C is an essential nutrient involved in the repair of tissue and the enzymatic production of certain neurotransmitters.^[2][3] It is required for the functioning of several enzymes and is important for immune system function.^[3][4] It also functions as an antioxidant.^[5]

Current evidence does not support its use for the prevention of the common cold.^[5][6] There is, however, some evidence that regular use may shorten the length of colds.^[7] It is unclear whether supplementation affects the risk of cancer, cardiovascular disease, or dementia.^[8][9] It may be taken by mouth or by injection.^[2]

Vitamin C is generally well tolerated.^[2] Large doses may cause gastrointestinal discomfort, headache, trouble sleeping, and flushing of the skin.^[2][6] Normal doses are safe during pregnancy.^[10] The United States Institute of Medicine recommends against taking large doses.^[3]

Vitamin C was discovered in 1912, isolated in 1928, and in 1933 was the first vitamin to be chemically produced.^[11] It is on the World Health Organization Model List of Essential Medicines, which lists the most effective and safe medicines needed in a health system.^[12]Vitamin C is available as an inexpensive generic and over-the-counter medication.^[2][13][14] Partly for its discovery, Albert Szent-Györgyiand Walter Norman Haworth were awarded the 1937 Nobel Prizes in Physiology and Medicine and Chemistry, respectively.^[15][16] Foods containing vitamin C include citrus fruits, kiwifruit, broccoli, Brussels sprouts, raw bell peppers, and strawberries.^[5] Prolonged storage or cooking may reduce vitamin C content in foods.^[5]

Contents

• 1Biology
  • 1.1Significance
  • 1.2Deficiency
• 2Uses
  • 2.1Scurvy
  • 2.2Infection
  • 2.3Cancer
  • 2.4Cardiovascular disease
  • 2.5Brain function
  • 2.6Other diseases
• 3Side effects
• 4Diet
  • 4.1Recommended levels
  • 4.2Food labeling
  • 4.3Sources
  • 4.4Food preparation
  • 4.5Supplements
  • 4.6Food fortification
  • 4.7Food additives
• 5Pharmacology
  • 5.1Pharmacodynamics
  • 5.2Pharmacokinetics
• 6Chemistry
• 7Testing for levels
• 8Biosynthesis
  • 8.1Animal pathway
  • 8.2Plant pathways
  • 8.3Evolution
• 9Industrial production
• 10History
  • 10.1Folk medicine
  • 10.2Scurvy at sea
  • 10.3Discovery
  • 10.4Large doses
• 11Society and culture
• 12Pharmacopoeias
• 13Notes
• 14References
• 15External links

Biology[edit]

Significance[edit]

Vitamin C is an essential nutrient for certain animals including humans. The term vitamin C encompasses several vitamers that have vitamin C activity in animals. Ascorbate salts such as sodium ascorbate and calcium ascorbate are used in some dietary supplements. These release ascorbate upon digestion. Ascorbate and ascorbic acid are both naturally present in the body, since the forms interconvert according to pH. Oxidized forms of the molecule such as dehydroascorbic acid are converted back to ascorbic acid by reducing agents.^[3]

Vitamin C functions as a cofactor in many enzymatic reactions in animals (and humans) that mediate a variety of essential biological functions, including wound healing and collagensynthesis. In humans, vitamin C deficiency leads to impaired collagen synthesis, contributing to the more severe symptoms of scurvy.^[3] Another biochemical role of vitamin C is to act as an antioxidant (a reducing agent) by donating electrons to various enzymatic and non-enzymatic reactions.^[3] Doing so converts vitamin C to an oxidized state - either as semidehydroascorbic acid or dehydroascorbic acid. These compounds can be restored to a reduced state by glutathione and NADPH-dependent enzymatic mechanisms.^[17][18][19]

In plants, vitamin C is a substrate for ascorbate peroxidase. This enzyme utilizes ascorbate to neutralize excess hydrogen peroxide (H₂O₂) by converting it to water (H₂O).^[4][20]

Deficiency[edit]

Main article: Scurvy

Scurvy is a disease resulting from a deficiency of vitamin C. Without this vitamin, collagen made by the body is too unstable to perform its function and several other enzymes in the body do not operate correctly.^[4]

Scurvy is characterized by spots on and bleeding under the skin, spongy gums, 'corkscrew' hair growth, and poor wound healing. The skin lesions are most abundant on the thighs and legs, and a person with the ailment looks pale, feels depressed, and is partially immobilized. In advanced scurvy there are open, suppurating wounds, loss of teeth, bone abnormalitiesand, eventually, death.^[21] The human body can store only a certain amount of vitamin C,^[22] and so the body stores are depleted if fresh supplies are not consumed.

Notable human dietary studies of experimentally induced scurvy were been conducted on conscientious objectors during World War II in Britain and on Iowa state prisoners in the late 1960s to the 1980s. Men in the prison study developed the first signs of scurvy about four weeks after starting the vitamin C-free diet, whereas in the earlier British study, six to eight months were required, possibly due to the pre-loading of this group with a 70 mg/day supplement for six weeks before the scorbutic diet was fed. Men in both studies had blood levels of ascorbic acid too low to be accurately measured by the time they developed signs of scurvy. These studies both reported that all obvious symptoms of scurvy could be completely reversed by supplementation of only 10 mg a day.^[23][24]

Uses[edit]

Vitamin C supplements at a drug store.

