1. Metabolic functions of vitamin C
Domina Petric, MD

2. Electron transport
Ascorbic acid loses electrons easily, and, because of its reversible monovalent oxidation to the ascorbyl radical, it can serve as a biochemical redox system.
11/10/2018
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3. Electron transport
Ascorbic acid is involved in many electron transport reactions:
synthesis of collagen
degradation of 4-hydroxyphenylpyruvate
synthesis of norepinephrine
desaturation of fatty acids
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

4. Antioxidant functions
Ascorbic acid can act as an antioxidant owing to its ability to react with free radicals, undergoing a single electron oxidation to yield a relatively poor reactive intermediate, the ascorbyl radical, which disproportionates to ascorbate and dehydroascorbate.
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5. Antioxidant functions
Ascorbic acid can reduce toxic, reactive oxygen species superoxide anion (O2•-) and hydroxyl radical (OH•), as well as organic (RO2•) and nitrogen (NO2•) oxyradicals.
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6. Antioxidant functions
The antioxidant efficiency of ascorbic acid is significant at physiological concentrations of the vitamin (20 to 90 µM).
Under those conditions, the predominant reaction is a radical chain-terminating one of ascorbate (AH-) with a peroxyl radical to yield a hydroperoxide and the ascorbyl radical (A•-), which proceeds to reduce a second peroxyl radical and yield the vitamin in its oxidized form, dehydroascorbic acid (A).
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7. Prooxidant potential
In the presence of oxidized metal ions ( Fe3+, Cu2+), high concentrations of ascorbic acid can have prooxidant functions at least in vitro.
It does so by donating a single electron to reduce such ions to forms that, in turn, can react with O2 to form oxygen radicals.
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8. Enzyme co-substrate functions
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9. Collagen synthesis
Ascorbic acid is involved in the hydroxylation of specific prolyl and lysyl residues of the unfolded (nonhelical) procollagen chain.
These reactions are catalyzed by the enzymes prolyl 4-hydroxylase, prolyl 3-hydroxylase and lysyl hydroxylase.
11/10/2018
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10. Collagen synthesis
Each of these enzymes is a dioxygenase that requires O2, Fe2+ and ascorbate.
Each is stoichiometrically linked to the oxidative decarboxylation of α-ketoglutarate.
The role of ascorbate in each reaction is to maintain iron in the reduced state (Fe2+), which dissociates from a critical region (an SH group) of the active site to reactivate the enzyme after catalysis.
11/10/2018
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11. Ebi.ac.uk
Collagen synthesis
The post-translational hydroxylation of these procollagen amino acid residues is necessary for folding into the triple helical structure that can be secreted by fibroblasts.
Hydroxyproline residues contribute to the stiffness of the collagen triple helix.
Hydroxylysine residues bind (via their hydroxyl groups) carbohydrates and form intramolecular cross-links that give structural integrity to the collagen mass.
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12. Wikipedia.org
Collagen synthesis
The underhydroxylation of procollagen, which then accumulates and is degraded, appears to be the basis of the pathophysiology of scurvy.
Vitamin C-deficient subjects usually show reduced urinary excretion of hydroxyproline.
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13. Elastin, complement
There is modest effect of vitamin C deficiency on the hydroxylation of proline in the conversion of the soluble tropoelastin to the soluble elastin.
A component of complement, C1q, resembles collagen in containing hydroxyproline and hydroxylysine.
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14. Complement
Vitamin C deprivation reduces overall complement activity but does not affect the synthesis of C1q.
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Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

