Vitamin E is the name given to all natural and synthetic tocol and tocotrienol derivatives (derivatives) that have the biological activity of alpha-tocopherol. Alpha-tocopherol or its stereoisomer RRR-alpha-tocopherol (old name: D-alpha-tocopherol) represents the most important compound occurring in nature [2, 3, 11-13]. The term “tocopherol” is derived from the Greek word syllables tocos (birth) and pherein (to bring forth). Due to the discovery in the early 1920s that the reproductive capacity as well as the prevention of atrophy (tissue atrophy) of reproductive organs of female and male rats depended on a fat-soluble dietary component, which was named vitamin E, vitamin E was named the “fertility vitamin”. Structural feature of tocopherols is the chroman-6-ol ring with a side chain consisting of three isoprene molecules. The number and position of the methyl groups on the chroman-6-ol ring determine the different vitamin E activity of the individual tocopherols.Tocopherols and tocotrienols occur both in free form and esterified with acetic or succinic acid attached to the phenolic hydroxyl (OH) group of the 6-chromanol ring. Vitamin E compounds of plant origin include:
- 4 Tocopherols – alpha-, beta-, gamma-, delta-tocopherol – with saturated isoprenoid side chain.
- 4 tocotrienols – alpha-, beta-, gamma-, delta-tocotrienol – with unsaturated isoprenoid side chain
The fully and semi-synthetic forms of vitamin E, respectively, are equimolar mixtures of the stereoisomers of alpha-tocopherol – all-rac-alpha-tocopherol (old name: D,L-alpha-tocopherol), a mixture of eight enantiomers that differ only in the position of the methyl groups in the molecule. Esterification of the OH group of the chroman-6-ol ring, for example with acetate (salts and esters of acetic acid), succinate (salts and esters of succinic acid) or nicotinate (salts and esters of nicotinic acid), increases the stability of the chroman structure. To standardize the vitamin E activity of a tocopherol derivative, according to the German Nutrition Society (DGE) and the US National Research Council (NRC), intake recommendations and levels in the diet are expressed as RRR-alpha-tocopherol equivalent (alpha-TE). The vitamin E activity of RRR-alpha-tocopherol is taken as 100% (reference substance) and the other compounds are expressed as a percentage of this according to their activity. Biological activity (in % to RRR-alpha-tocopherol) and conversion factors for individual vitamin E forms:
- 1 mg RRR-alpha-tocopherol (5,7,8-trimethyltocol) = 100%.
- Equivalent to 1.00 mg alpha-TE = 1.49 I.U. (International Units).
- 1 mg RRR-beta-tocopherol (5,8-dimethyltocol) = 50%.
- Equivalent to 0.50 mg alpha-TE = 0.75 I.U.
- 1 mg RRR-gamma-tocopherol (7,8-dimethyltocol) = 10%.
- Equivalent to 0.10 mg alpha-TE = 0.15 I.U.
- 1 mg RRR-delta-tocopherol (8-methyltocol) = 3 %.
- Equivalent to 0.03 mg alpha-TE = 0.05 I.U.
- 1 mg RRR-alpha-tocopheryl acetate = 91%.
- Equivalent to 0.91 mg alpha-TE = 1.36 I.U.
- 1 mg RRR-alpha-tocopheryl hydrogen succinate = 81%.
- Equivalent to 0.81 mg alpha-TE = 1.21 I.U.
- 1 mg R-alpha-tocotrienol (5,7,8-trimethyltocotrienol) = 30%.
- Equivalent to 0.30 mg alpha-TE = 0.45 I.U.
- 1 mg R-beta-tocotrienol (5,8-dimethyltocotrienol) = 5 %.
- Equivalent to 0.05 mg alpha-TE = 0.08 I.U.
- 1 mg all-rac-alpha-tocopherol = 74 %.
- Equivalent to 0.74 mg alpha-TE = 1.10 I.U.
- 1 mg all-rac-alpha-tocopheryl acetate = 67 %.
- Equivalent to 0.67 mg alpha-TE = 1.00 I.U.
- 1 mg all-rac-alpha-tocopheryl hydrogen succinate = 60%.
- Equivalent to 0.60 mg alpha-TE = 0.89 I.U.
Compared to naturally occurring RRR-alpha-tocopherol (biological activity: 110%), the eight stereoisomers of synthetic RRR-alpha-tocopheryl acetate have the following biological activities.
- RRR-alpha-tocopherol acetate = 100%.
- RRS-alpha-tocopherol acetate = 90%.
