Ascorbic acid
Experimental scurvy was first accidentally induced in guinea pigs in 1907 by Holst and Frolich in Norway; these animals, unlike rats, chickens, dogs, and other domestic animals, develop characteristic hemorrhages around the joints, teeth, and other bony structures very similar to the symptoms of scurvy in human. The antiscorbutic food factor was named vitamin C in 1919 by Drummond, as it was clear that its properties and distribution in foods were very different from the antiberiberi and growth factors earlier designated as water-soluble B andfat-soluble A. Humans, the primates, guinea pigs, some fish, and a few other exotic species do not possess the ability to synthesize vitamin C and must rely totally on the vitamin C ingested with their food.
By 1932 the isolation of vitamin C in pure crystalline form had been accomplished independently by two groups of workers. The chemical structure was identified and the product synthesized in physiologically active form soon afterwards; in 1938 ascorbic acid was officially accepted as the chemical name for vitamin C. It occurs naturally in foods in two forms, the reduced form (usually designated as ascorbic acid) and the oxidized form, (dehydroascorbic acid). Both are physiologically active, and both are found in body tissues. Further oxidation of dehydroascorbic acid to diketogulonic acid results in irreversible inactivation of the vitamin. shows the chemical structures and interconversions of these compounds. The ascorbic acid in fruits and vegetables and the synthetic form are equally well utilized.
Functions of ascorbic acid
Vitamin C appears to have a variety of roles in the life processes, but to date its specific functions at the biochemical level are not fully understood. Its major form, L-ascorbic acid, is a powerful reducing agent and tion reactions, which are known to be impaired in vitamin C deficiency.
Perhaps the most significant, and certainly best characterized, are the hydroxylations required in the synthesis of collagen. Collagen is a fibrous protein made up of three polypeptide chains coiled together to form a helix. These pep tides have an unusual amino acid composition, consisting mainly of glycine, hydrm.yproline and hydroxylysine. The last two amino acids are not found in other proteins. The hydroxylations of proline and lysine take place after they have been incorporated into the polypeptides and are essential for normal physical structure ofthe completed protein molecule. These reactions are performed by enzymes prolyl hydroxylase and lysyl hydroxylase; the roles of ascorbic acid and other cofactors (iron, 02' and alphaketoglutarate) in the reaction have been characterized recently, 1-3 Reduced iron (Fe++) participates in the reaction and is oxidized in the process (Fe+++). Ascorbic acid apparently serves as a specific, nonreplaceable reducing agent to regenerate Fe+- and is itself converted to dehydroascorbic acid.
Collagen fibers give rigidity to the amorphous ground substance of connective tissue that fills the space between the cellular and circulatory components of tissues and aids in holding them together. It also is a major component in the organic matrix of bone and teeth and in the scar tissue formed during healing of wounds and bone pathologic lesions of scurvy. The widespread bleemng has been attributed to defects in the basement membrane and intercellular cement of the capillaries. However, Hodges has questioned this conclusion after his group was unable to detect such defects by electron microscopic examination of tissues from patients with evidence of hemorrhaging due to vitamin C deficiency.
Other hydroxylations that are known to utilize the same cofactors include the conversion of thymine to hydroxymethyluracil, and two steps in the biosynthesis of carnitine, which functions in fatty acid metabolism.\ Ascorbic acid-dependent hydroxylations also take place in the synthesis of at least two neurotransmitters, serotonin (5-0H-tryptamine) from tryptophan and norepinephrine from tyrosine;4 the exact role of ascorbic acid in these hydroxylations has not been established, but reduction of required enzyme cofactors is likely (Cu+ is required in norepinephrine formation). Para-OH-phenylpyruvate oxidase is another enzyme in tyrosine metabolism that i: stimulated by ascorbic acid. The activity of this enzyme develops late in fetal life and may be low in some premature infants. The resulting transient tyrosinemia is corrected by ascorbic acid supplementation (usually 100 m per day).5 Regulation by ascorbate of the biosynthesis of tyrosine hydroxylase another enzyme in the pathway of epinephrine synthesis, has been reported,6 but this proposed role of ascorbic acid needs confirmation.
Intestinal absorption of iron is enhanced by the presence of ascorbic acid in the lumen7 (see Chap. 6, Iron). Mobilization of iron stores in guinea pigs from the spleen appears to be impaired in vitamin C deficiency, causin depletion of hepatic iron stores.s However, evidence regarding mobilization and redistribution of iron stores in vi tamin C deficiency is equivocal. 9
Because the two forms of ascorbic acid are reaml" interconvertible, they are believed to participate in other cellular functions, such as regulation of oxidation-reduction potential and transfer of hydrogen in the various electron transport systems; involvement of ascorbic acid in microsomal drug metabolism has been reported.the reducedform may also function as a cellular antioxidant that protects other easily oxidizable substances, such as vitamins A and E, and the active forms of folic acid.4
Clinical observation of a number of infections accompanied by fever shows a decreased blood level of ascorbic acid, indicating either increased need for this vitamin or increased destruction of it. It appears, however, that a suboptimal intake of vitamin C is not a predisposing cause of any of these diseases. It has also been observed that the normally high concentration of ascorbic acid in the adrenal cortex is depleted whenever the gland is stimulated by hormones or certain toxins. The role of ascorbic acid in the adrenal gland remains unclear. One suggestion is that its presence in high concentration prevents the release of cortical hormones and that its depletion upon stimulation of the gland is necessary for normal hormonal response to various stresses.5
Administration of large doses of ascorbic acid appears to protect an individual exposed to very low environmental temperatures. However, the controversy involving the use oflarge doses of ascorbic acid to prevent and cure the common coldll has not been resolved. Anderson,12 in reporting the results of a large double-blind Canadian study, stated that vitamin C in large amounts appeared to have some pharmacologic effects not related to its vitamin function at nutritional levels.
Disturbances in protein and lipid metabolism have been observed in scurvy. 13 Loss of ni trogen in the urine was increased and the plasma albumin to globulin ratio lowered. The level of plasma cholesterol appeared to be reduced and increased during repletion of tissue ascorbic acid. However, the role of ascorbic acid in cholesterol metabolism is controversial. Its participation in the removal of cholesterol from the tissues to the liver14 and in the conversion of cholesterol to bile acidsl5.16 has been proposed. It has been suggested that water-soluble cholesterol sulfate is formed by an ascorbic acid metabolite, ascorbic acid sulfate, to facilitate the removal of cholesterol from the enterohepatic circulation. Ii Such mechanisms have been linked to the reported hypocholesterolemic role of large doses of ascorbic acid in hypercholesterolemic subjects,18 but other attempts to demonstrate such effects have failed to support these claims.12,19 Even more controversial and unproven to date are the claims20 for the effectiveness of ascorbic acid in the prevention and treatment of cancer and other diseases.