15. Catecholamine biosynthesis
Ascorbic acid has important roles in several hydroxylases involved in the metabolism of neurotransmitters, steroids, drugs and lipids.
It serves as an electron donor for dopamine β-monooxygenase, a copper enzyme located in the chromaffin vesicles of the adrenal medulla and in adrenergic synapses.
This enzyme hydroxylates dopamine to form the neurotransmitter norepinephrine.
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16. Catecholamine biosynthesis
In this reaction, ascorbate is oxidized to ascorbyl radical (monodehydroascorbate), which is returned to the reduced state by monodehydroascorbate reductase.
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17. Carnitine synthesis
Ascorbic acid is a cofactor of two Fe2+-containing hydroxylases involved in the synthesis of carnitine, which is required for the transport of fatty acids into mitochondria for oxidation to provide energy for the cell.
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18. Drug and steroid metabolism
Ascorbic acid is involved in microsomal hydroxylation reactions of drug and steroid metabolism: those coupled to the microsomal electron transport chain.
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19. Drug and steroid metabolism
Studies in animal models have clearly demonstrated positive correlations between ascorbic acid status, hepatic activity of cytochrome P-450 and drug metabolism (hydroxylations, demethylations).
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20. Tyrosine metabolism
Vitamin C is involved in the oxidative degradation (which normally proceeds completely to CO2 and water) of tyrosine via two mixed-function oxidases that are dependent on the presence of ascorbic acid.
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21. Tyrosine metabolism
The first is 4-hydroxyphenylpyruvate dioxygenase, which catalyzes the oxidation and decarboxylation of the intermediate of tyrosine degradation, 4-hydroxylphenylpyruvic acid, to homogentisic acid.
The second ascorbate-requiring enzyme catalyzes the next step in tyrosine degradation: homogentisate 1,2-dioxygenase.
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22. Tyrosine metabolism Both conditions respond to vitamin C supplements.
Vitamin C deficiency can result in tyrosinemia and the excretion of tyrosine metabolites in the urine.
Both conditions respond to vitamin C supplements.
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23. Nonenzymatic Functions
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Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

24. Cellular antioxidation
Ascorbic acid is the most effective aqueous antioxidant in plasma, interstitial fluids and soluble phases of cells.
It is the first line of defense against reactive oxygen species arising in those compartments.
Those species include superoxide and hydrogen peroxide arising from activated polymorphonuclear leukocytes or other cells, and from gas-phase cigarette smoke, which can promote the oxidation of critical cellular components of proteins and of DNA.
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25. Prevention of lipid peroxidation
The LDL protective action of vitamin E appears to be dependent on the presence of ascorbic acid.
Ascorbic acid reduces the tocopheroxyl radical, thus preventing the latter from acting prooxidatively by abstracting hydrogen from a cholesteryl-polyunsaturated fatty ester to yield a peroxyl radical.
11/10/2018
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26. Prevention of protein oxidation
Reactive oxygen species can oxidize proteins to produce carbonyl derivatives and other oxidative changes associated with loss of function.
Whether ascorbic acid provides such protection in vivo is not clear, but this has been suggested as the basis of effects reported for vitamin C in reducing risks to cataracts and other illnesses.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

27. Prevention of DNA oxidation
As a physiological antioxidant, ascorbic acid plays a role in the prevention of oxidative damage to DNA, which is elevated in cells at sites of chronic inflammation and in many pre-neoplastic lesions.
The continuing attack of DNA by unquenched reactive oxygen species is believed to contribute to cancer.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

28. Prevention of NO oxidation
Ascorbic acid protects nitric oxide (NO) from oxidation, supporting the favorable effects of nitric acid on vascular epithelial function.
This appears to be the basis for the effects of high-level vitamin C intake in lowering blood pressure.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

29. Metal ion metabolism
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30. Promotion of nonheme iron bioavailability
Ascorbic acid increases the bioavailability of iron in foods.
This effect is associated with increased enteric absorption (which is normally low) of the mineral.
It affects both nonheme and heme iron.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

31. Promotion of nonheme iron bioavailability
The effect on nonheme iron involves reduction of the ferric form of the element (Fe3+), predominant in the acidic environment of the stomach, to the ferrous form (Fe2+) and then forming a soluble stable chelate that stays in solution in the alkaline environment of the small intestine and is well absorbed.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

32. Promotion of heme-iron bioavailability
Ascorbic acid also promotes the utilization of heme iron, which appears to involve enhanced incorporation of iron into its intracellular storage form, ferritin.
This effect involves facilitation of ferritin synthesis.
Ascorbate enhances the iron-stimulated translation of ferritin mRNA by maintaining the iron-responsive element-binding protein in its enzymatically active form.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

33. Interactions with other mineral elements
Ascorbic acid can also interact with several other metallic elements of nutritional significance.
Owing to its activity as a reductant, ascorbic acid reduces the toxicities of elements whose reduced forms are poorly absorbed or more rapidly excreted: selenium, nickel, lead, vanadium and cadmium.
11/10/2018
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34. Interactions with other mineral elements
High dietary levels of the vitamin have been shown to increase tissue levels of manganese, but to reduce the efficiency of enteric absorption of copper.
Ascorbic acid can enhance the utilization of physiologic doses of selenium, increasing the apparent biologic availability of a variety of inorganic and organic forms of that essential nutrient.
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35. Health effects
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36. Antihistamine reactions
Ascorbic acid is involved in histamine metabolism, acting with Cu2+ to inhibit its release and enhance its degradation.
It does so by undergoing oxidation to dehydroascorbic acid with the concomitant rupture of the histamine imidazole ring.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

