Vitamin C Physiological function in mammals:
In humans, vitamin C is essential to a healthy diet as well as being a highly effective antioxidant, acting to lessen oxidative stress; a substrate for ascorbate peroxidase in plants (APX is plant specific enzyme); and an enzyme cofactor for the biosynthesis of many important biochemicals. Vitamin C acts as an electron donor for important enzymes:
Collagen, carnitine, and tyrosine synthesis, and microsomal metabolism
Ascorbic acid performs numerous physiological functions in the human body. These functions include the synthesis of collagen, carnitine, and neurotransmitters; the synthesis and catabolism of tyrosine; and the metabolism of microsome. During biosynthesis ascorbate acts as a reducing agent, donating electrons and preventing oxidation to keep iron and copper atoms in their reduced states.
Vitamin C acts as an electron donor for eight different enzymes:
Three enzymes participate in collagen hydroxylation.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. 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.
Two enzymes are necessary for synthesis of carnitine. Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.
The remaining three enzymes have the following functions in common, but have other functions as well:
dopamine beta hydroxylase participates in the biosynthesis of norepinephrine from dopamine.
another enzyme adds amide groups to peptide hormones, greatly increasing their stability.
one modulates tyrosine metabolism.
Antioxidant
Ascorbic acid is well known for its antioxidant activity, acting as a reducing agent to reverse oxidation in liquids. When there are more free radicals (reactive oxygen species, ROS) in the human body than antioxidants, the condition is called oxidative stress, and has an impact on cardiovascular disease, hypertension, chronic inflammatory diseases, diabetes as well as on critically ill patients and individuals with severe burns. Individuals experiencing oxidative stress have ascorbate blood levels lower than 45 µmol/L, compared to healthy individual who range between 61.4-80 µmol/L.
It is not yet certain whether vitamin C and antioxidants in general prevent oxidative stress-related diseases and promote health. Clinical studies regarding the effects of vitamin C supplementation on lipoproteins and cholesterol have found that vitamin C supplementation does not improve disease markers in the blood. Vitamin C may contribute to decreased risk of cardiovascular disease and strokes through a small reduction in systolic blood pressure, and was also found to both increase ascorbic acid levels and reduce levels of resistin serum, another likely determinant of oxidative stress and cardiovascular risk. However, so far there is no consensus that vitamin C intake has an impact on cardiovascular risks in general, and an array of studies found negative results. Meta-analysis of a large number of studies on antioxidants, including vitamin C supplementation, found no relationship between vitamin C and mortality. Thus vitamin C does not appear to help people live longer.
Vitamin C Pro-oxidant
Ascorbic acid behaves not only as an antioxidant but also as a pro-oxidant. Ascorbic acid has been shown to reduce transition metals, such as cupric ions (Cu2+), to cuprous (Cu1+), and ferric ions (Fe3+) to ferrous (Fe2+) during conversion from ascorbate to dehydroascorbate in vitro. This reaction can generate superoxide and other ROS. However, in the body, free transition elements are unlikely to be present while iron and copper are bound to diverse proteins and the intravenous use of vitamin C does not appear to increase pro-oxidant activity. Thus, ascorbate as a pro-oxidant is unlikely to convert metals to create ROS in vivo. However, vitamin C supplementation has been associated with increased DNA damage in the lymphocytes of healthy volunteers.
Vitamin C Immune system
Vitamin C is found in high concentrations in immune cells, and is consumed quickly during infections. It is not certain how vitamin C interacts with the immune system, it has been hypothesized to modulate the activities of phagocytes, the production of cytokines and lymphocytees, and the number of cell adhesion molecules in monocytes.
Vitamin C Antihistamine
Vitamin C is a natural antihistamine. It both prevents histamine release and increases the detoxification of histamine. A 1992 study found that taking 2 grams vitamin C daily lowered blood histamine levels 38 percent in healthy adults in just one week. It has also been noted that low concentrations of serum vitamin C has been correlated with increased serum histamine levels.
Physiologic Vitamin C function in plants
Ascorbic acid is associated with chloroplasts and apparently plays a role in ameliorating the oxidative stress of photosynthesis. In addition, it has a number of other roles in cell division and protein modification. Plants appear to be able to make ascorbate by at least one other biochemical route that is different from the major route in animals, although precise details remain unknown.
Vitamin C Daily requirements
The North American Dietary Reference Intake recommends 90 milligrams per day and no more than 2 grams (2,000 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, as a result of the osmotic water-retaining effect of the unabsorbed portion in the gastrointestinal tract (similar to cathartic osmotic laxatives). Proponents of orthomolecular medicine claim the onset of diarrhea to be an indication of where the body’s true vitamin C requirement lies, though this has not been clinically verified.
