Vitamin C belongs to the group of water-soluble vitamins and is a historically interesting vitamin. In 1933, the structure of vitamin C was elucidated by the Englishmen Haworth and Hirst. In the same year, the vitamin was named ascorbic acid by Haworth and the Hungarian biochemist Szent-Györgyi. At the same time, Haworth and the Swiss Tadeus Reichstein independently produced vitamin C from glucose (Reichstein synthesis). Because of its antiscorbutic effect, ascorbic acid is also called “antiscorbutic factor” (scorbutus; lat. = scurvy). Vitamin C is the generic name for L-threo-hex-2-enono-1,4-lactone and its derivatives (derivatives), which qualitatively exhibit the biological effect of L-(+)-ascorbic acid. In contrast, the stereoisomers D-ascorbic acid, L-isoascorbic acid, and D-isoascorbic acid (erythrobic acid) are biologically inactive. L-ascorbic acid has a strong redox potential (reduction/oxidation potential) and is readily autoxidizable in aqueous solution depending on oxygen partial pressure (proportion of oxygen to total pressure within a gas mixture), pH, temperature, and presence of heavy metal traces. While the vitamin remains stable in acidic aqueous solutions (pH < 6), it is rapidly oxidized or decomposed in alkaline solutions. Traces of heavy metals, especially iron and copper ions, catalytically accelerate the destructive oxidation process. Acids such as citric acid, mono- and polysaccharides, peptides and flavonoids, on the other hand, can significantly reduce the oxidative decomposition of ascorbic acid and thus act as protective substances. In the oxidation process, L-ascorbic acid is reversibly (reversibly) converted to dehydroascorbic acid (DHA) via the reactive intermediate semidehydroascorbic acid – giving up one electron. DHA is a highly reactive compound that undergoes condensation reactions with amino compounds in (dried) fruits or fruit juices, resulting in an undesirable browning of the products. DHA can be irreversibly converted to the vitamin-ineffective 2,3-diketogulonic acid – excretion metabolite – by opening the lactone ring by means of hydration (addition of water molecules) or reversibly converted to ascorbic acid by reduction by means of glutathione (GSH; consisting of the amino acids glutamic acid, cysteine and glycine). Finally, L-ascorbic acid with semidehydro- and dehydroascorbic acid constitutes a reversible redox system, resulting in the antioxidant effect of vitamin C.
Synthesis
L-ascorbic acid is a 2,3-endiol-L-gulonic acid gamma-lactone and is synthesized from D-glucose by higher plants and most animals via the glucuronate pathway. The glucuronate pathway involves the following synthetic steps:
- D-glucose → D-glucuronic acid → L-gluconic acid → L-gulonolactone → 3-oxo-L-gulonolactone → L-(+)-ascorbic acid.
The oxidation of L-gulonolactone to 3-oxo-L-gulonolactone occurs by the enzyme L-gulonolactone oxidase. Humans, great apes, as well as guinea pigs and some insect species, including grasshoppers, are unable to synthesize L-gulonolactone oxidase endogenously (in the body itself) due to a gene mutation, and therefore rely on exogenous dietary vitamin C intake. While the biosynthesis of L-ascorbic acid in mammals occurs in the liver, vitamin C in birds is synthesized in the kidney.
Absorption
Orally ingested ascorbic acid is already marginally absorbed (taken up) through the oral mucosa, presumably by a carrier-mediated, nonactive process, with the carrier (membrane-bound transport protein) having a high transport capacity. However, the main sites of absorption represent the duodenum and proximal jejunum.The mechanism of duodenal and jejunal vitamin C absorption, respectively, is species-specific and dose-dependent. In rats and hamsters, intestinal absorption of L-ascorbic acid occurs by simple diffusion. Humans and guinea pigs absorb low doses of L-ascorbic acid stereoselectively through an active sodium–potassium-ATPase (Na+/K+-ATPase)-driven transport system. To date, two transport proteins – SCVT1 and SCVT2 – have been identified that transfer L-ascorbic acid to mucosal cells (mucosal cells) of the upper small intestine following saturation kinetics.High doses of L-ascorbic acid are additionally absorbed passively by diffusion, since increased vitamin C concentrations reduce the activity of Na+/K+-ATPase.In contrast to L-ascorbic acid, the oxidized form DHA passes the enterocyte membrane (membrane of intestinal epithelial cells) exclusively by facilitated diffusion. As the administered dose of vitamin C increases, the rate of absorption decreases, partly because of downregulation (downregulation) of the transmembrane vitamin C transport proteins in the enterocytes (epithelial cells) of the upper small intestine when the vitamin C content in the intestinal lumen is high, and partly because of the ineffectiveness of the passive absorption pathway compared with the active transport mechanism. Thus, in the context of the usual dietary intake or oral dose up to 180 mg/day, between 80-90 %, at a dose of 1 g (1,000 mg)/day about 65-75 %, at 3 g (3,000 mg)/day about 40 % and at 12 g (12,000 mg)/day only about 16 % of vitamin C is absorbed. Non-absorbed vitamin C is mainly degraded by the large intestine flora to carbon dioxide (CO2) and organic acids. For this reason, intake of high doses of vitamin C may result in gastrointestinal (stomach) symptoms, such as diarrhea (diarrhea) and abdominal pain (abdominal pain).
