vitamin C

The reduced form of vitamin C, ascorbic acid, is well known for its function as an antioxidant and as a protective agent against scurvy.

High intake of vitamin C has beneficial effects on cell growth, gene transcription, host resistance to infection, uptake of polyamines and clearance of misfolded proteins.

Vitamin C exerts its effects indirectly via hypoxia-inducible factor, nitric oxide synthase and the heparan sulfate proteoglycan glypican-1 (GPC1), which is deglycanated in a vitamin C- and copper-dependent reaction.

Functions

In humans, vitamin C is a highly effective antioxidant, acting to lessen oxidative stress, a substrate for ascorbate peroxidase, as well as an enzyme cofactor for the biosynthesis of many important biochemicals.

Vitamin C acts as an electron donor for eight different enzymes.

 Three 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), thereby allowing the collagen molecule to assume its triple helix structure and making vitamin C essential to the development and maintenance of scar tissue, blood vessels, and cartilage.

 Two are necessary for synthesis of carnitine. Carnitine is essential for the transport of fatty acids into mitochondria for ATP generation.

 The remaining three have the following functions:

• 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.

Sources

Unlike some other vitamins, ascorbic acid cannot be synthesized endogenously, and therefore humans are dependent on intake with food. A deficiency of vitamin C leads to the development of scurvy, characterized principally by bone disease in growing children and hemorrhages and healing defects in both children and adults.

Ascorbic acid is present in milk and some animal products (liver, fish) and is abundant in a variety of fruits and vegetables. All but the most restricted diets provide adequate amounts of vitamin C.

Ascorbic acid functions in a variety of biosynthetic pathways by accelerating hydroxylation and amidation reactions. The most clearly established function of vitamin C is the activation of prolyl and lysyl hydroxylases from inactive precursors, providing for hydroxylation of procollagen.

Inadequately hydroxylated precursors cannot acquire a stable helical configuration and cannot be adequately cross-linked, so they are poorly secreted from the fibroblast. Those that are secreted lack tensile strength, are more soluble, and are more vulnerable to enzymatic degradation.

Collagen, which normally has the highest content of hydroxyproline, is most affected, particularly in blood vessels, accounting for the predisposition to hemorrhages in scurvy. In addition, it appears that a deficiency of vitamin C leads to suppression of the rate of synthesis of pro-collagen peptides, independent of an effect on proline hydroxylation.

While the role of vitamin C in collagen synthesis has been known for many decades, it is only in relatively recent years that its antioxidant properties have been recognized. Vitamin C can scavenge free radicals directly in aqueous phases of the cell and can act indirectly by regenerating the antioxidant form of vitamin E.

Thus, vitamins E and C act in concert. It is because of these synergistic actions that both of these vitamins have attracted interest as agents that may retard atherosclerosis by reducing the oxidation of LDL.

However, at present, there is no conclusive evidence that vitamin C supplementation is useful in primary or secondary prevention of coronary artery disease. Similarly, despite much attention in the lay press, there is no evidence that vitamin C supplements prevent the common cold; high doses may reduce the duration of symptoms.

Pathology

With the abundance of ascorbic acid in many foods, scurvy has ceased to be a global problem, although it is sometimes encountered even in affluent populations as a conditioned deficiency, particularly among elderly individuals, persons who live alone, and alcoholics-all groups that often have erratic and inadequate eating patterns.

Scurvy occasionally appears in patients undergoing peritoneal dialysis and hemodialysis and among food faddists. Tragically, the condition sometimes appears in infants who are maintained on formulas of processed milk without supplementation.

Scurvy in a growing child is far more dramatic than in an adult. Hemorrhages constitute one of the most striking features. Because the defect in collagen synthesis results in inadequate support of the walls of capillaries and venules, purpura and ecchymoses often appear in the skin and in the gingival mucosa. Furthermore, the loose attachment of the periosteum to bone, together with the vascular wall defects, leads to extensive subperiosteal hematomas and bleeding into joint spaces after minimal trauma. Retrobulbar, subarachnoid, and intracerebral hemorrhages may prove fatal.

Skeletal changes may also develop in infants and children. The primary disturbance is in the formation of osteoid matrix, rather than in mineralization or calcification, such as occurs in rickets. In scurvy, the palisade of cartilage cells is formed as usual and is provisionally calcified. However, there is insufficient production of osteoid matrix by osteoblasts. Resorption of the cartilaginous matrix then fails or slows; as a consequence, there is cartilaginous overgrowth, with long spicules and plates projecting into the metaphyseal region of the marrow cavity, and sometimes widening of the epiphysis (Fig. 9-29). The scorbutic bone yields to the stresses of weight bearing and muscle tension, with bowing of the long bones of the lower legs and abnormal depression of the sternum with outward projection of the ends of the ribs. The bone changes in adults are similar to those in children, with decreased formation of osteoid matrix, but deformation does not occur.

In severely scorbutic children and adults, gingival swelling, hemorrhages, and secondary bacterial periodontal infection are common. A distinctive perifollicular, hyperkeratotic, papular rash that may be ringed by hemorrhage often appears. Wound healing and localization of focal infections are impaired because of the derangement in collagen synthesis. Anemia is common, resulting from bleeding and from a secondary decrease in iron absorption (Chapter 13). The major features of scurvy are summarized in Figure 9-30.

References

 Fransson LA, Mani K. Novel aspects of vitamin C: how important is glypican-1 recycling? Trends Mol Med. 2007 Apr;13(4):143-9. PMID: 17344097