Vitamin C has a definitive role in treating scurvy, which is a disease caused by vitamin C deficiency. Beyond that, a role for vitamin C as prevention or treatment for various diseases is disputed, with reviews reporting conflicting results. A 2012 Cochrane review reported no effect of vitamin C supplementation on overall mortality.^[25] It is on the World Health Organization's List of Essential Medicines as one of the most effective and safe medicines needed in a health system.^[12]

Scurvy[edit]

The disease scurvy is caused by vitamin C deficiency and can be prevented and treated with vitamin C-containing foods or dietary supplements.^[2][3] It takes at least a month of little to no vitamin C before symptoms occur.^[23] Early symptoms are malaise and lethargy, progressing to shortness of breath, bone pain, bleeding gums, susceptibility to bruising, poor wound healing, and finally fever, convulsions and eventual death.^[2] Until quite late in the disease the damage is reversible, as healthy collagen replaces the defective collagen with vitamin C repletion. Treatment can be orally or by intramuscular or intravenous injection.^[2] Scurvy was known to Hippocrates in the classical era. The disease was shown to be prevented by citrus fruit in an early controlled trial by a Royal Navy surgeon, James Lind, in 1747, and from 1796 lemon juice was issued to all Royal Navy crewmen.^[26][27]

Infection[edit]

Further information: Vitamin C and the common cold

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

The effect of vitamin C on the common cold has been extensively researched. The earliest publication of a controlled clinical trial appears to be from 1945.^[28] Researchers continued to work on this question, but research interest and public interest spiked after Linus Pauling, two-time awardee of the Nobel Prize (Chemistry Prize, 1954, Peace Prize 1962), started publishing research on the topic and also published a book "Vitamin C and the Common Cold" in 1970.^[29] A revised and expanded edition "Vitamin C, the Common Cold and the Flu" was published in 1976.^[30]

Research on vitamin C in the common cold has been divided into effects on prevention, duration, and severity. A Cochrane review which looked at least 200 mg/day concluded that vitamin C taken on a regular basis was not effective in prevention of the common cold. At least 1000 mg/day also made no difference. However, taking vitamin C on a regular basis did reduce the average duration by 8% in adults and 14% in children, and also reduced severity of colds.^[7] A subset of trials reported that supplementation reduced the incidence of colds by half in marathon runners, skiers, or soldiers in subarctic conditions.^[7] Another subset of trials looked at therapeutic use, meaning that vitamin C was not started unless the people started to feel the beginnings of a cold. In these, vitamin C did not impact duration or severity.^[7] An earlier review stated that vitamin C did not prevent colds, did reduce duration, did not reduce severity.^[31] The authors of the Cochrane review concluded that "...given the consistent effect of vitamin C on the duration and severity of colds in the regular supplementation studies, and the low cost and safety, it may be worthwhile for common cold patients to test on an individual basis whether therapeutic vitamin C is beneficial for them."^[7]

Vitamin C distributes readily in high concentrations into immune cells, has antimicrobial and natural killer cell activities, promotes lymphocyteproliferation, and is consumed quickly during infections, effects indicating a prominent role in immune system regulation.^[32] The European Food Safety Authority found a cause and effect relationship exists between the dietary intake of vitamin C and functioning of a normal immune system in adults and in children under three years of age.^[33][34]

Cancer[edit]

There are two approaches to the question of whether vitamin C has an impact on cancer. First, within the normal range of dietary intake without additional dietary supplementation, are people who consume more vitamin C at lower risk for developing cancer, and if so, does an orally consumed supplement have the same benefit? Second, for people diagnosed with cancer, will large amounts of ascorbic acid administered intravenously treat the cancer, reduce the adverse effects of other treatments, and so prolong survival and improve quality of life? A 2013 Cochrane review found no evidence that vitamin C supplementation reduces the risk of lung cancer in healthy people or those at high risk due to smoking or asbestos exposure.^[35] A second meta-analysis found no effect on the risk of prostate cancer.^[36] Two meta-analyses eval‎uated the effect of vitamin C supplementation on the risk of colorectal cancer. One found a weak association between vitamin C consumption and reduced risk, and the other found no effect from supplementation.^[37][38] A 2011 meta-analysis failed to find support for the prevention of breast cancer with vitamin C supplementation,^[39] but a second study concluded that vitamin C may be associated with increased survival in those already diagnosed.^[40]

Under the rubric of orthomolecular medicine, "Intravenous vitamin C is a contentious adjunctive cancer therapy, widely used in naturopathic and integrative oncology settings." ^[41] With oral administration absorption efficiency decreases as amounts increase. Intravenous administration bypasses this.^[42] Doing so makes it possible to achieve plasma concentrations of 5 to 10 millimoles/liter (mmol/L), which far exceed the approximately 0.2 mmol/L limit from oral consumption.^[43] The theories of mechanism are contradictory. At high tissue concentrations ascorbic acid is described as acting as a pro-oxidant, generating hydrogen peroxide (H₂O₂) to kill tumor cells. The same literature claims that ascorbic acid acts as an antioxidant, thereby reducing the adverse effects of chemotherapy and radiation therapy.^[41][42] Research continues in this field, but a 2014 review concluded: "Currently, the use of high-dose intravenous vitamin C [as an anticancer agent] cannot be recommended outside of a clinical trial."^[44] A 2015 review added: "There is no high-quality evidence to suggest that ascorbate supplementation in cancer patients either enhances the antitumor effects of chemotherapy or reduces its toxicity. Evidence for ascorbate's anti-tumor effects was limited to case reports and observational and uncontrolled studies."^[45]

Cardiovascular disease[edit]

A 2013 meta-analysis found no evidence that vitamin C supplementation reduces the risk of myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality.^[8] However, a second analysis found an inverse relationship between circulating vitamin C levels or dietary vitamin C and the risk of stroke.^[46]

A meta-analysis of 44 clinical trials has shown a significant positive effect of vitamin C on endothelial function when taken at doses greater than 500 mg per day. The endothelium is a layer of cells that line the interior surface of blood vessels. Endothelial dysfunction is implicated in many aspects of vascular diseases. The researchers noted that the effect of vitamin C supplementation appeared to be dependent on health status, with stronger effects in those at higher risk of cardiovascular disease.^[47]

