Vitamin C
Vitamin C or L-ascorbate is an essential nutrient for a large number of higher primate species, a small number of other mammalian species (notably guinea pigs and bats), a few species of birds, and some fish. The presence of ascorbate is required for a range of essential metabolic reactions in all animals and plants. It is made internally by almost all organisms, humans being the most well-known exception. It is widely known as the vitamin whose deficiency causes scurvy in humans. 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, since it protects the body against oxidative stress, and is a cofactor in several vital enzymatic reactions.
The uses and the daily requirement amounts of vitamin C are matters of on-going debate. People consuming diets rich in ascorbate from natural foods, such as fruits and vegetables, are healthier and have lower mortality from a number of chronic illnesses. However, a recent meta-analysis of 68 reliable antioxidant supplementation experiments involving a total of 232,606 individuals concluded that consuming additional ascorbate from supplements may not be as beneficial as thought.
Biological significance
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. L-dehydroascorbate can then be reduced back to the active L-ascorbate form in the body by enzymes and glutathione.
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.
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. 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. 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 (specifically the suborder haplorrhini), guinea pigs, a number of species of passerine birds (but not all of them), and in apparently many major families of bats and perhaps all of them. Humans have no enzymatic 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 GULO, is defective. The mutation has not been lethal because vitamin C is abundant in their food sources. It has been found that species with this mutation (including humans) have adapted a vitamin C recycling mechanism to compensate.
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans. This discrepancy constitutes the basis of the controversy on current recommended dietary allowances.
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. 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". Trauma or injury has also been demonstrated to use up large quantities of vitamin C in humans. Some microorganisms such as the yeast Saccharomyces cerevisiae have been shown to be able to synthesize vitamin C from simple sugars.
Deficiency
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 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, and so the body soon depletes itself if fresh supplies are not consumed.
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.
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). Other related species sharing the same inability to produce vitamin C and requiring exogenous vitamin C consume 20 to 80 times this reference intake. 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. 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.
High doses (thousands of milligrams) may result in diarrhea in healthy adults. Proponents of alternative medicine (specifically orthomolecular medicine) claim the onset of diarrhea to be an indication of where the body’s true vitamin C requirement lies, though this has yet to be clinically verified.
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. 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," it can prevent and, in many cases, cure, a wide range of common and/or lethal diseases, notably the common cold and heart disease, although the NIH considers there to be "fair scientific evidence against this use." Some proponents issued controversial statements involving it being a cure for AIDS, bird flu, and SARS.
Probably the most controversial issue, the putative role of ascorbate in the management of AIDS, is still unresolved, more than 16 years after a study published in the Proceedings of National Academy of Sciences (USA) showing that non toxic doses of ascorbate suppress HIV replication in vitro. Other studies expanded on those results, but still, no large scale trials have yet been conducted.
In an animal model of lead intoxication, vitamin C demonstrated "protective effects" on lead-induced nerve and muscle abnormalities In smokers, blood lead levels declined by an average of 81% when supplemented with 1,000 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. 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".
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, but these results have not been replicated. Small clinical trials have found that vitamin C might improve the sperm count, sperm motility, and sperm morphology in infertile men, or improve immune function related to the prevention and treatment of age-associated diseases. 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. 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". 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." Additional studies over several years would be needed to demonstrate whether it is effective.
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. 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".
Vitamin C has been shown to lower IOP in glaucoma patients when taken in massive amounts according to the September 2007 issue of GLEAMS.
In an August, 2008 article in the Proceedings of the National Academy of Sciences Mark Levine and colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases found that direct injection of high doses of vitamin C reduced tumor weight and growth rate by about 50 percent in mouse models of ovarian, brain, and pancreatic cancers. No human therapies have yet been developed using this technique.
A Cochrane Review in 2008 found no evidence to support any increase in lifespan as a result of vitamin C supplementation. As opposed to supplementation with vitamin A, vitamin E, and beta-carotene, vitamin C was not linked with a decrease in lifespan.
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