Metabolism and Excretion of Ascorbate

The major fate of ascorbic acid in human metabolism is excretion in the urine, either unchanged or as dehydroascorbate emd diketogulonate. Both ascorbate 

Ascorbate catabolism is increased in subjects with iron overload, probably as a result of nonenzymic reactions with iron that is not protein-bound. The transferrin polymorphisms that are associated with susceptibility to iron overload result in higher vitamin C requirements for those subjects with high iron 

Although a number of studies have suggested that high inttdces of tiscorbate lead to synthesis and excretion of oxalate (Section 13.6.5.1), this seems to be the result of nonenzymic formation of oxalate in urine stunples after collection. There is no known pathway for oxtdate synthesis from tiscorbate. 

Some species (but not primates) excrete ascorbate 2-sulfate, emd in vitro ascorbic acid is a substrate for catechol O-methyltremsfertise, forming 2-methyl tiscorbate. 

Ascorbic acid has specific and well-defined roles in two classes of enzymes the copper-contairdng hydroxylases (such as dopcunine -hydroxylase and peptidyl glycine hydroxylase) and the 2-oxoglutarate-linked iron-containing hydroxylases, of which the best studied are the proUne and lysine hydroxylases involved in maturation of connective tissue (and other) proteins. 

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Mega vitamin intake of vitamin C may result in diarrhea due to intestinal irritation. Since ascorbic acid is partially metabolized and excreted as oxalate, renal oxalate stones may form in some patients. 

Erythorbic acid is widely used in food applications as an antioxidant. It is also used in oral pharmaceutical applications as an antioxidant. Erythorbic acid is generally regarded as nontoxic and nonirritant when used as an excipient. Erythorbic acid is readily metabolized and does not affect the urinary excretion of ascorbic acid. 

Effects of Excess Tissue Iron on Ascorbic Acid Metabolism. Epidemiological observations among the Bantu of South Africa showed an apparent association of clinical scurvy in adult males with hemosiderosis common to this group. Both plasma clearance of ascorbic acid and urinary excretion of ascorbic acid were altered in severe iron overload plasma clearance was increased and urinary excretion was decreased in siderotic subjects (40,41), The evidence was interpreted as a demonstration of enhanced oxidative catabolism of ascorbic acid in the presence of excess tissue iron. 

Zinc and Ascorbic Acid Metabolism and Excretion. Iron has an oxidizing effect on ascorbic acid, reducing its urinary excretion therefore, Keltz et al. (61) questioned whether zinc would show a similar effect. Human subjects were fed a diet containing either 11.5 or 19.5 mg of zinc/d for 7-d balance periods. Daily ascorbic acid intake was 100 mg. Consistent with the findings from iron-loaded Africans, the higher zinc intake caused a significant 30% decrease in urinary ascorbate excretion. No explanation for the zinc-related reduction in ascorbic acid beyond the analogy with the iron-loaded individuals is readily available. 

The administration of polychlorinated biphenyl (PCB) isomers increases hepatic tissue content of ascorbic acid as well as urinary excretion of ascorbic acid in the rat (Horio et al., 1986) and similarly increases the content of the major cytochrome P-450 enzymes induced by both phenobarbital and 3-methylcholanthrene (De-nomme et aL, 1983 Parkinson et ai, 1983). Guinea pigs fed an ascorbic acid-deficient diet have lower content of cytochrome P-450. A trend has been observed toward a higher cytochrome P-450 content with increasing dietary ascorbic acid, suggesting that ascorbic acid also influences drug metabolism (Peterson et al., 1983). 

Folic Acid—Ascorbic Acid Relationships. Folic acid and ascorbic acid have some interesting metabolic relationships, among which is a role in tyrosine metabolism. Abnormal excretion of tyrosine metabolites occurs in human infants with scurvy, and in premature infants when the diet is high in this amino acid. Folic acid, in large doses, will prevent or relieve this abnormal excretion, as does ascorbic acid. Folic acid exerts a similar action in scorbutic guinea pigs. ... 

Kellie and Zilva found, in one subject, that, when 30 mg. of ascorbic acid was ingested daily, almost none was excreted in the urine this suggested complete utilization. When the dietary intake was 100 mg., about 50 mg. was metabolized when intake was 50 mg. about 40 mg. was metabolized. Dodds studied plasma concentration and urinary excretion of ascorbic acid at several levels of intake (50, 75, and 100 mg. daily) and calculated that utilization of ascorbic acid was slightly less than 1 mg. per kilogram of body weight. 

Additional errors of phenylalanine and tyrosine metabolism include tyrosinosis, or hereditary tyrosinemia, neonatal tyrosinemia, and alcaptonuria. In the first case, there is a probable defect in p-hydroxyphenylpyruvate oxidase. In neonatal tyrosinemia, the problem is transient and may be solved by the administration of ascorbic acid. Ascorbic acid is apparently a cofactor for p-hydroxy-phenylpyruvate oxidase. Alcaptonuria is a benign disorder in which homogen-tisic acid oxidase is inoperative and homogentisic acid is excreted in the urine. Air oxidizes the homogentisic acid to a pigment, giving urine a black color. This pigment also accumulates in the patient s tissues. 

The course of carbon-14-radioactivity derived from oral (l- C)ascorbic acid in plasma and several tissues was studied in male guinea pigs up to 320 h after intake. The excretion of label was followed in respiratory carbon dioxide, urine, and feces. The evaluation by pharmacokinetic principles yielded an overall half-life of 61 h and a body pool of 21 mg with a total turnover of about 10 mg/d. The total turnover of ascorbate is lower than the daily intake (16 mg/d), indicating incomplete absorption. Ascorbic acid seemed to be bound in several tissues (adrenals, testes) to a higher percentage than in plasma. The maximum rate of excretion as carbon dioxide occurred at 0.5 h, whereas peak concentration of radioactivity in plasma was reached at 1.5 h. Therefore, presystemic metabolism must be considered. 