Brain function[edit]

A 2017 systematic review found lower vitamin C concentrations in people with cognitive impairment, including Alzheimer's disease and dementia, compared to people with normal cognition.^[48] The cognitive testing, however, relied on the Mini-Mental State Examination, which is only a general test of cognition, indicating an overall low quality of research assessing the potential importance of vitamin C on cognition in normal and impaired people.^[48] A review of nutrient status in people with Alzheimer's disease reported low plasma vitamin C, but also low blood levels of folate, vitamin B₁₂, and vitamin E.^[49]

Other diseases[edit]

Studies examining the effects of vitamin C intake on the risk of Alzheimer's disease have reached conflicting conclusions.^[50][51] Maintaining a healthy dietary intake is probably more important than supplementation for achieving any potential benefit.^[52] A 2010 review found no role for vitamin C supplementation in the treatment of rheumatoid arthritis.^[53] Vitamin C supplementation does not prevent or slow the progression of age-related cataract.^[54]

Side effects[edit]

Vitamin C is a water-soluble vitamin,^[22] with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine, so it exhibits remarkably low acute toxicity.^[4] More than two to three grams may cause indigestion, particularly when taken on an empty stomach. However, taking vitamin C in the form of sodium ascorbate and calcium ascorbate may minimize this effect.^[30] Other symptoms reported for large doses include nausea, abdominal cramps and diarrhea. These effects are attributed to the osmotic effect of unabsorbed vitamin C passing through the intestine.^[3] In theory, high vitamin C intake may cause excessive absorption of iron. A summary of reviews of supplementation in healthy subjects did not report this problem but left as untested the possibility that individuals with hereditary hemochromatosis might be adversely affected.^[3]

There is a longstanding belief among the mainstream medical community that vitamin C increases risk of kidney stones.^[55] "Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease".^[3] Reviews state that "data from epidemiological studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals",^[3][56] although one large, multi-year trial did report a nearly two-fold increase in kidney stones in men who regularly consumed a vitamin C supplement.^[57]

Diet[edit]

Recommended levels[edit]

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

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

• 40 milligrams per day: India National Institute of Nutrition, Hyderabad^[58]
• 45 milligrams per day or 300 milligrams per week: the World Health Organization^[59]
• 80 milligrams per day: the European Commission Council on nutrition labeling^[60]
• 90 mg/day (males) and 75 mg/day (females): Health Canada 2007^[61]
• 90 mg/day (males) and 75 mg/day (females): United States National Academy of Sciences.^[3]
• 100 milligrams per day: Japan National Institute of Health and Nutrition.^[62]
• 110 mg/day (males) and 95 mg/day (females): European Food Safety Authority^[63]

In 2000 the North American Dietary Reference Intake chapter on vitamin C updated the Recommended Dietary Allowance (RDA) to 90 milligrams per day for adult men and 75 mg/day for adult women, and set a Tolerable upper intake level (UL) for adults of 2,000 mg/day.^[3] The table shows RDAs for the United States and Canada for children, and for pregnant and lactating women.^[3]For the European Union, the EFSA set higher recommendations for adults, and also for children: 20 mg/day for ages 1–3, 30 mg/day for ages 4–6, 45 mg/day for ages 7–10, 70 mg/day for ages 11–14, 100 mg/day for males ages 15–17, 90 mg/day for females ages 15–17. For pregnancy 100 mg/day; for lactation 155 mg/day.^[63] India, on the other hand, has set recommendations much lower: 40 mg/day for ages 1 through adult, 60 mg/day for pregnancy, and 80 mg/day for lactation.^[58] Clearly, there is not consensus among countries.

Cigarette smokers and people exposed to secondhand smoke have lower plasma vitamin C levels than nonsmokers. The thinking is that inhalation of smoke causes oxidative damage, depleting this antioxidant vitamin.^[3][62] The U.S. Institute of Medicine estimated that smokers need 35 mg more vitamin C per day than nonsmokers, but did not formally establish a higher RDA for smokers.^[3] One meta-analysis showed an inverse relationship between vitamin C intake and lung cancer, although it concluded that more research is needed to confirm‎ this observation.^[64]

The U.S. National Center for Health Statistics conducts biannual National Health and Nutrition Examination Survey (NHANES) to assess the health and nutritional status of adults and children in the United States. Some results are reported as What We Eat In America. The 2013-2014 survey reported that for adults ages 20 years and older, men consumed on average 83.3 mg/d and women 75.1 mg/d. This means that half the women and more than half the men are not consuming the RDA for vitamin C.^[65] The same survey stated that about 30% of adults reported they consumed a vitamin C dietary supplement or a multi-vitamin/mineral supplement that included vitamin C, and that for these people total consumption was between 300 and 400 mg/d.^[66]

In 2000 the Institute of Medicine of the U.S. National Academy of Sciences set a Tolerable upper intake level (UL) for adults of 2,000 mg/day. The amount was chosen because human trials had reported diarrhea and other gastrointestinal disturbances at intakes of greater than 3,000 mg/day. This was the Lowest-Observed-Adverse-Effect Level (LOAEL), meaning that other adverse effects were observed at higher intakes.^[3] The European Food Safety Authority (EFSA) reviewed the safety question in 2006 and reached the conclusion that there was not sufficient evidence to set a UL for vitamin C.^[67] The Japan National Institute of Health and Nutrition reviewed the same question in 2010 and also reached the conclusion that there was not sufficient evidence to set a UL.^[62]

Food labeling[edit]

