TOCOPHEROL

Any of a group of related substances (α-, β-, γ-, andΔ-tocopherol) that constitute vitamin E. 
The α-form (which occurs naturally as the d-isomer) is the most potent. 
Occurs naturally in plants, especially wheat germ. 

CAS:    1406-18-4
MF:    C29H50O2
MW:    430.71
EINECS:    215-798-8

Synonyms
naturalvitaminee;RAC-ALPHA-TOCOPHEROL;(2R)-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-3,4-dihydrochromen-6-ol;dl-alpha-Tocopheryl Polyethylene Glycol Succinate;VitaMin E natural vitaMine e;Mixed Tocopherols;vitamin e 1.36 iu /mg;5-(4-Morpholinylmethyl)-d2 &delta

All are derivatives of dihydrobenzo-γ-pyran and differ from each other only in the number and position of methyl groups. 
Tocopherol  is required by certain rodents for normal reproduction. 
Muscular and central nervous system depletion along with generalized edema are deficiency symptoms in all animals. 
Tocopherol is not required as a dietary supplement for humans.
Tocopherol are a class of organic compounds comprising various methylated phenols, many of which have vitamin E activity. 
Because the vitamin activity was first identified in 1936 from a dietary fertility factor in rats, Tocopherol was named tocopherol, from Greek τόκος tókos 'birth' and φέρειν phérein 'to bear or carry', that is 'to carry a pregnancy', with the ending -ol signifying its status as a chemical alcohol.
Tocopherol is the main source found in supplements and in the European diet, where the main dietary sources are olive and sunflower oils, while γ-tocopherol is the most common form in the American diet due to a higher intake of soybean and corn oil.

Tocopherol exists in four different forms designated as α, β, δ, and γ. 
They present strong antioxidant activities, and it is determined as the major form of vitamin E. 
Tocopherol, as a group, is composed of soluble phenolic compounds that consist of a chromanol ring and a 16-carbon phytyl chain. 
The classification of the tocopherol molecules is designated depending on the number and position of the methyl substituent in the chromanol ring. 
The different types of tocopherol can be presented trimethylated, dimethylated or methylated in the positions 5-, 7- and 8-. 

When the carbons at position 5- and 7- are not methylated, they can function as electrophilic centers that can trap reactive oxygen and nitrogen species. 
Tocopherol can be found in the diet as part of vegetable oil such as corn, soybean, sesame, and cottonseed.
Tocopherol is currently under the list of substances generally recognized as safe (GRAS) in the FDA for the use of human consumption.
Tocopherol is abundant in whole wheat, rice germ, and vegetable oils. 
Tocopherol is destroyed by the refining and bleaching of flour. 
Tocopherol prevents oils from going rancid. 
Large amounts of Tocopherol, such as from vitamin supplements, do not appear to provide any health benefit.

Tocopherol Chemical Properties
Melting point: 292 °C
Storage temp.: 0-6°C
Solubility: Soluble ((CH3)2CO, ethanol, CHCl3, (C2H5)2O), insoluble (water)
Odor: Typical vegetable oil
LogP: 10.962 (est)
CAS DataBase Reference: 1406-18-4(CAS DataBase Reference)
NIST Chemistry Reference: Tocopherol(1406-18-4)
EPA Substance Registry System: Tocopherol (1406-18-4)

Viscous oils. Soluble in fats; insoluble in water. 
Stable to heat in the absence of oxygen, to strong acids, and to visible light; unstable to UV light, alkalies, and oxidation.

Forms
Tocopherol exists in eight different forms, four tocopherols and four tocotrienols. 
All feature a chromane ring, with a hydroxyl group that can donate a hydrogen atom to reduce free radicals and a hydrophobic side chain that allows for penetration into biological membranes. 
Both the tocopherols and tocotrienols occur in α (alpha), β (beta), γ (gamma), and δ (delta) forms, determined by the number and position of methyl groups on the chromanol ring.

The tocotrienols have the same methyl structure at the ring and the same Greek-letter methyl notation, but differ from the analogous tocopherols by the presence of three double bonds in the hydrophobic side chain. 
The unsaturation of the tails gives tocotrienols only a single stereoisomeric carbon (and thus two possible isomers per structural formula, one of which occurs naturally), whereas tocopherols have three centers (and eight possible stereoisomers per structural formula, again, only one of which occurs naturally).

Each form has a different biological activity.
In general, the unnatural l-isomers of tocotrienols lack almost all vitamin activity, and half of the possible 8 isomers of the tocopherols (those with 2S chirality at the ring–tail junction) also lack vitamin activity. 
Of the stereoisomers that retain activity, increasing methylation, especially full methylation to the α-form, increases vitamin activity. 
In tocopherols, this is due to the higher binding energy of the α-tocopherol form of the vitamin to the tocopherol binding protein.

