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Vitamin C, General Overview. Truth and Lies in Healing Effect
Posted on: November 5, 2003

Organism is an integrated system; all processes are closely related there. Lots of molecules in billions of cells interact every second. As a result of such interactions organisms get lots of different chemical reactions and compounds. Some of them are useful, other harmful. As an engine: we use fuel and get energy plus waist. In organism during such reactions we get lots of "waist" compounds, one of them are reactive oxygen species (ROS). It is already known that ROS play a crucial role in aging and age related diseases. As being very reactive it damages our hereditary/information (DNA) system, proteins, general function of cells in common. To neutralize ROS organism should use antioxidant compounds. One of them and most widely spread is vitamin C (ascorbic acid). Of course there are much more anti-oxidative compounds known, but here we will review ascorbic acid in general. It really deserves it.

Historical perspective
The sea voyager/sailors developed a peculiar disease called scurvy when they were on sea. This was found to be due to eating non-perishable items and lack of fresh fruits and vegetables in their diet. A British naval Physician, Lind documented that there was some substance in citrus fruits that can cure scurvy. He developed a method to concentrate and preserve citrus juice for use by sailors. British Navy was given a daily ration of lime or lemon juice to overcome ascorbic acid deficiency. Ascorbic acid was first isolated from natural sources and structurally characterized by Szent-Gyorgyi, Waugh and King. Haworth and Hirst first synthesized this vitamin. Currently ascorbic acid is the most widely used vitamin supplement through out the world.

Sources of Ascorbic acid
Ascorbic acid is widely distributed in fresh fruits and vegetables. It is present in fruits like orange, lemons, grapefruit, watermelon, papaya, strawberries, cantaloupe, mango, pineapple, raspberries and cherries. It is also found in green leafy vegetables, tomatoes, broccoli, green and red peppers, cauliflower and cabbage. Most of the plants and animals synthesize ascorbic acid from D-glucose or D-galactose. A majority of animals produce relatively high levels of ascorbic acid from glucose in liver. However, guinea pigs, fruit eating bats, apes and humans cannot synthesize ascorbic acid due to the absence of the enzyme L-gulonolactone oxidase. Hence, in humans ascorbic acid has to be supplemented through food and/or as tablets. Ascorbic acid is a labile molecule; it may be lost from foods during cooking/processing even though it has the ability to preserve foods by virtue of its reducing property. Synthetic ascorbic acid is available in a wide variety of supplements. Both natural and synthetic ascorbic acid are chemically identical and there are no known differences in their biological activities or bioavailability. Ascorbic acid present in foods is readily available and easily absorbed by active transport in the intestine. Most of it (80-90%) will be absorbed when the intake is up to 100 mg/day, whereas at higher levels of intake (500 mg/day) the efficiency of absorption of ascorbic acid rapidly declines. Ascorbic acid is sensitive to air, light, heat and easily destroyed by prolonged storage and over processing of food. Ascorbic acid being a water-soluble compound is easily absorbed but it is not stored in the body.