For U.S. food and dietary supplement labeling purposes, the amount in a serving is expressed as a percent of Daily Value (%DV). For vitamin C labeling purposes, 100% of the Daily Value was 60 mg, but as of May 27, 2016 it was revised to 90 mg to bring it into agreement with the RDA.^[68] A table of the old and new adult Daily Values is provided at Reference Daily Intake. The original deadline to be in compliance was July 28, 2018, but on September 29, 2017 the FDA released a proposed rule that extended the deadline to January 1, 2020 for large companies and January 1, 2021 for small companies.^[69] European Union regulations require that labels declare energy, protein, fat, saturated fat, carbohydrates, sugars, and salt. Voluntary nutrients may be shown if present in significant amounts. Instead of Daily Values, amounts are shown as percent of Reference Intakes (RIs). For vitamin C, 100% RI was set at 80 mg in 2011.^[70]

Sources[edit]

The richest natural sources of vitamin C are fruits and vegetables.^[4] The vitamin is the most widely taken nutritional supplement and is available in a variety of forms,^[4] including tablets, drink mixes, and in capsules.

Plant sources[edit]

While plant foods are generally a good source of vitamin C, the amount in foods of plant origin depends on the variety of the plant, soil condition, climate where it grew, length of time since it was picked, storage conditions, and method of preparation.^[71][72] The following table is approximate and shows the relative abundance in different raw plant sources.^[73][74] As some plants were analyzed fresh while others were dried (thus, artificially increasing concentration of individual constituents like vitamin C), the data are subject to potential variation and difficulties for comparison. The amount is given in milligrams per 100 grams of the edible portion of the fruit or vegetable:

Plant source[75]	Amount (mg / 100g)
Kakadu plum	1000–5300[76]
Camu camu	2800[74][77]
Acerola	1677[78]
Seabuckthorn	695
Indian gooseberry	445
Rose hip	426
Guava	228
Blackcurrant	200
Yellow bell pepper/capsicum	183
Red bell pepper/capsicum	128
Kale	120
Kiwifruit, broccoli	90

Plant source[75]	Amount (mg / 100g)
Green bell pepper/capsicum	80
Loganberry, redcurrant, Brussels sprouts	80
Cloudberry, elderberry	60
Papaya, strawberry	60
Orange, lemon	53
Pineapple, cauliflower	48
Cantaloupe	40
Grapefruit, raspberry	30
Passion fruit, spinach	30
Cabbage, lime	30
Mango	28
Blackberry	21

Plant source[75]	Amount (mg / 100g)
Potato, honeydew melon	20
Tomato	14
Cranberry	13
Blueberry, grape	10
Apricot, plum, watermelon	10
Avocado	8.8
Onion	7.4
Cherry, peach	7
Carrot, apple, asparagus	6

Animal sources[edit]

Goats, like many animals but not humans, make their own vitamin C. An adult goat, weighing approx. 70 kg, will manufacture more than 13,300 mg of vitamin C per day in normal health, and levels manyfold higher when faced with stress.^[79]

Animal-sourced foods do not provide much vitamin C, and what there is, is largely destroyed by the heat of cooking. For example, raw chicken liver contains 17.9 mg/100 g, but fried, the content is reduced to 2.7 mg/100 g. Chicken eggs contain no vitamin C, raw or cooked.^[75] Vitamin C is present in human breast milk at 5.0 mg/100 g and 6.1 mg/100 g in one tested sample of infant formula, but cow's milk contains only 1.0 mg/ 100 g.^[80]

Food preparation[edit]

Vitamin C chemically decomposes under certain conditions, many of which may occur during the cooking of food. Vitamin C concentrations in various food substances decrease with time in proportion to the temperature at which they are stored.^[81] Cooking can reduce the vitamin C content of vegetables by around 60%, possibly due to increased enzymatic destruction.^[82] Longer cooking times may add to this effect.^[83]

Another cause of vitamin C loss from food is leaching, which transfers vitamin C to the cooking water, which is decanted and not consumed. Broccoli may retain vitamin C during cooking or storage more than most vegetables.^[84]

Supplements[edit]

Vitamin C dietary supplements are available as tablets, capsules, drink mix packets, in multi-vitamin/mineral formulations, in antioxidant formulations, and as crystalline powder.^[2] Vitamin C is also added to some fruit juices and juice drinks. Tablet and capsule content ranges from 25 mg to 1500 mg per serving. The most commonly used supplement compounds are ascorbic acid, sodium ascorbate and calcium ascorbate.^[2] Vitamin C molecules can also be bound to the fatty acid palmitate, creating ascorbyl palmitate, or else incorporated into liposomes.^[85]

Food fortification[edit]

In 2014, the Canadian Food Inspection Agency eval‎uated the effect of fortification of foods with ascorbate in the guidance document, Foods to Which Vitamins, Mineral Nutrients and Amino Acids May or Must be Added.^[86] Voluntary and mandatory fortification was described for various classes of foods. Among foods classified for mandatory fortification with vitamin C were fruit-flavored drinks, mixes, and concentrates, foods for a low-energy diet, meal replacement products, and evaporated milk.^[86]

Food additives[edit]

Ascorbic acid and some of its salts and esters are common additives added to various foods, mostly to retard oxidation. The relevant European food additive E numbers are:

1. E300 ascorbic acid (approved for use as a food additive in the EU,^[87] U.S.^[88] and Australia and New Zealand)^[89]
2. E301 sodium ascorbate (approved for use as a food additive in the EU,^[87] U.S.^[90] and Australia and New Zealand)^[89]
3. E302 calcium ascorbate (approved for use as a food additive in the EU,^[87] U.S.^[88] and Australia and New Zealand)^[89]
4. E303 potassium ascorbate (approved in Australia and New Zealand,^[89] but not in U.S.)
5. E304 fatty acid esters of ascorbic acid such as ascorbyl palmitate (approved for use as a food additive in the EU,^[87] U.S.^[88] and Australia and New Zealand)^[89]

Pharmacology[edit]

See also: Chemistry of ascorbic acid

Pharmacodynamics[edit]

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

Vitamin C – specifically, in the form of ascorbate – performs numerous physiological functions in the human body by serving as an enzyme substrate and/or cofactor and an electron donor. These functions include the synthesis of collagen, carnitine, and neurotransmitters; the synthesis and catabolism of tyrosine; and the metabolism of microsome.^[19] During biosynthesis, ascorbate acts as a reducing agent, donating electrons and preventing oxidation to keep iron and copper atoms in their reduced states.