- RSS-alpha-tocopherol acetate = 73 %
- SSS-alpha-tocopherol acetate = 60 %
- RSR-alpha-tocopherol acetate = 57 %
- SRS-alpha-tocopherol acetate = 37 %
- SRR-alpha-tocopherol acetate = 31 %
- SSR-alpha-tocopherol acetate = 21 %
The biological efficacy of the different forms of vitamin E has been determined experimentally using fertility studies in rats – absorption and pregnancy related. This involved first an alimentary (affecting the food) vitamin E depletion (emptying) of the animals to the critical deficiency stage with subsequent oral administration of the various vitamin E derivatives in defined quantities and determination of the preventive (prophylactically) effective dose – compared to RRR-alpha-tocopherol.The biological activity of tocopherol derivatives decreases with the number of methyl groups on the chroman-6-ol ring and has no direct relation to the antioxidant potential.
Synthesis
Only plants are capable of vitamin E synthesis. The various tocopherol and tocotrienol derivatives arise from homogentisic acid, which is formed as an intermediate in the breakdown of the amino acids phenylalanine and tyrosine. The ratio of the individual tocopherols to each other changes in the course of plant growth.Whereas (dark) green plant parts contain relatively high levels of alpha-tocopherol in accordance with their chloroplast content (cell organelles capable of photosynthesis), a comparatively low concentration of vitamin E can be found in yellow plant tissues, stems, roots and fruits of green plants. In the non-green plants or plant tissues, in addition to alpha-tocopherol, mainly gamma-tocopherol is present, and the vitamin E content is proportional (proportionate) to the concentration of chromoplasts (color-producing plastids). When comparing slow-growing and mature plants with fast-growing and young plants, tocopherol contents are higher in the former. Vitamin E enters the animal organism through the food chain and is thus detectable in animal foods, such as meat, liver, fish, milk, and eggs. However, tocopherol levels in foods of animal origin are much lower than in plant products and are highly dependent on the diet of the animals.
Absorption
Like all fat-soluble vitamins, vitamin E is absorbed (taken up) in the upper small intestine during fat digestion, i.e. the presence of dietary fats as transporters of lipophilic (fat-soluble) molecules, bile acids to solubilize (increase solubility) and form micelles (form transport beads that make fat-soluble substances transportable in aqueous solution), and pancreatic esterases (digestive enzymes from the pancreas) to cleave tocopheryl esters is necessary for optimal intestinal absorption (absorption through the intestine). Tocopheryl esters derived from food first undergo hydrolysis (cleavage by reaction with water) in the intestinal lumen by means of esterases (digestive enzymes) from the pancreas. In this process, lipases (fat-cleaving esterases) prefer the esters of RRR-alpha-tocopherol and exhibit a high affinity (binding strength) and activity to acetyl esters.Free RRR-alpha-tocopherol reaches the brush border membrane of enterocytes (cells of the small intestinal epithelium) as a component of the mixed micelles and is internalized (taken up internally). Intracellularly (within the cell), incorporation (uptake) of vitamin E occurs into chylomicrons (lipid-rich lipoproteins), which transport the lipophilic vitamin via the lymph into the peripheral blood circulation. The mechanism of intestinal uptake of RRR-alpha-tocopherol occurs in the physiological (normal for metabolism) concentration range according to saturation kinetics in an energy-independent manner corresponding to carrier-mediated passive diffusion. Pharmacological doses are absorbed by passive diffusion.An absorption rate of between 25-60% can be expected with physiological intake of vitamin E. The bioavailability of the lipophilic vitamin depends on the dose supplied, the type and amount of dietary lipids present, and the presence of bile acids and esterases from the pancreas. With administrations of 12 mg, 24 mg, and 200 mg of vitamin E, absorption rates of approximately 54%, 30%, and 10%, respectively, were observed under an average fat intake. Medium-chain saturated fatty acids stimulate, and long-chain polyunsaturated fatty acids inhibit, the enteric absorption of alpha-tocopherol.Acetate-esterified alpha-tocopherol has a similar absorption rate to free alpha-tocopherol.
