Human ascorbic acid metabolism

The desire to prepare radiolabeled material for use in the study of L-ascorbic acid metabolism in plants, fish, animals, and humans. 

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. 

We have advanced arguments elsewhere indicating that one important factor in host resistance is the free availability of ascorbic acid (1-3). These arguments are based upon the demonstration that cancer patients have a much greater requirement for this substance than normal healthy individuals, on the realization that ascorbic acid metabolism can be implicated in a number of mechanisms known to be involved in host resistance, and finally, and most convincingly, on the published evidence that ascorbic acid can sometimes produce quite dramatic remissions in advanced human cancer (4, 5). 

Kakar. S., and Wilson. C. W. M. Ascorbic acid metabolism in human cancer. Abstract. Proc. Nutr. Soc. 33 110,1974. 

Glucuronate is reduced to L-gulonate in an NADPH-dependent reaction L-gulonate is the direct precursor of ascorbate in those animals capable of synthesizing this vitamin. In humans and other primates as well as guinea pigs, ascorbic acid cannot be synthesized because of the absence of L-g ulonolactone oxidase. L-Gulonate is metabolized ultimately to D-xylulose 5-phosphate, a constituent of the pentose phosphate pathway. 

It should be remembered that some of the established antioxidants have other metabolic roles apart from free-radical scavenging. The finding of reduced antioxidant defences in diabetes, for example, may not be prima fascie evidence of increased oxidative stress, since alternative explanations may operate. For example, this may reflect a response to reduced free-radical activity as su ested by the results of a previous study (Collier et al., 1988). In the case of ascorbate, an alternative explanation has been proposed by Davis etal. (1983), who demonstrated competitive inhibition of ascorbate uptake by glucose into human lymphocytes. This view is supported by the similar molecular structure of glucose and ascorbic acid (see Fig. 12.4) and by a report of an inverse relationship between glycaemic control and ascorbate concentrations in experimental diabetes in rats. Other investigators, however, have not demonstrated this relationship (Som etal., 1981 Sinclair etal., 1991). 

In addition to the well-known iron effects on peroxidative processes, there are also other mechanisms of iron-initiated free radical damage, one of them, the effect of iron ions on calcium metabolism. It has been shown that an increase in free cytosolic calcium may affect cellular redox balance. Stoyanovsky and Cederbaum [174] showed that in the presence of NADPH or ascorbic acid iron ions induced calcium release from liver microsomes. Calcium release occurred only under aerobic conditions and was inhibited by antioxidants Trolox C, glutathione, and ascorbate. It was suggested that the activation of calcium releasing channels by the redox cycling of iron ions may be an important factor in the stimulation of various hepatic disorders in humans with iron overload. 

Group-transfer reactions often involve vitamins3, which humans need to have in then-diet, since we are incapable of realizing their synthesis. These include nicotinamide (derived from the vitamin nicotinic acid) and riboflavin (vitamin B2) derivatives, required for electron transfer reactions, biotin for the transfer of C02, pantothenate for acyl group transfer, thiamine (vitamin as thiamine pyrophosphate) for transfer of aldehyde groups and folic acid (as tetrahydrofolate) for exchange of one-carbon fragments. Lipoic acid (not a vitamin) is both an acyl and an electron carrier. In addition, vitamins such as pyridoxine (vitamin B6, as pyridoxal phosphate), vitamin B12 and vitamin C (ascorbic acid) participate as cofactors in an important number of metabolic reactions. 

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. 

Whilst these acids are of minor importance in man, another multifunctional acid, ascorbic add (vitamin C 6), has an apparent role in human iron metabolism as one of the postulated factors aiding iron uptake. Ascorbic add reduces Fe111 to Fe" with probable complexation of the latter. It thus converts Fe"1 to a more soluble form. Ascorbic acid can also reduce Cu" to Cu1 (equation 1), and there is accumulating evidence of a link between the metabolism of ascorbic acid and that of Cu.34... 

For the most part, adequate copper is received in diet and widespread human deficiencies do not occur, but deficiencies may arise because of antagonists. The metals Cd, Hg, Ag and Zn interfere with copper metabolism, probably by competing for copper-binding sites in proteins. Ascorbic acid depresses intestinal absorption of copper56 (in contrast to iron). Some proteins in the diet adversely affect utilization of copper. The sulfide ion is a well known inhibitor of copper absorption, since it forms copper(II) sulfide which is insoluble.56... 

Ascorbic acid is a vitamin in primates. In most other animals, it can be synthesized by a branch of the glucoronic acid pathway (Chapter 18). It is apparently not changed into any coenzyme in the human being and participates as a vitamin in a reducing capacity in several biochemical reactions. These include the post-translational hydroxylation of proline in collagen biosynthesis (Chapter 8) and in tyrosine metabolism (Chapter 20). Ascorbic acid is oxidized to dehydroascorbic acid, a diketo derivative of ascorbate. Scurvy is a deficiency disease caused by a shortage of dietary ascorbic acid. In children, this results in defective bone formation in adults, extensive bleeding occurs in a number of locations. Scurvy is to be suspected if serum ascorbic acid levels fall below 1 jug/mL. 

Schroder and co-workers (Schroder etal., 1999,2000) studied PolyP metabolism in bone tissues and osteblast cultures. They revealed that PolyP metabolism in human osteoblasts was modulated by stimulators of osteoblast proliferation and differentiation (Leyhausen et al., 1998). A combined treatment of the cells with dexamethasone, ft-glycerophosphate, epidermal growth factor (EGF), and ascorbic acid resulted in a dramatic decrease in PolyP content. This decrease is caused mainly by a decrease in the amount of soluble long-chain PolyPs. The amount of this PolyP fraction, but not the amount of insoluble long-chain PolyPs, further decreases after additional treatment of the cells with la, 25-dihydroxy vitamin D3. The decrease in PolyP content during treatment with dexamethasone, ft-glycerophosphate, EGF and ascorbic acid is accompanied by a decrease in exopolyphosphatase activity. However, additional treatment with la, 25-dihydroxyvitamin D3 results in a significant increase of the enzyme activity. Therefore, it is reasonable to assume that PolyP... 

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

Baker EM, Hodges RE, Hood J, Sauberlich HE, March SC, and Canham ]E (1971) Metabolism of C- and H-labeled L-ascorbic acid in human scurvy. American Journal of Clinical Nutrition 24, 444-54. 

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 direct extrapolations from animals that synthesize ascorbic acid to a 70-kg human ignores the observations that in large animals the synthesis of ascorbic acid only accounts for a small fraction of the L-gulonate oxidized (132), Also, extrapolation to 70 kg of body weight should first correct for differences in metabolic body size the correction should include (wtkg ), which is appropriate in many instances (133),... 

Kinetic parameters were estimated in nonsmokers and smokers to help elucidate the quantitative ascorbate metabolism in humans. This approach allows calculation of turnover rates at different levels of steady state intakes of ascorbate. Metabolic and renal turnovers were calculated separately. At plasma levels above about 0.7 mg/100 mL the renal elimination increased sharply and the metabolic turnover showed a saturation at a plasma level corresponding to a total turnover of about 60 mg/d. At the tested levels of intake of ascorbic acid the calculated total pool size increased to a level reached at a steady state plasma concentration achieved at an intake of about 90 mg/d. At intakes of this magnitude the absorption is substantially less than 100%. A daily intake of 100 mg of ascorbate for larger populations should be attained. Similar experiments with smokers showed an increase in the metabolic turnover corresponding to a demand of 140 mg/d to reach a similar stage. 

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