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L-Ascorbic acid, also known as antisorbutic vitamin and vitamin C, has the chemical formula C6H8O6 and a molecular weight of 176. This water-soluble vitamin is important in forming collagen, a protein that gives structure to bones, cartilage, muscle, and blood vessels. It also helps maintain capillaries, bones, and teeth and aids in the absorption of iron. Ascorbic acid, a reducing agent, is necessary to maintain the enzyme prolyl hydroxylase in an active form, most likely by keeping its iron atom in a reduced state. The precursor molecule to the protein collagen, procollagen, contains an unusual amino acid sequence in that every third amino acid is a glycine and contains a high frequency of two amino acids not found in any other proteins - hydroxyproline and hydroxylysine.
These latter two amino acids are converted from proline and lysine, respectively, after the procollagen molecule has been synthesized. The hydroxylation of proline and lysine in procollagen is carried out by the enzyme prolyl hydroxylase using ascorbic acid as a cofactor. The natural form of the vitamin is the L-isomer. Ascorbic acid plays an important role as a component of enzymes involved in the synthesis of collagen and carnitine; however, its most vital role is as a water-soluble vitamin in the human body. Ascorbic acid is a powerful antioxidant because it can donate a hydrogen atom and form a relatively stable ascorbyl free radical. As a scavenger of reactive oxygen and nitrogen oxide species, ascorbic acid has been shown to be effective against the superoxide radical ion, hydrogen peroxide, the hydroxyl radical and singlet oxygen.
Ascorbic acid protects folic acid reductase, which converts folic acid to folinic acid, and may help release free folic acid from its conjugates in food. Ascorbic acid facilitates the absorption of iron. Scurvy is the classic disease associated with vitamin C deficiency. The earliest symptom is fatigue followed by cutaneous findings such as follicular hyperkeratosis, perifollicular hemorrhage, bent or coiled body hair; petechiae, purpuras, and ecchymoses beginning on the back of the lower extremities; and xerosis. Hemorrhage into the muscles of the arms and legs and joints may lead to phlebothrombosis and pain. In severe deficiency states hemorrhage in the viscera leads to vomiting of blood and a bloody stool. In terminally scorbutic patients, syncope, cerebral hemorrhage, high fever, convulsions, shock, and death may occur abruptly.
Oral manifestations of scurvy include gingival edema, bleeding, and ulcerations; secondary bacterial infections; and the loosening of teeth. Severe deficiency of ascorbic acid causes scurvy. Symptoms appear when the serum level falls below 0.2 mg/dl. A total body pool of less than 300 mg is associated with symptoms of scurvy, while maximum body pools are limited to about 2 g. These symptoms reflect the role of ascorbic acid in the maintenance of collagen and blood vessel integrity. It is an acute or chronic disease characterised by hemorrhagic manifestations and abnormal osteoid and dentin formation. The psychological manifestations of scurvy include depression and hysteria. This potentially fatal disease can be prevented with as little as 10 mg ascorbic acid per day, an amount easily obtained through consumption of fresh fruits and vegetables.
Bioavailability, nutrient-nutrient interactions, gender and antioxidant protection are important factors affecting ascorbic acid requirement. Periodontal disease is causally related to anaerobic bacteria. Tissue damage occurs as a result of complex molecular interactions between pathogenic bacteria and host immune responses. In susceptible patients, both local and systemic factors affect the pathogenesis of the infection. Vitamin C deficiency has been shown histologically to result in a lack of collagen formation by affecting the hydroxylation of proline and increasing the permeability of the oral mucosa to endotoxins.9 Vitamin C also enhances the mobility of polymorphonuclear leukocytes, and a deficiency of vitamin C is associated with decreased host immune responses.Animals placed on a diet deficient in vitamin C exhibit adverse changes in the periodontium related to a lack of collagen formation characterized by degenerative soft and hard tissue changes, distorted nuclear morphology of polymorphonuclear leukocytes, and reduced chemotactic responses. Vitamin C has long been a candidate for modulating periodontal disease.
A recent study, which evaluated the role of dietary vitamin C as a contributing factor for periodontal disease, has shown there is a relationship between reduced dietary vitamin C and increased risk for periodontal disease in the general population. The initial inflammatory stage of bone healing is characterized by the formation of granulation tissue and the induction of precursor cells that differentiate into fibroblasts, chondroblasts, chondroclasts, osteoblasts, osteoclasts, and cells essential for capillary proliferation. The major difference between calcifying and non-calcifying cartilage is the amount of type II and type IV collagen. In non-calcifying cartilage, type II collagen Predominates, because it is the major component of cartilage matrix. In calcifying cartilage, type X collagen predominates under the influence of alkaline phosphatase, which is induced by ascorbate.In an animal study, it was found the vitamin C supplemented group progressed through the various stages of bone healing faster than the control group.
In another experimental animal study, bone healing was impaired by the presence of free oxygen radicals.Another benefit of vitamin C in bone healing may be through its antioxidant effect. Vitamin C deficiency has also been associated with decreased bone density in a number of animal studies.In a recent human study, low intake of vitamin C was found to be a risk factor for hip fractures in the elderly. Dietary ascorbic acid intake was independently associated with bone density among premenopausal women. The possible anticarcinogenic effect of vitamin C appears to be related to its ability to detoxify carcinogens or block carcinogenic processes through its action as an antioxidant or as a freeradical scavenger.