Vitamin C functions as a cofactor for the following enzymes:

• Three groups of enzymes (prolyl-3-hydroxylases, prolyl-4-hydroxylases, and lysyl hydroxylases) that are required for the hydroxylation of proline and lysine in the synthesis of collagen.^[91][92][93] These reactions add hydroxyl groups to the amino acids proline or lysine in the collagen molecule via prolyl hydroxylase and lysyl hydroxylase, both requiring vitamin C as a cofactor. The role of vitamin C as a cofactor is to oxidize prolyl hydroxylase and lysyl hydroxylase from Fe²⁺ to Fe³⁺ and to reduce it from Fe³⁺ to Fe²⁺. Hydroxylation allows the collagen molecule to assume its triple helix structure, and thus vitamin C is essential to the development and maintenance of scar tissue, blood vessels, and cartilage.^[22]
• Two enzymes (ε-N-trimethyl-L-lysine hydroxylase and γ-butyrobetaine hydroxylase) that are necessary for synthesis of carnitine.^[94] Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.
• Hypoxia-inducible factor-proline dioxygenase enzymes (isoforms: EGLN1, EGLN2, and EGLN3)^[94][95]
• Dopamine beta-hydroxylase participates in the biosynthesis of norepinephrine from dopamine.^[96][97]
• Peptidylglycine alpha-amidating monooxygenase amidates peptide hormones by removing the glyoxylate residue from their c-terminal glycine residues. This increases peptide hormone stability and activity.^[98][99]

Pharmacokinetics[edit]

Absorption[edit]

From the U.S. National Institutes of Health: [In humans] "Approximately 70%–90% of vitamin C is absorbed at moderate intakes of 30–180 mg/day. However, at doses above 1,000 mg/day, absorption falls to less than 50%."^[5] It is transported through the intestine via both glucose-sensitive and glucose-insensitive mechanisms, so the presence of large quantities of sugar in the intestine can slow absorption.^[100]

Ascorbic acid is absorbed in the body by both active transport and simple diffusion. Sodium-Dependent Active Transport—Sodium-Ascorbate Co-Transporters (SVCTs) and Hexose transporters (GLUTs)—are the two transporter proteins required for active absorption. SVCT1 and SVCT2 import the reduced form of ascorbate across plasma membranes.^[101]GLUT1 and GLUT3 are glucose transporters, and transfer only the dehydroascorbic acid (DHA) form of vitamin C.^[102] 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.^[103]

Transport[edit]

SVCTs appear to be the predominant system for vitamin C transport in the body,^[101] the notable exception being red blood cells, which lose SVCT proteins during maturation.^[104] In both vitamin C synthesizers (example: rat) and non-synthesizers (example: human) cells with few exceptions maintain ascorbic acid concentrations much higher than the approximately 50 micromoles/liter (µmol/L) found in plasma. For example, the ascorbic acid content of pituitary and adrenal glands can exceed 2,000 µmol/L, and muscle is at 200-300 µmol/L.^[105] The known coenzymatic functions of ascorbic acid do not require such high concentrations, so there may be other, as yet unknown functions. Consequences of all this organ content is that plasma vitamin C is not a good indicator of whole-body status, and people may vary in the amount of time needed to show symptoms of deficiency when consuming a diet very low in vitamin C.^[105]

Excretion[edit]

Excretion can be as ascorbic acid, via urine. In humans, during times of low dietary intake, vitamin C is reabsorbed by the kidneys rather than excreted. Only when plasma concentrations are 1.4 mg/dL or higher does re-absorption decline and the excess amounts pass freely into the urine. This salvage process delays onset of deficiency.^[106] Ascorbic acid also converts (reversibly) to dehydroascorbate (DHA) and from that compound non-reversibly to 2,3-diketogluonate and then oxalate. These three compounds are also excreted via urine. Humans are better than guinea pigs at converting DHA back to ascorbate, and thus take much longer to become vitamin C deficient.^[107]

Chemistry[edit]

ascorbic acid
(reduced form)

dehydroascorbic acid
(oxidized form)

Further information: Ascorbic acid (molecular aspects)

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

Numerous analytical methods have been developed for ascorbic acid detection. For example, vitamin C content of a food sample such as fruit juice can be calculated by measuring the volume of the sample required to decolorize a solution of dichlorophenolindophenol (DCPIP) and then calibrating the results by comparison with a known concentration of vitamin C.^[108][109]

Testing for levels[edit]

Simple tests are available to measure the levels of vitamin C in the urine and in serum or blood plasma. However these reflect recent dietary intake rather than total body content.^[3] It has been observed that while serum or blood plasma concentrations follow a circadian rhythm or reflect short-term dietary impact, content within tissues is more stable and can give a better view of the availability of ascorbate within the entire organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses.^[110][111]

Biosynthesis[edit]

