This article is about the nutrient. For the chemical compound, see
ascorbic
acid.
Vitamin C or L-ascorbate is an essential nutrient for
higher primates, and a small number of other species. The presence of ascorbate is required for a
range of essential metabolic reactions in all animals and in plants and is made internally by almost all organisms, humans being one notable exception. It is widely known as the
vitamin whose deficiency causes scurvy in humans.[1][2][3] It is also widely
used as a food additive.
The pharmacophore of vitamin C is the ascorbate ion. In
living organisms, ascorbate is an antioxidant, as it protects the body against
oxidative stress,[4] and is a cofactor in several vital
enzymatic reactions.[5]
The uses and the daily requirement of vitamin C are matters of on-going debate.
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.[5] L-dehydroascorbate can then be reduced back to the active
L-ascorbate form in the body by enzymes and glutathione.[6]
L-ascorbate is a weak sugar acid
structurally related to glucose which naturally occurs either attached to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate.
Function
In humans, vitamin C is a highly effective antioxidant, acting to lessen oxidative stress, a substrate for ascorbate
peroxidase,[3] as well as an enzyme
cofactor for the biosynthesis of many
important biochemicals. Vitamin C acts as an electron donor for eight different
enzymes:[7]
- The remaining three have the following functions:
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.[20] 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.
Biosynthesis
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.[5] 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.[21] 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,
guinea pigs, the red-vented bulbul,and
fruit-eating bats.[22] Most notably, humans have no capability to manufacture vitamin C. The cause of this
phenomenon is that the last enzyme in the synthesis process, L-gulonolactone oxidase, cannot be made by the listed animals because the gene
for this enzyme, Pseudogene ΨGULO, is defective.[23] The mutation has not been lethal because
vitamin C is abundant in their food sources, with many of these species' natural diets consisting largely of fruit.
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by
governments for humans.[24] This discrepancy constitutes
the basis of the controversy on current recommended dietary allowances (see Vitamin C as a
macronutrient - Evolutionary rationales).
It has been noted that the loss of the ability to synthesize ascorbate strikingly parallels the evolutionary loss of the
ability to break down uric acid. 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.[25] Ascorbic acid can be
oxidised (broken down) in the human body by the enzyme ascorbic acid
oxidase.
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 "many fold under stress".[26] Trauma or injury has also been demonstrated to also use up large
quantities of vitamin C in humans.[27] Some
microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from
simple sugars.[28][29]
Deficiency
Scurvy is an avitaminosis resulting from lack of vitamin
C, as without this vitamin, the synthesised collagen is too unstable to meet its function.
Scurvy leads to the formation of liver 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.,[30] and so the body soon depletes
itself if fresh supplies are not consumed through the digestive system.
History of human understanding
The need to include fresh plant food or raw animal flesh in the diet to prevent disease was known from ancient times. Native
peoples 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.[31][32]
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."
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 comparing results on two populations of a factor applied to one group only with
all other factors the same. The results conclusively showed that citrus fruits prevented the disease. Lind published his work in
1753 in his Treatise on the Scurvy.
Citrus fruits were one of the first sources of vitamin C available to ship's surgeons.
Lind's work was slow to be noticed, partly because he gave conflicting evidence within the book, and partly because the
British admiralty saw care for the well-being of crews as a sign of weakness. In addition, 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[33]). Ship captains assumed wrongly
that Lind's suggestions didn't work because those juices failed to 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 weren't 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 fresh and
preserved foods, such as sauerkraut, by taking his crews to the Hawaiian Islands and beyond without losing any of his men to scurvy. 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.
In 1907, Axel Holst and Theodor Frølich, two
Norwegian physicians studying beriberi contracted aboard ship's
crews in the Norwegian Fishing Fleet, wanted a small test mammal to substitute for the pigeons they used. They fed guinea pigs their test diet, which had
earlier produced beriberi in their pigeons, and were surprised when scurvy resulted instead. Until that time scurvy had not been
observed in any organism apart from humans, and had been considered an exclusively human disease.