37. Antihistamine reactions
Ascorbic acid may enhance the synthesis of the prostaglandin E series (over the F series), members of which mediate histamine sensitivity.
Circulating histamine concentration is known to be reduced by high doses of vitamin C.
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38. Immune function
Ascorbic acid can stimulate the production of interferons, the proteins that protect cells against viral attack.
It can stimulate the positive chemotactic and proliferative responses of neutrophils.
It can protect against free-radical-mediated protein inactivation associated with the oxidative burst of neutrophils.
11/10/2018
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39. Immune function
Ascorbic acid can stimulate the synthesis of humoral thymus factor and antibodies of the IgG and IgM classes.
Phagocytic cells of the immune system produce oxidants during infections that may play some role in the appearance of signs and symptoms.
Ascorbic acid, which is present in high concentrations in phagocytes and lymphocytes, will provide some antioxidant protection.
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40. Protective effects of vitamin C: Common cold
Immune function
Protective effects of vitamin C:
Common cold
Helicobacter pylori infection
Herpes simplex virus infections
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41. Inflammation
Vitamin C might have anti-inflammatory effects associated with reduced levels of endothelial dysfunction.
11/10/2018
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42. Cardiovascular disease
The antioxidant characteristics of ascorbic acid allow it to have an anti-atherogenic function in reducing the oxidation of low-density lipoproteins (LDLs), a key early event leading to atherosclerosis.
Being rich in both cholesterol and polyunsaturated fatty acids (PUFAs), LDLs are susceptible to lipid peroxidation by the oxidative attack of reactive oxygen species.
11/10/2018
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43. Cardiovascular disease
Oxidized LDLs stimulate the recruitment, in the subendothelial space of the vessel wall, of monocyte-macrophages that can take up the oxidized particles via scavenger receptors to form the lipid- containing foam cells found in the early stages of atherogenesis.
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44. Cardiovascular disease
The full protection of LDLs appears to involve both ascorbic acid and vitamin E!
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45. Exercise tolerance
Vigorous physical activity increases ventilation rates and produces oxidative stress.
Antioxidant supplementation can alleviate muscle damage and protein oxidation induced by exercise.
Vitamin C prevented acute endothelial dysfunction induced by exercise in patients with intermittent claudication (calf pain during walking).
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46. Diabetes
Diabetic patients typically show lower serum concentrations of ascorbic acid than nondiabetic, healthy controls.
Vitamin C supplementation has been found to reduce the glycosylation of plasma proteins.
11/10/2018
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47. Neurologic function
The brain and spinal cord are among the richest tissues in ascorbic acid contents, with concentrations of µM.
It is estimated that 2% of the ascorbic acid in the brain turns over each hour.
Plasma ascorbic acid concentrations have been shown to be positively associated with memory performance in patients that have dementia and with cognitive performance in older subjects.
11/10/2018
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48. Pregnancy outcomes
Low vitamin C status has been shown to be associated with increased risks of gestational diabetes and premature delivery due to premature rupture of chorioamniotic membranes.
11/10/2018
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49. Skin health
Ascorbic acid is critical for the health of the epidermis, by virtue of its essential role in collagen synthesis.
Greater concentrations of ascorbic acid are required for the maintenance of wound integrity than for collagen development.
Topical application of ascorbic acid has been found useful in treating photo-damaged skin, as well as inflammatory conditions of the skin such as acne and eczema.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

50. Dental health
Limited studies have found low vitamin C intake to be associated with slightly increased periodontal disease risk and amount of visible dental plaque.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

51. Cataracts Ascorbic acid Tocopherol Reduced glutathione
Wikipedia.org
Cataracts
Cataract, involving opacification of the ocular lens, is thought to result from the cumulative photo- oxidative effects of ultraviolet light, from which the lens is protected by three antioxidants:
Ascorbic acid
Tocopherol
Reduced glutathione
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52. Pulmonary function
Ascorbic acid has an important role in the antioxidant protection of the lung.
11/10/2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

53. Cancer
Ascorbic acid has been observed to reduce the binding of polycyclic aromatic carcinogens to DNA and to reduce/delay tumor formation in several animal models.
Ascorbic acid is also a potent inhibitor of nitrosamine-induced carcinogenesis, functioning as a nitrite scavenger.
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Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

54. Literature
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc
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