The vast majority of animals and plants are able to synthesize vitamin C, through a sequence of enzyme-driven steps, which convert monosaccharides to vitamin C. Yeasts do not make l-ascorbic acid but rather its stereoisomer, erythorbic acid.^[112] In plants, this is accomplished through the conversion of mannose or galactose to ascorbic acid.^[113][114] In animals, the starting material is glucose. In some species that synthesize ascorbate in the liver (including mammals and perching birds), the glucose is extracted from glycogen; ascorbate synthesis is a glycogenolysis-dependent process.^[115] In humans and in animals that cannot synthesize vitamin C, the enzyme l-gulonolactone oxidase (GULO), that catalyses the last step in the biosynthesis, is highly mutated and non-functional.^{[116][117][118][119]}

Animal pathway[edit]

Vitamin C biosynthesis in vertebrates

The biosynthesis of ascorbic acid in vertebrates starts with the formation of UDP-glucuronic acid. UDP-glucuronic acid is formed when UDP-glucose undergoes two oxidations catalyzed by the enzyme UDP-glucose 6-dehydrogenase. UDP-glucose 6-dehydrogenase uses the co-factor NAD⁺ as the electron acceptor. The transferase UDP-glucuronate pyrophosphorylase removes a UMP and glucuronokinase, with the cofactor ADP, removes the final phosphate leading to d-glucuronic acid. The aldehyde group of this compound is reduced to a primary alcohol using the enzyme glucuronate reductase and the cofactor NADPH, yielding l-gulonic acid. This is followed by lactone formation—utilizing the hydrolase gluconolactonase—between the carbonyl on C1 and hydroxyl group on C4. l-Gulonolactone then reacts with oxygen, catalyzed by the enzyme l-gulonolactone oxidase (which is nonfunctional in humans and other Haplorrhini primates) and the cofactor FAD+. This reaction produces 2-oxogulonolactone (2-keto-gulonolactone), which spontaneously undergoes enolization to form ascorbic acid.^{[120][121] [107]}

Some mammals have lost the ability to synthesize vitamin C, including simians and tarsiers, which together make up one of two major primate suborders, Haplorrhini. This group includes humans. The other more primitive primates (Strepsirrhini) have the ability to make vitamin C. Synthesis does not occur in most bats^[116] nor in species in the rodent family Caviidae, that includes guinea pigs and capybaras, but does occur in other rodents, including rats and mice.^[122]

Reptiles and older orders of birds make ascorbic acid in their kidneys. Recent orders of birds and most mammals make ascorbic acid in their liver.^[114] A number of species of passerine birds also do not synthesize, but not all of them, and those that do not are not clearly related; there is a theory that the ability was lost separately a number of times in birds.^[123] In particular, the ability to synthesize vitamin C is presumed to have been lost and then later re-acquired in at least two cases.^[124] The ability to synthesize vitamin C has also been lost in about 96% of fish (the teleosts).^[123]

Most tested families of bats (order Chiroptera), including major insect and fruit-eating bat families, cannot synthesize vitamin C. A trace of gulonolactone oxidase was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested.^[125] There are at least two species of bats, frugivorous bat (Rousettus leschenaultii) and insectivorous bat (Hipposideros armiger), that retain (or regained) their ability of vitamin C production.^[126][127]

Some of these species (including humans) are able to make do with the lower levels available from their diets by recycling oxidised vitamin C.^[128]

Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans.^[129] This discrepancy constitutes much of the basis of the controversy on current recommended dietary allowances. It is countered by arguments that humans are very good at conserving dietary vitamin C, and are able to maintain blood levels of vitamin C comparable with simians on a far smaller dietary intake, perhaps by recycling oxidized vitamin C.^[128]

Plant pathways[edit]

Vitamin C biosynthesis in plants

There are many different biosynthesis pathways for ascorbic acid in plants. Most of these pathways are derived from products found in glycolysis and other pathways. For example, one pathway goes through the plant cell wall polymers.^[116] The plant ascorbic acid biosynthesis pathway most principal seems to be l-galactose. l-Galactose reacts with the enzyme  l-galactose dehydrogenase, whereby the lactone ring opens and forms again but with lactone between the carbonyl on C1 and hydroxyl group on C4, resulting in l-galactonolactone.^[121]  l-Galactonolactone then reacts with the mitochondrial flavoenzyme l-galactonolactone dehydrogenase.^[130] to produce ascorbic acid.^[121] l-Ascorbic acid has a negative feedback on l-galactose dehydrogenase in spinach.^[131]Ascorbic acid efflux by embryo of dicots plants is a well-established mechanism of iron reduction, and a step obligatory for iron uptake.^[a]

All plants synthesize ascorbic acid. Ascorbic acid functions as a cofactor for enzymes involved in photosynthesis, synthesis of plant hormones, as an antioxidant and also regenerator of other antioxidants.^[133] Plants use multiple pathways to synthesize vitamin C. The major pathway starts with glucose, fructose or mannose (all simple sugars) and proceeds to L-galactose, L-galactonolactone and ascorbic acid.^[133][134] There is feedback regulation in place, in that the presence of ascorbic acid inhibits enzymes in the synthesis pathway.^[135] This process follows a diurnal rhythm, so that enzyme expression‎ peaks in the morning to support biosynthesis later on when mid-day sunlight intensity demands high ascorbic acid concentrations.^[134] Minor pathways may be specific to certain parts of plants; these can be either identical to the vertebrate pathway (including the GLO enzyme), or start with inositol and get to ascorbic acid via L-galactonic acid to L-galactonolactone.^[133]

Evolution[edit]

Ascorbic acid is a common enzymatic cofactor in mammals used in the synthesis of collagen, as well as a powerful reducing agent capable of rapidly scavenging a number of reactive oxygen species (ROS). Given that ascorbate has these important functions, it is surprising that the ability to synthesize this molecule has not always been conserved. In fact, anthropoid primates, Cavia porcellus (guinea pigs), teleost fishes, most bats, and some Passeriform birds have all independently lost the ability to internally synthesize Vitamin C in either the kidney or the liver.^[136][124] In all of the cases where genomic analysis was done on an ascorbic acid auxotroph, the origin of the change was found to be a result of loss-of-function mutations in the gene that codes for L-Gulono-γ-lactone oxidase, the enzyme that catalyzes the last step of the ascorbic acid pathway outlined above.^[137] One explanation for the repeated loss of the ability to synthesize vitamin C is that it was the result of genetic drift; assuming that the diet was rich in vitamin C, natural selection would not act to preserve it.^[138][139]