Other proposed mechanisms of action for vitamin C in the prevention and treatment of cancer include enhancement of the immune system, stimulation of collagen formation necessary for “walling off” tumors, inhibition of hyaluronidase which may keep the ground substance around the tumor intact and prevent metastasis, inhibition of oncogenic viruses, improved wound healing after cancer surgery, enhancement of the effect of certain chemotherapy drugs, reduction in the toxicity of chemotherapeutic agents such as adriamycin, prevention of free radical damage, and neutralization of carcinogenic substances. Several studies that investigated the association between vitamin C and cancer suggest an inverse relationship between vitamin C intake and cancers of the mouth, pharynx, esophagus, stomach, lung, and pancreas.
It has been shown oxidation of low-density lipoprotein (LDL) and lipid membranes play a crucial role in atherosclerosis.Although the mechanism is still unclear, it has been suggested vitamin C can protect circulating and membrane lipids from free radicals. Vitamin C is also believed to protectlipids indirectly by sparing or reconstituting the active forms of vitamin E. Atherosclerotic plaques impair endothelium-dependent vasodilation in human coronary and peripheral blood vessels, and it has been suggested the acute administration of vitamin C may reverse this endothelial dysfunction. Nitric oxide (NO), a labile endothelial relaxing factor, is derived from L-arginine by the activity of the enzyme NO synthase.Essential hypertension is characterized by impaired endothelium-dependent vasodilation to specific agonists due to an alteration in the L-arginine-NO pathway.This appears to be associated with the production of superoxide anions, which impair the ability of the endothelium to induce NO-mediated relaxations of vascular smooth muscles.In patients with essential hypertension, this impaired endothelial vasodilation can be improved by the administration of vitamin C, an effect that can be reversed by a NO synthase inhibitor. Iron deficiency is regarded as the major cause of nutritional anemia, but vitamins A, B12, C, E, folic acid, and riboflavin have also been linked to its development and control. Ascorbic acid has been reported to play a key role in the absorption of dietary non-heme iron. The cellular uptake of vitamin C is promoted by insulin and is inhibited by hyperglycemia.
In the absence of insulin, hyperglycemia produces “tissue scurvy.” The complications of diabetes mellitus (DM), in part, are believed to result from either the intracellular accumulation of sorbitol or the nonenzymatic glycoxidation of proteins or both. In type 1 diabetic patients, vitamin C supplementation may be necessary to prevent protein glycoxidation and to optimize aldose reductase inhibition. Ascorbic acid status depends on the interactions of dietary vitamin C intake, plasma insulin concentrations, and glycemia. Insulin promotes the active cellular uptake of vitamin C whereas hyperglycemia inhibits renal vitamin C reabsorption. In type 1 diabetes mellitus, an adequate dietary intake of vitamin C is often associated with an unexpectedly low ascorbic acid status. The role of vitamin C as an aldose reductase inhibitor and a water soluble antioxidant in body fluids is an important adjunct to tight glycemic control. Vitamin C in renal transplant recipients has been shown to improve flow mediated, endothelium-dependent vasodilation and increase the resistance of lipoproteins in dilute serum to oxidation.
Degenerative eye disorders are common among the elderly. There is evidence vitamin C can reduce oxidative stress and lower the risk of such age-related degenerative changes. There is evidence in patients with Alzheimer’s disease (AD) that there is increased sensitivity of the cerebral cortex to free radicals, perhaps relatedto lower activity of antioxidant enzymes such as superoxide dismutase. The major targets for oxidation in the brain are lipids and lipoproteins. Supplementation with vitamin E and C significantly increases the concentrations of both vitamins in plasma and CSF and significantly decreases the in vitro oxidation of plasma lipoproteins. The role of vitamin C in the prevention and treatment of the common cold remains controversial. A review of controlled studies suggests a reduction of at least 80% in the incidence of pneumonia in vitamin C groups and substantial treatment benefit from vitamin C in elderly patients hospitalized with pneumonia or bronchitis. Antioxidants such as N-acetyl cysteine, glutathione, glutathione-esters, and vitamin C have been demonstrated to inhibit HIV replication in vitro and several of these antioxidants appear to have cooperative interactions.In vivo, vitamin C and E have been shown to reduce oxidative stress in HIV infected patients and to reduce the viral load. Vitamin C is also potentially important in the prevention of gastric cancer by scavenging nitrate and preventing the nitrosation of dietary substances by potentially carcinogenic N-nitrosoamines.
Smokers have a higher requirement for vitamin C than nonsmokers.Vitamin C concentrations in smokers are inversely related to cigarette consumption.This is most likely due to increased demand as a result of increased oxidative stress. Pregnant or lactating women also require a higher intake of vitamin C to maintain optimal plasma vitamin C concentrations.The higher requirement is due to active placental vitamin C transport, whereby vitamin C concentrations are significantly higher in cord blood and in newborn infants than in the mothers, and the loss of vitamin C through milk. The elderly are prone to vitamin C deficiency because of dietary habits.They also appear to have a higher requirement for vitamin C, although the evidence is inconsistent.
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