Transport and distribution in the body
During transport to the liver, free fatty acids (FFS), monoglycerides, and, to a lesser extent, alpha-tocopherol are released from chylomicrons to peripheral tissues, such as adipose tissue and muscle, under the action of the enzyme lipoprotein lipase (LPL), which is located on cell surfaces and cleaves triglycerides. This process degrades chylomicrons to chylomicron remnants (low-fat chylomicron remnants), which bind to specific receptors (binding sites) in the liver. Uptake of vitamin E compounds into liver parenchymal cells occurs via receptor-mediated endocytosis. In the cytoplasm of the parenchymal cells, vitamin E is transferred to the alpha-tocopherol-binding protein or transfer protein (alpha-TBP/-TTP), which preferentially binds RRR-alpha-tocopherol and transports it in the blood plasma in the form of lipoproteins. VLDL (very low density lipoproteins) synthesized in the liver only stores vitamin E molecules with fully methylated chroman-6-ol ring and free OH group and with a carbon side chain with R-stereochemical configuration at chirality center 2 (→ RRR-alpha-tocopherol). VLDL is secreted (secreted) by the liver and introduced into the bloodstream to distribute RRR-alpha-tocopherol to extrahepatic (outside the liver) tissues. Target organs include muscle, heart, nervous system, and depot fat. Uptake of vitamin E by target cells is tightly coupled to lipoprotein catabolism (degradation of lipoproteins). As VLDL binds to peripheral cells, a portion of alpha-tocopherol, free fatty acids, and monoglycerides are internalized by passive diffusion through the action of lipoprotein lipase (LPL). This results in catabolism of VLDL to IDL (intermediate density lipoproteins) and subsequently to LDL (low density lipoproteins; cholesterol-rich low density lipoproteins), which may still contain up to 60-65% vitamin E.Alpha-tocopherol bound to LDL is taken up into liver and extrahepatic tissues via receptor-mediated endocytosis on the one hand and transferred to HDL (high density lipoproteins; protein-rich high density lipoproteins) on the other. HDL has a vitamin E content between 20-25% and is significantly involved in the transport of alpha-tocopherol from peripheral cells back to the liver. In addition to hepatic alpha-TBP, another transport protein for alpha-tocopherol has been discovered that is ubiquitous (distributed everywhere) but is expressed (produced) more abundantly in the liver, prostate, and brain. It is the intracellular alpha-tocopherol-associated protein (TAP), a hydrophobic ligand-binding protein that has the CRAL sequence (cis-retinal binding motif) and a GTP-binding site. Database analyses suggest that three similar TAP genes are currently postulated (hypothesized)-TAP1, TAP2, and TAP3.
Storage
There are no specific storage organs for alpha-tocopherol. The total body stock of vitamin E is about 2-5 g [1, 2, 12,13]. Vitamin E is detectable in the following body tissues:
- Adipose tissue – 0.2 mg/g lipid; 150 µg/g wet weight.
- Adrenal gland/adrenal cortex – 0.7 mg/g lipid; 132 µg/g wet wt.
- Pituitary gland – 1.2 mg/g lipid; 40 µg/g wet wt.
- Testes (testis) – 1.2 mg/g lipid; 40 µg/g wet wt.
- Platelets (blood platelets) – 1.3 mg/g lipid; 30 µg/g wet weight.
- Muscle – 0.4 mg/g lipid; 19 µg/g wet weight.
- Liver – 0.3 mg/g lipid; 13 µg/g wet wt.
In the above tissues, vitamin E is found mainly in fractions rich in membranes, such as mitochondria (“energy power plants” of the cell), microsomes (enzyme-containing vesicles) and nuclei (→ protection against lipid peroxidation). In this process, the vitamin is integrated into the cell membrane via its lipophilic side chain. For every 1,000-3,000 fatty acid molecules, there are about 0.5-5 tocopherol molecules. While alpha-tocopherol can only be mobilized very slowly from the lipid compartment of adipose tissue, muscle, erythrocytes (red blood cells), brain and spinal cord – nerve tissue (half-life 30-100 days), tissues such as plasma, liver, kidney and spleen show a more rapid turnover of vitamin E (half-life 5-7 days).In competitive athletes, however, it was found that the serum vitamin E concentration increases after intense muscular activity. In all tissues except the liver, the alpha form and the RRR stereoisomer of tocopherol (→ RRR-alpha-tocopherol) are preferentially retinylated (retained). A preferential occurrence of the natural stereoisomer – plasma factor 2:1 – is also observed in blood plasma. The vitamin E content of the human body consists of approximately 90% RRR-alpha-tocopherol and about 10% gamma-tocopherol. Other forms of vitamin E are present only in trace amounts.
Excretion
Excretion of vitamin E is related to their antioxidant function. After hepatic (occurring in the liver) oxidation of the tocopheroxyl radical to tocopherylquinone by peroxyl radicals, the quinone is reduced to the corresponding hydroquinone by microsomal enzymes. Alpha-tocopherylhydroquinone can be eliminated via bile and feces or further degraded in the kidneys to tocopheronic acid and the corresponding lactone. Only about 1% of orally ingested vitamin E is excreted in the urine as the so-called Simon metabolite, a glucuronide formed from tocopheronolactone. However, the main route of excretion of metabolized as well as unabsorbed tocopherol is fecal elimination, mainly in the form of tocopherylquinone, tocopherylhydroquinone, and polymerization products. In the presence of adequate or excess vitamin E supply, tocopherol excretion is increased in the form of the metabolite 2,5,7,8-tetramethyl-2 (2′-carboxyethyl)-6-hydroxy-chroman (alpha-CEHC), which, in contrast to tocopherol molecules that have antioxidant effects, has a chroman structure that is still intact and is eliminated renally (via the kidney) as a water-soluble sulfate ester or as a glucuronide. Studies have shown that gamma- and delta-tocopherol, as well as the synthetic all-rac-alpha-tocopherol, are more rapidly degraded to CEHC than RRR-alpha-tocopherol – indicating that the RRR-alpha stereoismer is preferentially retained in the body.