Physiological functions of Ascorbic acid
The physiological functions of ascorbic acid are largely dependent on the oxido-reduction properties of this vitamin. L-ascorbic acid is a co-factor for hydroxylases and monooxygenase enzymes involved in the synthesis of collagen, carnitine and neurotransmitters. Ascorbic acid accelerates hydroxylation reactions by maintaining the active center of metal ions in a reduced state for optimal activity of enzymes hydroxylase and oxygenase. Ascorbic acid plays an important role in the maintenance of collagen, which represents about one third of the total body protein. It constitutes the principal protein of skin, bones, teeth, cartilage, tendons, blood vessels, heart valves, inter vertebral discs, cornea and eye lens. Ascorbic acid is essential to maintain the enzyme prolyl and lysyl hydroxylase in an active form. The hydroxylation of proline and lysine is carried out by the enzyme prolyl-hydroxylase using ascorbic acid as co-factor. Ascorbic acid deficiency results in reduced hydroxylation of proline and lysine, thus affecting collagen synthesis. Ascorbic acid is essential for the synthesis of muscle carnitine (β-hydroxy butyric acid). Carnitine is required for transport and transfer of fatty acids into mitochondria where it can be used for energy production. Ascorbic acid acts as co-factor for hydroxylations involved in carnitine synthesis. Further, ascorbic acid acts as co-factor for the enzyme dopamine-β-hydroxylase, which catalyzes the conversion of neurotransmitter dopamine to norepinephrine. Thus ascorbic acid is essential for synthesis of catecholamines. In addition, ascorbic acid catalyzes other enzymatic reactions involving amidation necessary for maximal activity of hormones oxytocin, vasopressin, cholecystokinin and alpha-melanotripin. Ascorbic acid is also necessary for the transformation of cholesterol to bile acids as it modulates the microsomal 7α-hydroxylation, the rate limiting reaction of cholesterol catabolism in liver. In ascorbic acid deficiency, this reaction becomes slowed down thus, resulting in an accumulation of cholesterol in liver, hypercholesterolemia, formation of cholesterol gallstones etc. Ascorbic acid is known to enhance the availability and absorption of iron from non-heme iron sources.

Ascorbic acid in disease
Ascorbic acid and atherosclerosis
Lipid peroxidation and oxidative modification of low-density lipoproteins (LDL) are implicated in development of atherosclerosis. Vitamin C protects against oxidation of isolated LDL by different types of oxidative stress, including metal ion dependent and independent processes. Addition of iron to plasma devoid of ascorbic acid resulted in lipid peroxidation, whereas endogenous and exogenous ascorbic acid was found to inhibit the lipid oxidation in iron-over loaded human plasma. Similarly, when ascorbic acid was added to human serum supplemented with Cu2+, antioxidant activity rather than pro-oxidant effects were observed. Ascorbic acid is known to prevent the oxidation of LDL primarily by scavenging the free radicals and other reactive oxygen species in the aqueous milieu. In addition, in vitro studies have shown that physiological concentrations of ascorbic acid strongly inhibit LDL oxidation by vascular endothelial cells. Adhesion of leukocytes to the endothelium is an important step in initiating atherosclerosis. in vivo studies have demonstrated that ascorbic acid inhibits leukocyte-endothelial cell interactions induced by cigarette smoke or oxidized LDL. Further, lipophilic derivatives of ascorbic acid showed protective effect on lipid-peroxide induced endothelial injury.

Ascorbic acid and cardiovascular disease
Numerous studies have looked at the association between ascorbic acid intake and the risk of developing cardiovascular disease (CHD). A large prospective epidemiological study suggested that high intake of ascorbic acid was associated with a reduced risk of death from CHD in women and not in men. A third American cohort study suggested that cardiovascular mortality was reduced in both sexes by vitamin C. In the UK, a study showed that the risk of stroke in those with highest intake of vitamin C was only half that of subjects with the lowest intake and no evidence suggestive of lower rate of CHD in those with high vitamin C intake. However, a recent analysis on the role of ascorbic acid and antioxidant vitamins showed no evidence of significant benefit in prevention of CHD. Thus, no conclusive evidence is available on the possible protective effect of ascorbic acid supplementation on cardiovascular disease.

Ascorbic acid and Cancer
Nobel laureate Pauling and Cameron advocated use of high doses of ascorbic acid (> 10 g/day) to cure and prevent cold infections and in the treatment of cancer. The benefits included were increased sense of well being much improved quality of life, prolongation of survival times in terminal patients and complete regression in some cases. However, clinical studies on cancer patients showed no significant differences between vitamin C and placebo groups in regard to survival time. Ascorbic acid combats cancer by promoting collagen synthesis and thus prevents tumors from invading other tissues. However, researchers now believe that ascorbic acid prevents cancer by neutralizing free radicals before they can damage DNA and initiate tumor growth and or may act as a pro-oxidant helping body's own free radicals to destroy tumors in their early stages.

