Metabolism, ascorbic acid excretion

Uronic acids are biosynthetic intermediates m various metabolic processes ascorbic acid (vitamin C) for example is biosynthesized by way of glucuronic acid Many metabolic waste products are excreted m the urine as their glucuronate salts... 

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. 

Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans and, therefore, must must be supplied by the diet. Nine vitamins (folic acid, cobalamin, ascorbic acid, pyridoxine, thiamine, niacin, riboflavin, biotin, and pantothenic acid) are classified as water-soluble, whereas four vitamins (vitamins A, D, K, and E) are termed fat-soluble (Figure 28.1). Vitamins are required to perform specific cellular functions, for example, many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. In contrast to the water-soluble vitamins, only one fat soluble vitamin (vitamin K) has a coenzyme function. These vitamins are released, absorbed, and transported with the fat of the diet. They are not readily excreted in the urine, and significant quantities are stored in Die liver and adipose tissue. In fact, consumption of vitamins A and D in exoess of the recommended dietary allowances can lead to accumulation of toxic quantities of these compounds. 

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

Disposition in the Body. Less than 5% of ingested oxalic acid is absorbed in healthy adults. About 8 to 40 mg of oxalic acid is normally excreted in the urine daily this is derived mainly from the metabolism of dietary ascorbic acid and glycine with small amounts from dietary oxalic acid and other minor metabolic sources. Calcium oxalate is a major constituent of kidney stones and is frequently found as crystals in freshly-voided urine. In normal subjects concentrations of oxalic acid in blood range from about 1 to 3 pg/ml. Small amounts of oxalate are produced as a metabolite of ethylene glycol. 

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. 

A DHA lactonase has been described (76,77) in the ox, rabbit, rat, and guinea pig. In the ox the lactonase is present in several tissues but is most abundant in the liver. The enzyme appears to be absent in human and monkey tissue. This result is consistent with the observation that primates and fishes do not catabolize labeled ascorbic acid to carbon dioxide. AA and DHA appear to be metabolized into a series of water soluble products that are excreted in the urine, but 2,3-DKG is decar-boxylated and otherwise degraded to intermediates that enter the C5 and C4 carbohydrate pools (78). 

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. 

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. 

Ascorbic acid is readily absorbed by an active process. Large doses can saturate this system, limiting the amounts absorbed. Once absorbed, it is distributed to all tissue. The vitamin is metabolized to oxalic acid before excretion. Ascorbic acid-2-sulfatc is also a metabolite found in the urine. Large doses result in the excretion of substantial amounts of unchanged ascorbic acid. The resultant acidification of the urine is the basis for most of the vitamin s adverse effects. 

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. 

Ascorbic add administration prevents the excretion. The isolated pHPP oxidase of liver under certain conditions requires ascorbic acid or related compounds for its continued activity (K8). Thus, the in vivo and in vitro requirements for this metabolic reactioii are similar. 

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). 

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