United States vitamin C recommendations
Recommended Vitamin C Dietary Allowance (adult male) 90 mg per day
Recommended Vitamin C Dietary Allowance (adult female) 75 mg per day
Tolerable Vitamin C Upper Intake Level (adult male) 2,000 mg per day
Tolerable Vitamin C Upper Intake Level (adult female) 2,000 mg per day
Government recommended Vitamin C intakes
Recommendations for vitamin C intake have been set by various national agencies:
40 milligrams per day: the United Kingdom's Food Standards Agency
45 milligrams per day: the World Health Organization
90 mg/day (males) and 75 mg/day (females): Health Canada 2007
60–95 milligrams per day: United States' National Academy of Sciences.
The United States defined Tolerable Upper Intake Level for a 25-year-old male is 2,000 milligrams per day.
Vitamin C Therapeutic uses
Further information: Vitamin C and the common cold
Vitamin C functions as an antioxidant and is necessary for the treatment and prevention of scurvy, though in nearly all cases dietary intake is adequate to prevent deficiency and supplementation is not necessary. Though vitamin C has been promoted as useful in the treatment of a variety of conditions, most of these uses are poorly supported by the evidence and sometimes contraindicated.Vitamin C may be useful in lowering serum uric acid levels, resulting in a correspondingly lower incidence of gout. Neither prophylactic nor therapeutic use is supported in the prevention or treatment of pneumonia.
Vitamin C's effect on the common cold has been extensively researched. It has not been shown effective in prevention or treatment of the common cold, except in limited circumstances (specifically, individuals exercising vigorously in cold environments). Routine vitamin C supplementation does not reduce the incidence or severity of the common cold in the general population, though it may reduce the duration of illness.
Vitamin C megadosage
Main article: Vitamin C megadosage
Several individuals and organizations advocate large doses of vitamin C in excess of 10–100 times RDI in the form of oral or intravenous therapy. Large, randomized clinical trials on the effects of high doses on the general population have never taken place. Arguments for megadosage are based on the diets of closely related apes, the hypothesized diet of prehistoric humans, and that most mammals synthesize vitamin C rather than relying on dietary intake. Linus Pauling spent much of his life advocating for the use of megadose vitamin C and believed the established RDA was sufficient to prevent scurvy, but not necessarily the dosage for optimal health. Megadoses have been promoted for the treatment or prevention of various conditions, including cancer, the common cold, and coronary disease. These uses are not supported by clinical evidence, and in some cases harm may result.
Testing for ascorbate Vitamin C levels in the body
Simple tests use dichlorophenolindophenol, a redox indicator, to measure the levels of vitamin C in the urine and in serum or blood plasma. However these reflect recent dietary intake rather than the level of vitamin C in body stores.Reverse phase high performance liquid chromatography is used for determining the storage levels of vitamin C within lymphocytes and tissue. It has been observed that while serum or blood plasma levels follow the circadian rhythm or short term dietary changes, those within tissues themselves are more stable and give a better view of the availability of ascorbate within the organism. However, very few hospital laboratories are adequately equipped and trained to carry out such detailed analyses, and require samples to be analyzed in specialized laboratories.
Adverse Vitamin C effects
Vitamin C Common side-effects
Relatively large doses of ascorbic acid may cause indigestion, particularly when taken on an empty stomach. However, taking vitamin C in the form of sodium ascorbate and calcium ascorbate may minimize this effect. When taken in large doses, ascorbic acid causes diarrhea in healthy subjects. In one trial in 1936, doses up to 6 grams of ascorbic acid were given to 29 infants, 93 children of preschool and school age, and 20 adults for more than 1400 days. With the higher doses, toxic manifestations were observed in five adults and four infants. The signs and symptoms in adults were nausea, vomiting, diarrhea, flushing of the face, headache, fatigue and disturbed sleep. The main toxic reactions in the infants were skin rashes.
Possible Vitamin C side-effects
As vitamin C enhances iron absorption, iron poisoning can become an issue to people with rare iron overload disorders, such as haemochromatosis. A genetic condition that results in inadequate levels of the enzyme glucose-6-phosphate dehydrogenase (G6PD) can cause sufferers to develop hemolytic anemia after ingesting specific oxidizing substances, such as very large dosages of vitamin C.