Discovery of ascorbic acid
Albert Szent-Györgyi, pictured here in 1948, was awarded the 1937
Nobel
Prize in Medicine for the discovery of vitamin C
In 1912, the Polish-American biochemist Casimir
Funk, while researching deficiency diseases, developed the concept of vitamins to refer to the nutrients which are
essential to health. Then, from 1928 to 1933, the Hungarian research team of Joseph L Svirbely and Albert Szent-Györgyi and, independently,
the American Charles Glen King, first isolated
vitamin C and showed it to be ascorbic acid. For this, Szent-Györgyi was awarded the 1937 Nobel Prize in Medicine.[34]
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 striking European Arctic explorers living on similar high-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.
Between 1933 and 1934, the British chemists Sir Walter Norman Haworth and Sir
Edmund Hirst and, independently, the Polish chemist Tadeus Reichstein, succeeded in synthesizing the vitamin, the first to be artificially produced. This
made possible the cheap mass-production of vitamin C. Only Haworth was awarded the 1937 Nobel Prize in Chemistry for this work, but the process for vitamin C retained Reichstein's
name.
In 1934 Hoffmann–La Roche became the first pharmaceutical company to mass-produce
synthetic vitamin C, under the brand name of Redoxon.
In 1957 the American J.J. Burns showed that the reason some mammals were susceptible to scurvy
was the inability of their liver to produce the active enzyme
L-gulonolactone oxidase, which is the last of the chain of four
enzymes which synthesize vitamin C.[35][36] 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.
Daily requirements
The North American Dietary Reference
Intake recommends 90 milligrams per day and no more than 2 grams per
day (2000 milligrams per day).[37] Other
related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this
reference intake.[38][39] 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.[40] It is
generally agreed that a balanced diet 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.[37]
High doses (thousands of milligrams) may result in diarrhea. Proponents of alternative
medicine (specifically orthomolecular medicine)[41] claim the onset of diarrhea to be
an indication of where the body’s true vitamin C requirement lies. Both Cathcart[41] and Cameron have hypothesized that very sick patients with cancer or influenza do not display any evidence of diarrhea at all until ascorbate
intake reaches levels as high as 200 grams (nearly half a pound).
| United States vitamin C recommendations[37] |
| 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.
Alternative recommendations on intakes
Some independent researchers have calculated the amount needed for an adult human to achieve similar blood serum levels as
vitamin C synthesising mammals as follows:
Vitamin C as a macronutrient
-
There is a strong advocacy movement for large doses of vitamin C, promoting a great deal of added benefits. Drawing on a wide,
[50] but still inconclusive, body of evidence
as to the benefits beyond those dosages recommended in the Dietary Reference Intakes, many pro-vitamin C organizations promote
usage levels well beyond the current Dietary Reference Intake. The movement is
led by scientists and doctors such as Robert Cathcart, Ewan Cameron,
Steve Hickey, Irwin Stone and the twice Nobel Prize laureate Linus Pauling and the more controversial
Matthias Rath. There is some scientific literature critical of governmental agency dose
recommendations.[40][51] The biological
halflife for vitamin C is fairly short, about 30 minutes in blood plasma, a fact which high dose advocates say that
mainstream researchers have failed to take into account. Researchers at the National Institutes of Health decided upon the current RDA based upon tests conducted 12
hours (24 half lives) after consumption.
Evolutionary rationales
Humans carry a mutated and ineffective form of the gene
required by all mammals for manufacturing the fourth of the four enzymes that manufacture vitamin
C.[52] The inability to produce vitamin C,
hypoascorbemia, is, according to the Online Mendeleian Inheritance in Man database, a "public" inborn error of
metabolism.
The gene, Pseudogene ΨGULO, lost its function millions of years ago, when the
anthropoids branched out.[53] In humans, the three
functional enzymes continue to produce the precursors to vitamin C, but the process is incomplete; these enzymes ultimately
undergo proteolytic degradation. Stone[54] and
Pauling[39] calculated,
based on the diet of our primate cousins[38] (similar to what our common descendants are likely to
have consumed when the gene mutated), that the optimum daily requirement of vitamin C is around 2,300 milligrams for a human
requiring 2,500 kcal a day.