In the case of the simians, it is thought that the loss of the ability to make vitamin C may have occurred much farther back in evolutionary history than the emergence of humans or even apes, since it evidently occurred soon after the appearance of the first primates, yet sometime after the split of early primates into the two major suborders Haplorrhini (which cannot make vitamin C) and its sister suborder of non-tarsier prosimians, the Strepsirrhini ("wet-nosed" primates), which retained the ability to make vitamin C.^[140] According to molecular clock dating, these two suborder primate branches parted ways about 63 to 60 million years ago.^[141] Approximately three to five million years later (58 million years ago), only a short time afterward from an evolutionary perspective, the infraorder Tarsiiformes, whose only remaining family is that of the tarsier (Tarsiidae), branched off from the other haplorrhines.^[142][143] Since tarsiers also cannot make vitamin C, this implies the mutation had already occurred, and thus must have occurred between these two marker points (63 to 58 million years ago).^[144]

It has also been noted that the loss of the ability to synthesize ascorbate strikingly parallels the inability to break down uric acid, also a characteristic of primates. Uric acid and ascorbate are both strong reducing agents. This has led to the suggestion that, in higher primates, uric acid has taken over some of the functions of ascorbate.^[145]

Industrial production[edit]

Vitamin C is produced from glucose by two main routes. The Reichstein process, developed in the 1930s, uses a single pre-fermentation followed by a purely chemical route. The modern two-step fermentation process, originally developed in China in the 1960s, uses additional fermentation to replace part of the later chemical stages. The Reichstein process and the modern two-step fermentation processes use sorbitol as the starting material and convert it to sorbose using fermentation. The modern two-step fermentation process then converts sorbose to 2-keto-l-gulonic acid (KGA) through another fermentation step, avoiding an extra intermediate. Both processes yield approximately 60% vitamin C from the glucose feed.^[146]

In 2017, China produced about 95% of the world supply of ascorbic acid (vitamin C),^[147] which is China's most exported vitamin, having total revenue of US$880 million in 2017.^[148]Due to pressure on Chinese industry to discontinue burning coal normally used for vitamin C manufacturing, the price of vitamin C rose three-fold in 2016 alone to US$12 per kg.^[147]

History[edit]

Folk medicine[edit]

The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native people living in marginal areas incorporated this into their medicinal lore. For example, spruce needles were used in temperate zones in infusions, or the leaves from species of drought-resistant trees in desert areas. In 1536, the French explorer Jacques Cartier, 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.^[149][150]

Scurvy at sea[edit]

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

In the 1497 expedition of Vasco da Gama, the curative effects of citrus fruit were known.^[151][152] Later, a Portuguese planted fruit trees and vegetables in Saint Helena, a stopping point for homebound voyages from Asia, which sustained passing ships.^[153]

Authorities occasionally recommended plant food to prevent scurvy during long sea voyages. John Woodall, the first surgeon to the British East India Company, recommended the preventive and curative use of lemon juice in his 1617 book, The Surgeon's Mate.^[154] In 1734, the Dutch writer Johann Bachstrom gave the firm opinion that "scurvy is solely owing to a total abstinence from fresh vegetable food, and greens."^[155][156]

Scurvy had long been a principal killer of sailors during the long sea voyages.^[157] 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."^[158]

James Lind, a British Royal Navy surgeon who, in 1747, identified that a quality in fruit prevented scurvy in one of the first recorded controlled experiments.^[27]

The first attempt to give scientific basis for the cause of this disease was by a ship's surgeon in the Royal Navy, James Lind. While at sea in May 1747, Lind provided some crew members with two oranges and one lemon per day, in addition to normal rations, while others continued on cider, vinegar, sulfuric acid or seawater, along with their normal rations, in one of the world's first controlled experiments.^[27] The results showed that citrus fruits prevented the disease. Lind published his work in 1753 in his Treatise on the Scurvy.^[26][159]

Fresh fruit was expensive to keep on board, whereas boiling it down to juice allowed easy storage but destroyed the vitamin (especially if boiled in copper kettles).^[83] It was 1796 before the British navy adopted lemon juice as standard issue at sea. In 1845, ships in the West Indies were provided with lime juice instead, and in 1860 lime juice was used throughout the Royal Navy, giving rise to the American use of the nickname "limey" for the British.^[27] Captain James Cook had previously demonstrated the advantages of carrying "Sour krout" on board, by taking his crews to the Hawaiian Islands without losing any of his men to scurvy.^[160] For this, the British Admiralty awarded him a medal.