As a food additive, tocopherol is labeled with these E numbers: E306 (tocopherol), E307 (α-tocopherol), E308 (γ-tocopherol), and E309 (δ-tocopherol). 
All of these are approved in the US, EU, and Australia and New Zealand for use as antioxidants.

Uses    
Fat-soluble Tocopherol, which is a light yellow oil readily degradable by heat. 
As a vitamin, Tocopherol is essential for normal muscle growth and prevents vitamin A destruction by deterioration. 
Tocopherol also functions as an antioxidant. 
Tocopherol prevents the oxidation of certain fatty acids and is stable unless the food becomes rancid. 
Vegetable oils contain a higher concentration of natural antioxidants, including tocopherols, than animal fats and are thus more stable. 
Tocopherol is obtained from vegetable oils, beans, eggs, and milk. 
Tocopherol is also termed alpha-tocopherol.
Medicine, nutrition, antioxidants for fats, animal feed additive.

Observational studies that measure dietary intake and/or serum concentration, and experimental studies that ideally are randomized clinical trials (RCTs), are two means of examining the effects or lack thereof of a proposed intervention on human health.
Healthcare outcomes may be expected to be in accord between reviews of observational and experimental studies. 
If there is a lack of agreement, then factors other than design need to be considered.
In observational studies on Tocopherol, an inverse correlation between dietary intake and risk of a disease, or serum concentration and risk of a disease, may be considered suggestive, but any conclusions also should rest on randomized clinical trials of sufficient size and duration to measure clinically significant results. 
One concern with correlations is that other nutrients and non-nutrient compounds (such as polyphenols) may be higher in the same diets that are higher in vitamin E. 
Another concern for the relevance of RCTs described below is that while observational studies are comparing disease risk between low and high dietary intake of naturally occurring Tocopherol from food (when worldwide, the adult median dietary intake is 6.2 mg/d for d-α-tocopherol; 10.2 mg/day when all of the tocopherol and tocotrienol isomers are included), the prospective RCTs often used 400 IU/day of synthetic dl-α-tocopherol as the test product, equivalent to 268 mg of α-tocopherol equivalents.

Preparation    
Tocopherol is synthesised in two ways. 
One is to extract Tocopherol from natural plant sources and the other is to obtain it by chemical synthesis. 
The following are the chemical synthesis routes:
The most important natural raw materials for production of tocopherols by extraction are deodoriser sludges, which are distillates obtained in the deodorisation of vegetable oils. 
Such distillates contain sterols, sterol esters and triacylglycerols, as well as tocopherols and tocotrienols. 
The concentration of tocopherols depends on the deodorisation parameters (temperature, vacuum, quantity of injected steam and equipment) but their amount is lower than 10%, usually 8–9 %, of unsaponifiable matter present. 
Separation of tocopherol from the other distilled compounds is possible by several methods: (1) by esterification with a lower alcohol, washing and vacuum distillation; 
(2) by saponification, or 
(3) by fractional liquid–liquid extraction. 
The concentrates obtained in this way may be purified further by molecular distillation, extraction, crystallisation, or combinations of these procedures.
The tocopherol concentrates recommended as antioxidants are mixtures with relatively high contents of γ-tocopherol and δ-tocopherol (being obtained from soybean oil), but α-tocopherol is also present. 
The total tocopherol concentration usually lies between 30 and 80%. The rest is constituted of triacylglycerols.

Pharmacology    
The antioxidant effects of Tocopherol can be translated into different changes at the pharmacodynamic level. 
In vitro studies have shown that this antioxidant activity can produce modification in protein kinase C (PKC) which will later be translated into an inhibition of cell death. 
Some other derivate effects are the anti-inflammatory properties of tocopherol which can be related to the modulation of cytokines or prostaglandins, prostanoids and thromboxanes.

Synthesis
Naturally sourced d-α-tocopherol can be extracted and purified from seed oils, or γ-tocopherol can be extracted, purified, and methylated to create d-alpha-tocopherol. 
In contrast to α-tocopherol extracted from plants, which also is called d-α-tocopherol, industrial synthesis creates dl-α-tocopherol. 
"Tocopherol is synthesized from a mixture of toluene and 2,3,5-trimethyl-hydroquinone that reacts with isophytol to all-rac-α-tocopherol, using iron in the presence of hydrogen chloride gas as a catalyst. 
The reaction mixture obtained is filtered and extracted with aqueous caustic soda. 
Toluene is removed by evaporation and the residue (all rac-α-tocopherol) is purified by vacuum distillation." Specification for the ingredient is >97% pure.
This synthetic dl-α-tocopherol has approximately 50% of the potency of d-α-tocopherol. Manufacturers of dietary supplements and fortified foods for humans or domesticated animals convert the phenol form of the vitamin to an ester using either acetic acid or succinic acid because the esters are more chemically stable, providing for a longer shelf-life. 
The ester forms are de-esterified in the gut and absorbed as free α-tocopherol.