Transport and distribution in the body
Vitamin C absorbed and appearing in blood plasma – 0.8-1.4 mg/dl – is 24% bound to protein and distributed throughout the organism, but with varying affinity (binding strength) to tissues. Particularly rich in vitamin C in humans in descending concentration are:
- Pituitary gland (pituitary gland).
- Adrenal gland
- Eye lens
- Leukocytes (white blood cells, especially lymphocytes (cellular components of the blood; they include the B cells, T cells and natural killer cells).
- Brain
- Liver
- Pancreas (pancreas)
- Spleen
- Kidney
- Myocardium (heart muscle)
- Lung
- Skeletal muscle
- Testes (testicles)
- Thyroid gland
In leukocytes and lymphocytes (white blood cells), respectively, vitamin C is located primarily in the cytosol. Humans do not have specific stores of ascorbic acid. Any excessive intake is not absorbed or is eliminated fecally (via the stool) and/or renally (via the kidney). The ascorbic acid pool in humans is about 1.5 to a maximum of 3 g at full satiety. A decrease in the total body pool to levels below 300 mg – vitamin C plasma concentration ≤ 0.2 mg/dl – leads to deficiency symptoms – scurvy is considered a classic clinical vitamin C deficiency symptom. Total daily turnover (turnover) is circa 1 mg/kg body weight, depends on pool size and daily intake, and is affected by stress, smoking, and chronic disease. The biological half-life of vitamin C varies between 10-30 days due to homeostatic regulation, whereas the pharmacokinetic half-life, in contrast, averages only 2.9 hours.
Excretion
Degradation of L-ascorbic acid in the liver and kidney occurs oxidatively via dehydroascorbic acid and 2,3-diketogulonic acid to oxalic acid. At a physiological vitamin C intake – plasma concentration 1.2-1.8 mg/dl; total body pool ~ 1.5 g – ascorbic acid (10-20 %) and its major metabolites (intermediates) DHA (approx. 20 %), 2,3-diketogulonic acid (approx. 20 %) and oxalic acid (approx. 40 %) are excreted by the kidneys, since the plasma concentration of vitamin C substantially exceeds the reabsorption capacity of the kidney – renal threshold for vitamin C > 1 mg/dl. In addition, a number of other metabolites have been described, such as L-threonic acid, L-xylose, and ascorbic acid-2-sulfate, which are predominantly eliminated renally.Renal elimination of vitamin C is not so much a measure of absorption as an indication of total tissue saturation. Approximately 35-50% of the daily urinary oxalic acid (approximately 30-40 mg) is derived from ascorbic acid in healthy adults following a normal diet. In this context, vitamin C-induced excretion of oxalic acid does not appear to play a role in the formation of calcium oxalate stones in the healthy population.According to the Harvard School of Public Health prospective cohort studies – Physician Health Study (PHS) and Nurses’ Health Study (NHS) – of 45,251 men and 85,557 women with no history of kidney stone disease, even high doses of vitamin C (≥ 1.5 g vitamin C/day) are not associated with an increased risk of nephrolithiasis (kidney stones). Gerster (1997), who provided a review of several clinical intervention and prospective studies including the NHS/PHS studies, reached the same conclusion. However, patients with recurrent nephrolithiasis (kidney stones), impaired renal function, or a defect in ascorbic acid or oxalate metabolism should limit their vitamin C intake to 50-100 mg per day. Below a plasma concentration of 1.2 mg/dl, ascorbic acid is reabsorbed by an active sodium-dependent process by means of a carrier (membrane-bound transport protein) in the proximal tubule (renal tubule). As the vitamin C content in blood plasma decreases, the tubular reabsorption rate increases. Under normal conditions, approximately 3% of orally ingested vitamin C is excreted in the feces unchanged and/or in the form of metabolites. Fecal elimination becomes increasingly important at high doses of vitamin C, so that at daily intakes of >3 g of vitamin C, nonmetabolized ascorbic acid is largely excreted fecally (via the stool) and only a small fraction is excreted renally (via the kidney) by glomerular filtration.