There is a longstanding belief among the mainstream medical community that vitamin C causes kidney stones, which is based on little science. Although recent studies have found a relationship, a clear link between excess ascorbic acid intake and kidney stone formation has not been generally established. Some case reports exist for a link between patients with oxalate deposits and a history of high-dose vitamin C usage.
In a study conducted on rats, during the first month of pregnancy, high doses of vitamin C may suppress the production of progesterone from the corpus luteum.Progesterone, necessary for the maintenance of a pregnancy, is produced by the corpus luteum for the first few weeks, until the placenta is developed enough to produce its own source. By blocking this function of the corpus luteum, high doses of vitamin C (1000+ mg) are theorized to induce an early miscarriage. In a group of spontaneously aborting women at the end of the first trimester, the mean values of vitamin C were significantly higher in the aborting group. However, the authors do state: 'This could not be interpreted as an evidence of casual association.' However, in a previous study of 79 women with threatened, previous spontaneous, or habitual abortion, Javert and Stander (1943) had 91% success with 33 patients who received vitamin C together with bioflavonoids and vitamin K (only three abortions), whereas all of the 46 patients who did not receive the vitamins aborted.
A study in rats and humans suggested that adding Vitamin C supplements to an exercise training program lowered the expected effect of training on VO2Max. Although the results in humans were not statistically significant, this study is often cited as evidence that high doses of Vitamin C have an adverse effect on exercise performance. In rats, it was shown that the additional Vitamin C resulted in lowered mitochondria production. Since rats are able to produce all of their needed Vitamin C, however, it is questionable whether they offer a relevant model of human physiological processes in this regard.
A cancer-causing mechanism of hexavalent chromium may be triggered by vitamin C.
Chance of Vitamin C overdose
Vitamin C is water soluble, with dietary excesses not absorbed, and excesses in the blood rapidly excreted in the urine. It exhibits remarkably low toxicity. The LD50 (the dose that will kill 50% of a population) in rats is generally accepted to be 11.9 grams per kilogram of body weight when given by forced gavage (orally). The mechanism of death from such doses (1.2% of body weight, or 1.8 lbs for a 150 lb human) is unknown, but may be more mechanical than chemical. The LD50 in humans remains unknown, given lack of any accidental or intentional poisoning death data. However, as with all substances tested in this way, the rat LD50 is taken as a guide to its toxicity in humans.
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. During this process semidehydroascorbic acid radical is formed. Ascorbate free radical reacts poorly with oxygen, and thus, will not create a superoxide. Instead two semidehydroascorbate radicals will react and form one ascorbate and one dehydroascorbate. With the help of glutathione, dehydroxyascorbate is converted back to ascorbate. The presence of glutathione is crucial since it spares ascorbate and improves antioxidant capacity of blood. Without it dehydroxyascorbate could not convert back to ascorbate.
L-Ascorbate is a weak sugar acid structurally related to glucose that naturally occurs attached either to a hydrogen ion, forming ascorbic acid, or to a metal ion, forming a mineral ascorbate. 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 and tarsiers, which together make up one of two major primate suborders, the anthropoidea, also called haplorrhini. This group includes humans. The other more primitive primates (strepsirrhini) have the ability to make vitamin C. Synthesis does not occur in a number of species (perhaps all species) in the small rodent family caviidae that includes guinea pigs and capybaras, but occurs in other rodents (rats and mice do not need vitamin C in their diet, for example). A number of species of passerine birds also do not synthesise, but not all of them, and those that don't are not clearly related; there is a theory that the ability was lost separately a number of times in birds. All tested families of bats, including major insect and fruit-eating bat families, cannot synthesise vitamin C. A trace of GLO was detected in only 1 of 34 bat species tested, across the range of 6 families of bats tested.
These animals all lack the L-gulonolactone oxidase (GULO) enzyme, which is required in the last step of vitamin C synthesis, because they have a differing non-synthesising gene for the enzyme (Pseudogene ?GULO). A similar non-functional gene however, is present in the genome of the guinea pigs and in primates, including humans. Some of these species (including humans) are able to make do with the lower levels available from their diets by recycling oxidised vitamin C.
Most simians consume the vitamin in amounts 10 to 20 times higher than that recommended by governments for humans. This discrepancy constitutes much of the basis of the controversy on current recommended dietary allowances. It is countered by arguments that humans are very good at conserving dietary vitamin C, and are able to maintain blood levels of vitamin C comparable with other simians, on a far smaller dietary intake.
An adult goat, a typical example of a vitamin C-producing animal, will manufacture more than 13,000 mg of vitamin C per day in normal health and the biosynthesis will increase "manyfold under stress". 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.