The established RDA has been criticized by Pauling to be one that will prevent acute
scurvy, and is not necessarily the dosage for optimal health.[49]
Therapeutic uses
-
Since its discovery vitamin C has been considered by some enthusiastic proponents a "universal panacea", although this led to suspicions by others of it being over-hyped.[55] Other proponents of high dose vitamin C consider that if it
is given "in the right form, with the proper technique, in frequent enough doses, in high enough doses, along with certain
additional agents and for a long enough period of time,"[56] it can prevent and, in many cases, cure, a wide range of common and/or lethal diseases, notably the
common cold and heart disease,[57] although the NIH considers there to be "fair scientific evidence against
this use."[58] Some proponents issued controversial
statements involving it being a cure for AIDS,[59] bird flu, and SARS.[60][61][62]
Probably the most controversial issue, the putative role of ascorbate in the management of AIDS, is still unresolved, more
than 16 years after the landmark study published in the Proceedings of National Academy of Sciences (USA) showing that non toxic
doses of ascorbate suppress HIV replication in vitro.[63] Other studies expanded on those results, but still, no large scale trials have
yet been conducted.[64][65][66]
In an animal model of lead intoxication, vitamin C demonstrated "protective effects" on lead-induced nerve and muscle
abnormalities[67] In smokers, blood
lead levels declined by an average of 81% when supplemented with 1000 mg of vitamin C, while 200 mg were ineffective, suggesting
that vitamin C supplements may be an "economical and convenient" approach to reduce
lead levels in the blood.[68] The Journal of the American Medical Association published a study which
concluded, based on an analysis of blood lead levels in the subjects of the Third National Health and Nutrition Examination
Survey, that the independent, inverse relationship between lead levels and vitamin C in the blood, if causal, would "have
public health implications for control of lead toxicity".[69]
Vitamin C has limited popularity as a treatment for autism spectrum symptoms. A
1993 study of 18 children with ASD found some symptoms reduced after treatment with vitamin C,[70] but these results have not been replicated.[71] Small clinical trials have found that vitamin C might improve the
sperm count, sperm motility, and sperm morphology in infertile men[72], or improve immune function related to the prevention and treatment of
age-associated diseases.[73] However, to date, no large clinical trials have verified these findings.
A preliminary study published in the Annals of Surgery found that the early administration of antioxidant supplementation
using α-tocopherol and ascorbic acid reduces the incidence of organ failure and shortens ICU length of stay in this cohort of
critically ill surgical patients.[74] More research on
this topic is pending.
Dehydroascorbic acid, the main form of oxidized Vitamin C in the body, was shown to reduce neurological deficits and mortality
following stroke, due to its ability to cross the blood-brain barrier, while "the antioxidant
ascorbic acid (AA) or vitamin C does not penetrate the blood-brain barrier".[75] In this study published by the Proceedings of the National Academy of Sciences in 2001, the authors
concluded that such "a pharmacological strategy to increase cerebral levels of ascorbate in stroke has tremendous potential to
represent the timely translation of basic research into a relevant therapy for thromboembolic stroke in humans". No such
"relevant therapies" are available yet and no clinical trials have been planned.
In January 2007 the US Food and Drug Administration approved a Phase I
toxicity trial to determine the safe dosage of intravenous vitamin C as a possible cancer treatment for "patients who have
exhausted all other conventional treatment options."[76]
Additional studies over several years would be needed to demonstrate whether it is effective.[77]
In February 2007, an uncontrolled study of 39 terminal cancer patients showed that, on subjective questionnaires, patients
reported an improvement in health, cancer symptoms, and daily function after administration of high-dose intravenous vitamin
C.[78] The authors concluded that
"Although there is still controversy regarding anticancer effects of vitamin C, the use of vitamin C is considered a safe and
effective therapy to improve the quality of life of terminal cancer patients".
Testing for ascorbate levels in the body
Simple tests use DCPIP 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.[5] Reverse phase high performance liquid chromatography is used for determining the storage levels
of vitamin C within