Extensive animal, clinical and epidemiological studies were carried out on the role of ascorbic acid in the prevention of different types of cancers. A mixture of ascorbic acid and cupric sulfate significantly inhibited human mammary tumor growth in mice, while administered orally. Ascorbic acid decreased the incidence of kidney tumors by estradiol or diethylstilbesterol in hamsters due to decrease in the formation of genotoxic metabolites. Ascorbic acid and its derivatives were shown to be cytotoxic and inhibited the growth of a number of malignant and non-malignant cell lines in vitro and in vivo. Ascorbic acid has been reported to be cytotoxic to some human tumor cells viz., neuorblastoma, osteosarcoma and retinoblastoma. Among ascorbic acid derivatives, fatty acid esters of ascorbic acid have attracted considerable interest as anticancer compounds in view of their lipophilic nature as they can easily cross cell membranes and blood brain barrier. Ascorbic acid and ascorbyl esters have been shown to inhibit the proliferation of mouse glioma and human brain tumor cells viz., glioma and glioblastoma cells and renal carcinoma cells. Ascorbyl stearate was found to be more potent than sodium ascorbate in inhibiting proliferation of human glioblastoma cells.

Numerous reports are available in literature on cytotoxic and anti-carcinogenic effect of ascorbic acid and its derivatives in different tumor model systems. However, the molecular mechanisms underlying the anti-carcinogenic potential of ascorbic acid are not completely elucidated.

Controversies on health benefits of Ascorbic acid
Does ascorbic acid acts as antioxidant or pro-oxidant?
Vitamin C is an important dietary antioxidant; it significantly decreases the adverse effect of reactive species such as reactive oxygen and nitrogen species that can cause oxidative damage to macromolecules such as lipids, DNA and proteins which are implicated in chronic diseases including cardiovascular disease, stroke, cancer, neurodegenerative diseases and cataractogenesis. Ascorbic acid is a potent water-soluble antioxidant capable of scavenging/ neutralizing an array of reactive oxygen species viz., hydroxyl, alkoxyl, peroxyl, superoxide anion, hydroperoxyl radicals and reactive nitrogen radicals such as nitrogen dioxide, nitroxide and peroxynitrite at very low concentrations. In addition ascorbic acid can regenerate other antioxidants such as α-tocopheroxyl, urate and β-carotene radical action from their radical species. Thus, ascorbic acid acts as co-antioxidant for α-tocopherol by converting α-tocopheroxyl radical to α-tocopherol and helps to prevent the α-tocopheroxyl radical mediated peroxidation reactions

These radical species are highly reactive and can trigger lipid peroxidation reactions. Thus the question arises whether vitamin C acts as a pro-oxidant in in vivo conditions? The answer appears to be "no" as though these reactions occur readily in vitro, its relevance in in vivo has been a matter of debate concerning ready availability of catalytically active free metal ions in vivo. In biological systems, iron is not freely available, but it is bound to proteins like transferrin, hemoglobin and ferritin. Mobilization of iron from these biomolecules may be required before it can catalyze lipid peroxidation. Further, the concentration of free metal ions in in vivo is thought to be very low as iron and other metals are sequestered by various metal binding proteins. Another factor that may affect pro-oxidant vs. antioxidant property of ascorbic acid is its concentration. The in vitro data suggest that at low concentrations ascorbic acid act as a pro-oxidant, but as an antioxidant at higher levels. Moreover, a recent report demonstrated that large doses of exogenous iron (200 mg) and ascorbic acid (75 mg) promote the release of iron from iron binding proteins and also enhance in vitro lipid peroxidation in serum of guinea pigs. This finding supports the hypothesis that high intake of iron along with ascorbic acid could increase in vivo lipid peroxidation of LDL and therefore could increase risk of atherosclerosis. However, another study demonstrated that in iron-overloaded plasma, ascorbic acid acts as an antioxidant and prevents oxidative damage to lipids in vivo.