The influence of ascorbic acid on tyrosine metabolism in man and intact animals has been discussed under alkaptonuria and tyrosinosis q.v.). Ty-rosyluria, also called hydroxyphenyluria, i.e., the excretion of p-hydroxy-phenyl compounds in the urine, can be affected by factors other than ascor-... 

Antiscorbutic activity per se is more widespread than the results of Table 1 would indicate. Many of the inactive or slightly active compounds are rapidly excreted by the kidneys of the test animals and so do not remain long in the body with the conventional scheme of daily dosages. D-Ascorbic acid behaves this way and is inactive in the usual bio-assay, as predicted from its configuration. But when n-ascorbic acid is given in many small doses throughout the day, it is fully as active as L-ascorbic acid (B42). The strict chemical specificity of antiscorbutic action therefore represents the summation of properties which determine distribution and excretion by the body, as well as the chemical requirements for its particular metabolic actions. The present available data clearly show that nutritionally useful antiscorbutic compounds are severely limited, but that the chemical limitations on structure for certain metabolic actions are apparently less severe. 

In planning this review the writer quickly persuaded himself that it was arduous and fortunately unnecessary to scan the whole exhaustive and exhausting literature on ascorbic acid. Many aspects of the vitamin— such as its relation to immune reactions and the interpretation of its excretion following a test dose—have been very well summarized in past reviews, some of which are listed below (Section I, 3). Instead it was decided to concentrate chiefly on those aspects of ascorbic acid metabolism that seem to he of special current interest to research workers. 

Studies on the excretion of 17-ketosteroids by female rats on a diet deficient in pantothenate have not been reported. These data would be interesting because of the observations of Dorfman (1947), who reported a sharp decrease in the excretion of 17-ketosteroids in female monkeys and guinea pigs following adrenalectomy. It was also observed that in the scorbutic female guinea pig (Dorfman, 1947 Banerjee and Deb, 1952) there was a sharp decrease in the excretion of 17-ketosteroids. These observations indicate that the adrenal is the source of these steroids and that diets deficient in ascorbic acid, which affects the adrenals, will also decrease the synthesis of these steroids. In view of the fact that there is a disturbance of ascorbic acid metabolism in pantothenate-deficient rats, it may well be that this would contribute to a disturbance in the synthesis of the 17-ketosteroids in the pantothenate deficiency. 

Radiotherapy destroys a fairly large volume of tissue and its effects can be likened to those of a deep burn. The cells and other exposed tissue structures disintegrate and die, forming toxic breakdown products that have to be carried off by the bloodstream and excreted in the urine. It is believed that the unpleasant systemic side effects of radiotherapy (nausea, lassitude) are caused by this sudden metabolic overload of toxic by-products. Ascorbic acid is essential for the proper functioning of a group of liver enzymes concerned with the detoxification and disposal of noxious substances, and it is therefore quite possible that a high intake of ascorbate reduces the unpleasant side effects of irradiation. 

Oxalate is a terminal product of normal metabolism. When [ " C]oxalate is injected, most of the labeled compound is excreted, and only a small fraction of the radioactivity is recovered in bone and muscle. There are only two immediate precursors of oxalic acid in normal metabolic pathways glyoxylic acid and 2,3-diketo-L-gulonic acid. The first of these compounds is the product of amino acid oxidation (serine and glycine), and the second is derived from the oxidation of ascorbic acid (see Fig. 3-25). 

In the scorbutic guinea pig, the excretion of 17-hydroxycorticosteroid increases and the concentration of ascorbic acid in the adrenals decreases. If vitamin C is added to the diet, both phenomena rapidly return to normal. The injection of cortisone reduces the amount of ascorbic acid in the adrenals. This reduction is absolute, and the amount of vitamin C per gram of tissue decreases. In contrast, the injection of ACTH reduces the total amount, but there is no reduction in the concentration in the adrenal, which indicates that the ACTH from the reaction reduces the size of the organ and doesn t directly affect vitamin release. (A more detailed description of the effects of vitamin C on the corticosteroid hormones appears in chapters in which the metabolism of these hormones is discussed.)... 

Adversed nutritional effects of high doses of ascorbic acid have been reported to lover vitamin 8 2 levels (Hines, 1975 Herbert and Jacob, 1974 Herbert, 1980). In contrast, others (Nevmark and Schelner, 1976) have suggested that methodology problems explain the vitamin 6 2 to ascorbic acid Interaction. Ascorbic acid has also been reported to elevate the excretion of urinary 4-pyridoxic acid, the major metabolite of vitamin Bg (Scllvanova, 1960). Other Interactions between ascorbic acid and vitamin Bg have also been reported (Baker et al, 1971 Baker et al, 1964). More recently, Shultz and Leklem (1982) concluded that short-term ascorbic acid supplementation did not alter vitamin Bg metabolism. 

The main source of carbon dioxide is the C-1 atom of the ascorbic acid molecule, whereas the C atoms 1 and 2 represent the basic structure for oxalic acid. The formation of oxalic acid with excessive supplies of ascorbic acid has been used as one argument against pharmacological doses, especially for persons who are sensitive to the development of a nephrolithiasis. The human daily excretion amounts to 30-40 mg oxalic acid and originates 35-50% from the metabolism of ascorbic acid and 50-65% from glycine and glyoxalic acid. The additional supply of 1-9 g ascorbic acid per day led to an increase of the normal excretion of oxalic acid by 0.0-68.0 mg/day (Moser et al., 1982). Normal persons without any metabolic disease are therefore not seriously affected in their oxalic acid excretion by single excessive doses of ascorbic acid. 

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