TOCOPHEROLS AND TOCOTRIENOLS

<a class="active" href="https://www.greenmedinfo.com/article/study-provides-first-evidence-egr-1-direct-target-vitamin-e-tocotrienol-sugges">This study provides the first evidence for EGR-1 as a direct target of vitamin E δ-tocotrienol, suggesting that EGR-1 may act as a proapoptotic factor in pancreatic cancer cells via induction of Bax.</a>

<a class="active" href="https://www.greenmedinfo.com/article/tocotrienol-induced-upregulation-a20-zinc-finger-protein">γ-tocotrienol induced upregulation of A20 zinc finger protein.</a>

Tocopherols constitute a series of related benzopyranols (or methyl tocols) that occur in plant tissues and vegetable oils and are powerful lipid-soluble antioxidants. In the tocopherols, the C16 side chain is saturated, and in the tocotrienols it contains three trans double bonds. Together, these two groups are termed the tocochromanols. In essence, the tocopherols have a 20-carbon phytyl tail (including the pyranol ring), with variable numbers of methyl groups attached to the benzene ring, and the tocotrienols a 20-carbon geranylgeranyl tail with double bonds at the 3', 7' and 11' positions, attached to the benzene ring. The side-chain methyl groups of natural tocopherols have R,R,R stereochemistry. The four main constituents of the two classes are termed - alpha (5,7,8-trimethyl), beta (5,8-dimethyl), gamma (7,8-dimethyl) and delta (8-methyl). The tocotrienols have a single chiral centre.
These compounds are only synthesised by plants and other oxygenic photosynthetic organisms, such as algae and some cyanobacteria, but they are essential components of the diet of animals, and collectively they are termed ‘vitamin E’ (the individual tocopherols are ‘vitamers’). In plants, there is a great range of tocochromanol contents and compositions, and photosynthetic plant tissues contain from 10 to 50 μg tocochromanols per g fresh weight. Tocopherols are present in all photosynthetic organisms, but the tocotrienols are found only in certain plant families. α-Tocopherol is often the main tocochromanol in leaves. Seed oils are a major source for the human diet and the compositions of tocopherols in some unrefined oils are listed in Table 1. Sunflower and olive oils are good sources of α-tocopherol and palm oil of the tocotrienols. In general, tocotrienols tend to be abundant only in seeds and fruits, especially of monocots such as wheat, rice and barley, though a major commercial source is palm oil. In leaf tissue, α-tocopherol is often the main isomer, while γ-tocopherol is the primary tocopherol of many seeds.

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<h5>Table 1. Tocopherol and tocotrienol contents (mg/Kg) in some seed oils.</h5>

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<td class="left">soybean</td>

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<td class="left">maize</td>

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<td class="left">sunflower</td>

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<td class="left">rapeseed</td>

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<td class="white2" colspan="9">* Abbreviations: T, tocopherol; TT, tocotrienol
Data from: Gunstone, F.D., Harwood, J.L. and Padley, F.B. The Lipid Handbook (Second Edition) (Chapman & Hall, London)(1994).</td>

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The mechanism of biosynthesis of tocopherols is well understood, and involves coupling of phytyl diphosphate with homogentisic acid (2,5-dihydroxyphenylacetic acid), followed by cyclization and methylation reactions.
The plant chloroplast is the site of biosynthesis, and the aromatic amino acid tyrosine can be considered the basic precursor. This is oxidized to p-hydroxypyruvic acid, which in the first committed step is converted to homogentisic acid by the enzyme p-hydroxyphenylpyruvate dioxygenase. Homogentisic acid is condensed with phytyl diphosphate in a reaction catalysed by a prenyl transferase to yield 2-methyl-6-phytyl-plastoquinol, which is first methylated to form 2,3-dimethyl-5-phytyl-1,4-benzoquinol and then converted by the enzyme tocopherol cyclase to γ-tocopherol. A further methylation reaction produces α-tocopherol, while modifications to the pathway produce β- and δ-tocopherols and <a href="http://lipidlibrary.aocs.org/Lipids/isoprene/index.htm#plast">plastoquinones</a>. Tocotrienols result from a similar series of reactions but with geranylgeranyl diphosphate as substrate in the condensation step.
Fish contain an unusual tocopherol that has been termed marine-derived α-tocomonoenol that is found together with α-tocopherol in a wide range of marine fish species. It appears to be a more efficient scavenger of free radicals at low temperatures. A related isomer with a Δ11 double bond has been found in palm oil and kiwi fruit. Pumpkin seeds contain both α- and γ-tocomonoenols.
α-Tocopheryl phosphate has recently been detected at low levels in liver and adipose tissue, and it is possible that it may be a common constituent of animal and plant tissues.
α-Tocopherol is a minor but ubiquitous component of the lipid constituents of animal cell membranes, with estimates ranging from one molecule of tocopherol to from 100 to 1000 molecules of phospholipid, depending on the membrane. The hydrophobic tail lies within the membrane, as might be expected, and the polar head group is orientated towards the surface but below the level of the phosphate moieties of the phospholipids. There may be some limited hydrogen bonding between the hydroxyl groups and phosphate depending on the degree of hydration of the membrane. On the other hand, there is a strong affinity of α-tocopherol for polyunsaturated fatty acids, where the chromanol unit may interact with the double bonds, suggesting that tocopherol is located deep within the membrane.
During the refining of vegetable oils, much of the natural tocopherols are lost or destroyed. Most commercial vitamin E is therefore prepared by chemical synthesis with trimethylhydroquinone and phytyl bromide as the precursors. The resulting product is a mixture of eight stereoisomers (from R,R,R to S,S,S methyl groups) of α-tocopherol, with the various stereoisomers differing by a factor of two in biologic activity, as a consequence of the stereochemistry of the 2 position (i.e. 2S-α- compared to 2R-α-tocopherol). It is usually administered as the acetate derivative in vivo. Tocopherols are not usually regarded as effective antioxidants in the polyunsaturated seed oils of commerce, and at higher concentrations can even act as pro-oxidants, although the reasons for this are not understood.

TOCOPHEROLS AND TOCOTRIENOLS

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