Is ascorbic acid harmful to cancer patients?
Tumor cells contain large amounts of ascorbic acid, although the role of ascorbic acid in tumors is not yet known. Vitamin C enters through the facilitative glucose transporters (GLUTs) in the form of dehydroascorbic acid, which is then reduced intracellularly and retained as ascorbic acid. It is speculated that high levels of ascorbic acid in cancer cells may interfere with chemotherapy or radiation therapy since these therapies induce cell death by oxidative mechanism. Thus, ascorbic acid supplementation might make cancer treatment less effective because, ascorbic acid being a strong antioxidant may scavenge or neutralize the oxidative stress induced by chemotherapy in cancer patients. However, more studies are needed to understand the role of ascorbic acid in tumors cells and the speculative contraindication of ascorbic acid for cancer chemotherapy.

Does ascorbic acid cause cancer?
Recently, it has been reported that lipid hydroperoxide can react with ascorbic acid to form products that could potentially damage DNA, suggesting that it may form genotoxic metabolites from lipid hydroperoxides implicating that ascorbic acid may enhance mutagenesis and risk of cancer. It was showed that ascorbic acid induces decomposition of lipid in presence of transition metals to DNA-reactive bifunctional electrophiles being a genotoxin can react with DNA bases to form mutations or apoptosis. Thus, the above process can give rise to substantial amounts of DNA damage in vivo. However there are many questions, which need to be considered before we accept the hypothesis that ascorbic acid can cause cancer by producing genotoxic metabolites from lipids. The hydroperoxides formed through lipid peroxidation reaction are rapidly reduced to aldehydes by a number of enzymes. Further, ascorbic acid being a strong antioxidant effectively inhibits the formation of lipid peroxides as ascorbic acid forms the first line of antioxidant defense mechanism in human plasma. The formation of lipid hydroperoxides occur only after ascorbic acid has been exhausted. Hence, interaction of ascorbic acid and hydroperoxide may not arise in human plasma. Recently, high intracellular vitamin C was reported to prevent oxidation-induced mutations in human cells. Thus, the physiological relevance of these results is yet to be established in in vivo experiments.

Ascorbic acid is one of the important and essential vitamins for human health. It is needed for many physiological functions in human biology. Fresh fruits, vegetables and also synthetic tablets supplement the ascorbic acid requirement of the body. However, stress, smoking, infections and burns deplete the ascorbic acid reserves in the body and demands higher doses of ascorbic acid supplementation. Based on available biochemical, clinical and epidemiological studies, the current RDA for ascorbic acid is suggested to be 100-120 mg/day to achieve cellular saturation and optimum risk reduction of heart diseases, stroke and cancer in healthy individuals. In view of its antioxidant property, ascorbic acid and its derivatives are widely used as preservatives in food industry. Many health benefits have been attributed to ascorbic acid namely antioxidant, anti-atherogenic and anti-carcinogenic activity. Lately some of these beneficial effects of ascorbic acid are contradicted. The relation between ascorbic acid and cancer is still a debatable as the molecular mechanism underlying anti-carcinogenic activity of ascorbic acid is not clearly elucidated. Regarding the pro-oxidant activity of vitamin C in presence of iron, there is compelling evidence for antioxidant protection of lipids by ascorbic acid both with and without iron co-supplementation in animals and humans. Current evidences also suggest that ascorbic acid protects against atherogenesis by inhibiting LDL oxidation. The data on vitamin C and DNA damage are conflicting and inconsistent. However, more mechanistic and human in vivo studies are warranted to establish the beneficial claims on ascorbic acid. Thus, though ascorbic acid was discovered in 17th century, the role of this important vitamin in human health and disease still remains a mystery in view of many beneficial claims and contradictions.

Source: Vitamin C in human health and disease is still a mystery? An overviewK Akhilender Naidu. Nutrition Journal 2003, 2:7, p.1-10
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