Animals, 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. 

Studies in animals have shown that, prior to the onset of diabetes, ascorbic acid metabolism is obviously altered in the spontaneously diabetic rat. Prediabetic rats exhibit raised dehydroascorbic acid levels and decreased plasma vitamin E (Behrens and Modere, 1991). Of interest are reports of altered ascorbic acid metabolism in the offspring of diabetic individuals, which were found to be most profound in... 

The timely help rendered in typing out the manuscript by Mr. V.T. Viswanathan is greatly appreciated. The Editor and Co- editors express grateful thanks to Madam Roda J. Chinoy for permitting the free and full access to all the relevant papers, data and literature of Late Professor J.J. Chinoy to enable uS to finalize the monograph. We also hasten to mention that the reference to work on Ascorbic Acid Metabolism in Animals is the research work carried out by Dr. (Hiss)... 

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. 

Ascorbic acid (vitamin C) depletion is the most consistent evidence of compromised antioxidant status in diabetes with reports of reduced levels and altered metabolic turnover in several tissues in experimentally induced diabetes in animals (Rikans, 1981 Yew, 1983 McLennan et al., 1988) and in patients with diabetes (Som et al., 1981 Jennings et al., 1987 Sinclair et al., 1991). 

N5,N10-methenyltetrahydrofolate (with ascorbic acid) was adjusted to neutral pH, autoclaved, and stored at -20° C prior to column purification on DEAE and G-15 Sephadex. These labeled products are the biologically active diastereomers, and they are used to study the metabolism of folinic acid in cells, tissues, and animals. 

A separate Section on the synthesis of variously labelled L-ascorbic acid is included here, because of the important role that these molecules have played in helping to elucidate the metabolic fate of 1 in plants and animals. Tritium, deuterium, and carbon-14 have each been incorporated into 1. 

Water-soluble vitamins and co-factors also appear to elicit an effect on xenobiotic metabolism. Ascorbic acid has been shown to inhibit chemically induced chemical carcinogenesis in test systems (Shamberger, ( ). When diets are deficient in choline, the animals appear to become much more susceptible to chemically-... 

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. 

Ascorbic acid is involved in carnitine biosynthesis. Carnitine (y-amino-P-hydroxybutyric acid, trimethylbetaine) (30) is a component of heart muscle, skeletal tissue, liver and other tissues. It is involved in the transport of fatty acids into mitochondria, where they are oxidized to provide eneigy for the ceU and animal. It is synthesized in animals from lysine and methionine by two hydroxjiases, both containing ferrous iron and L-ascorbic acid. Ascorbic acid donates electrons to the enzymes involved in the metabolism of L-tyrosine, cholesterol, and histamine (128). 

Respiratory Carbon Dioxide Urine and Feces. After dosage of the labeled ascorbic acid, the animal was immediately placed in a closed, tight metabolic chamber equipped with a trap for the collection of urine and feces. The incoming air passed with a flow of 280 L/h through the metabolic chamber (volume 22 L) by suction from an electric pump. The respiratory carbon dioxide was absorbed by ethanol amine (Merck) contained in two flasks (50 mL) that were connected to the chamber by tubes. To determine the absorbed carbon dioxide, the two flasks could be removed after the outcoming airstream... 

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),... 

Animals may manifest toxicity to salicylates with signs and symptoms similar to those seen in humans. These may include fever, hyperpnea, seizures, respiratory alkalosis, metabolic acidosis, gastric hemorrhage, and kidney damage. Methemoglobinemia has also been seen in animals following salicylate toxicity. Activated charcoal has been used in animals. Methylene blue or ascorbic acid may be utilized for the treatment of methemoglobinemia. 

Use Manufacture of ascorbic acid (vitamin C), preparation of special diets, and media for the study of metabolism in animals and microorganisms. 

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-... 

The demonstration by Knox that ascorbic acid is a cofactor in tyrosine metabolism has been discussed earlier. Though ascorbic acid is essential both for this purpose and for the prevention of scurvy, the latter is probably not due to any appreciable extent to inadequate tyrosine metabolism (e.g., 723). Further experiments with liver preparations have shown that a number of other substances can replace ascorbic acid, o-isoascorbic acid being as effective as ascorbic acid itself (160, 489). Many other ene-diols are effective in tissue homogenates (522,791) but not necessarily in the intact animal, where poor absorption or retention reduces their efficacy (661,975). Substances such as 3-methylascorbic acid (791), which do not contain an ene-diol structure, cannot replace ascorbic acid. 

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. 

The new knowledge of ascorbic acid biosynthesis and degradation has called attention to the variable metabolism of ascorbic acid, induced by drugs of various kinds, and to the complementary effects on the metabolism of drugs, produced by ascorbic acid. Changes of this sort may eventually explain many puzzling features of the metabolism of ascorbic acid in scorbutic animals in different physiological states. 

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