The name antiscorbutic was used in the eighteenth and nineteenth centuries for foods known to prevent scurvy. These foods included lemons, limes, oranges, sauerkraut, cabbage, malt, and portable soup.^[161] In 1928, the Canadian Arctic anthropologist Vilhjalmur Stefansson showed that the Inuitavoid scurvy on a diet of largely raw meat. Later studies on traditional food diets of the Yukon First Nations, Dene, Inuit, and Métis of Northern Canada showed that their daily intake of vitamin C averaged between 52 and 62 mg/day,^[162] comparable with the Estimated Average Requirement.^[3]

Discovery[edit]

Albert Szent-Györgyi wrote that he won a Nobel Prize after he found a way to mass-produce vitamin C for research purposes when he lived in Szeged, which had become the center of the paprika (red pepper) industry.^[163]

Vitamin C was discovered in 1912, isolated in 1928 and synthesized in 1933, making it the first vitamin to be synthesized.^[11] Shortly thereafter Tadeus Reichstein succeeded in synthesizing the vitamin in bulk by what is now called the Reichstein process.^[164] This made possible the inexpensive mass-production of vitamin C. In 1934 Hoffmann–La Roche trademarked synthetic vitamin C under the brand name Redoxon^[165]and began to market it as a dietary supplement.^[b]

In 1907 a laboratory animal model which would help to identify the antiscorbutic factor was discovered by the Norwegian physicians Axel Holstand Theodor Frølich, who when studying shipboard beriberi, fed guinea pigs their test diet of grains and flour and were surprised when scurvy resulted instead of beriberi. By luck, this species did not make its own vitamin C, whereas mice and rats do.^[167] In 1912, the Polish biochemist Casimir Funk developed the concept of vitamins. One of these was thought to be the anti-scorbutic factor. In 1928, this was referred to as "water-soluble C," although its chemical structure had not been determined.^[168]

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

From 1928 to 1932, Albert Szent-Györgyi and Joseph L. Svirbely's Hungarian team, and Charles Glen King's American team, identified the anti-scorbutic factor. Szent-Györgyi isolated hexuronic acid from animal adrenal glands, and suspected it to be the antiscorbutic factor.^[169] In late 1931, Szent-Györgyi gave Svirbely the last of his adrenal-derived hexuronic acid with the suggestion that it might be the anti-scorbutic factor. By the spring of 1932, King's laboratory had proven this, but published the result without giving Szent-Györgyi credit for it. This led to a bitter dispute over priority.^[169]In 1933, Walter Norman Haworth chemically identified the vitamin as l-hexuronic acid, proving this by synthesis in 1933.^{[170][171][172][173]} Haworth and Szent-Györgyi proposed that L-hexuronic acid be named a-scorbic acid, and chemically l-ascorbic acid, in honor of its activity against scurvy.^[173][11]The term's etymology is from Latin, "a-" meaning away, or off from, while -scorbic is from Medieval Latin scorbuticus (pertaining to scurvy), cognate with Old Norse skyrbjugr, French scorbut, Dutch scheurbuik and Low German scharbock.^[174] Partly for this discovery, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine,^[175] and Haworth shared that year's Nobel Prize in Chemistry.^[16]

In 1957, J.J. Burns showed that some mammals are susceptible to scurvy as their liver does not produce the enzyme l-gulonolactone oxidase, the last of the chain of four enzymes that synthesize vitamin C.^[176][177] 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.^[178]

In 2008, researchers at the University of Montpellier discovered that in humans and other primates the red blood cells have evolved a mechanism to more efficiently utilize the vitamin C present in the body by recycling oxidized l-dehydroascorbic acid (DHA) back into ascorbic acid for reuse by the body. The mechanism was not found to be present in mammals that synthesize their own vitamin C.^[128]

Large doses[edit]

Further information: Vitamin C megadosage

Vitamin C megadosage is a term describing the consumption or injection of vitamin C in doses comparable to or higher than the amounts produced by the livers of mammals which are able to synthesize vitamin C. The theory behind this, although not the actual term, was described in 1970 in an article by Linus Pauling. Briefly, his position was that for optimal health, humans should be consuming at least 2,300 mg/day to compensate for the inability to synthesize vitamin C. The recommendation also fell into the consumption range for gorillas - a non-synthesizing near-relative to humans.^[179] A second argument for high intake is that serum ascorbic acid concentrations increase as intake increases until it plateaus at about 190 to 200 micromoles per liter (µmol/L) once consumption exceeds 1,250 milligrams.^[180] As noted, government recommendations are a range of 40 to 110 mg/day and normal plasma is approximately 50 µmol/L, so 'normal' is about 25% of what can be achieved when oral consumption is in the proposed megadose range.

Pauling popularized the concept of high dose vitamin C as prevention and treatment of the common cold in 1970. A few years later he proposed that vitamin C would prevent cardiovascular disease, and that 10 grams/day, initially (10 days) administered intravenously and thereafter orally, would cure late-stage cancer.^[181] Mega-dosing with ascorbic acid has other champions, among them chemist Irwin Stone and the controversial Matthias Rath and Patrick Holford, who both have been accused of making unsubstantiated treatment claims for treating cancer and HIV infection.

The mega-dosing theory is to a large degree discredited. Modest benefits are demonstrated for the common cold. Benefits are not superior when supplement intakes of more than 1,000 mg/day are compared to intakes between 200 and 1,000 mg/day, and so not limited to the mega-dose range.^[182][183] The theory that large amounts of intravenous ascorbic acid can be used to treat late-stage cancer is - some forty years after Pauling's seminal paper - still considered unproven and still in need of high quality research.^[44][45] However, a lack of conclusive evidence has not stopped individual physicians from prescribing intravenous ascorbic acid to thousands of people with cancer.^[45]

Society and culture[edit]

In February 2011, the Swiss Post issued a postage stamp bearing a depiction of a model of a molecule of vitamin C to mark the International Year of Chemistry.^[184]

Pharmacopoeias[edit]

• British Pharmacopoeia^[185]
• Japanese Pharmacopoeia ^[186]

Notes[edit]

1. ^ Dicot plants transport only ferrous iron (Fe²⁺), but if the iron circulates as ferric complexes (Fe3+), it has to undergo a reduction before it can be actively transported. Plant embryos efflux high amounts of ascorbate that chemically reduce iron(III) from ferric complexes.^[132]
2. ^ "In 1934, Hoffman-La Roche, which bought the Reichstein process patent, became the first pharmaceutical company to mass produce and market synthetic vitamin C, under the brand name Redoxon."^[166]

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