Е витаминіне иелік антиоксиданттар токоферолдары

Antioxidant compounds with vitamin E activity

Tocopherols (/t//oʊ/'/k//ɒ//f//ə/,/r//ɒ//l/; TCP) 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, it 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. α 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. 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 alpha form, increases vitamin activity. In tocopherols, this is due to the preference of the tocopherol binding protein for the α tocopherol form of the vitamin. 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.

α Tocopherol is the form of vitamin E that is preferentially absorbed and accumulated in humans. The measurement of "vitamin E" activity in international units (IU) was based on fertility enhancement by the prevention of miscarriages in pregnant rats relative to α tocopherol. Although the mono methylated form ddd γ tocopherol is the most prevalent form of vitamin E in oils, there is evidence that rats can methylate this form to the preferred α tocopherol, since several generations of rats retained α tocopherol tissue levels, even when those generations were fed only γ tocopherol through their lives. There are three stereocenters in α tocopherol, so this is a chiral molecule.

Tocopherols are radical scavengers, delivering an H atom to quench free radicals. At 323 kJ/mol, the O H bond in tocopherols is approximately 10% weaker than in most other phenols. This weak bond allows the vitamin to donate a hydrogen atom to the peroxyl radical and other free radicals, minimizing their damaging effect. The thus generated tocopheryl radical is relatively unreactive, but reverts to tocopherol by a redox reaction with a hydrogen donor such as vitamin C. As they are fat soluble, tocopherols are incorporated into cell membranes, which are thus protected from oxidative damage.

The U. S. Recommended Dietary Allowance (RDA) for adults is 15 mg/day. The U. S. Institute of Medicine has set an upper tolerable intake level (UL) for vitamin E at 1,000 mg (1,500 IU) per day. The European Food Safety Authority sets UL at 300 mg α tocopherol equivalents /day.

For dietary purposes, vitamin E activity of vitamin E isomers is expressed as α tocopherol equivalents (a TEs). One a TE is defined by the biological activity of 1 mg (natural) d α tocopherol in the resorption gestation test. According to listings by FAO and others β tocopherol should be multiplied by 0.5, γ tocopherol by 0.1, and α tocotrienol by 0.3. These factors do not correlate with the antioxidant activity of vitamin E isomers, where tocotrienols show even much higher activity in vivo.

Synthetic vitamin E derived from petroleum products is manufactured as all racemic α tocopheryl acetate with a mixture of eight stereoisomers. In this mixture, one α tocopherol molecule in eight molecules are in the form of RRR α tocopherol (12.5% of the total). The 8 isomer all rac vitamin E is always marked on labels simply as dl tocopherol or dl tocopheryl acetate, even though it is (if fully written out) The present largest manufacturers of this type are DSM and BASF. Natural α tocopherol is the RRR α (or ddd α) form. The synthetic ("dl α") form is not so active as the natural ddd α ("d α") tocopherol form. This is mainly due to reduced vitamin activity of the four possible stereoisomers that are represented by the l or S enantiomer at the first stereocenter (an S or l configuration between the chromanol ring and the tail, i. e., the SRR, SRS, SSR, and SSS stereoisomers). The three unnatural "2R" stereoisomers with natural R configuration at this 2' stereocenter, but S at one of the other centers in the tail (i. e., RSR, RRS, RSS), appear to retain substantial RRR vitamin activity, because they are recognized by the alpha tocopherol transfer protein, and thus maintained in the plasma, where the other four stereoisomers (SRR, SRS, SSR, and SSS) are not. Thus, the synthetic all rac α tocopherol, in theory, would have approximately half the vitamin activity of RRR α tocopherol in humans. Experimentally, the ratio of activities of the 8 stereoisomer racemic mixture to the natural vitamin, is 1 to 1.36 in the rat pregnancy model (suggesting a measured activity ratio of 1/1.36 = 74% of natural, for the 8 isomer racemic mix). Although it is clear that mixtures of stereoisomers are not so active as the natural RRR α tocopherol form, in the ratios discussed above, specific information on any side effects of the seven synthetic vitamin E stereoisomers is not readily available.

Manufacturers also commonly convert the phenol form of the vitamins (with a free hydroxyl group) to esters, using acetic or succinic acid. These tocopheryl esters are more stable and are easy to use in vitamin supplements. α Tocopheryl esters are de esterified in the gut and then absorbed as the free tocopherol. Tocopheryl nicotinate, tocopheryl linolate, and tocopheryl palmitate esters are also used in cosmetics and some pharmaceuticals.

"Mixed tocopherols" in the USA contain at least 20% w/w other natural R, R,R tocopherols, i. e. R, R,R α tocopherol content plus at least 25% R, R,R β , R, R,R γ , R, R,R δ tocopherols. Some brands may contain 20.0% w/w or more of the other tocopherols and measurable tocotrienols. Some mixed tocopherols with higher γ tocopherol content are marketed as "High Gamma Tocopherol". The label should report each component in milligrams, except R, R,R α tocopherol may still be reported in IU. Mixed tocopherols also may be found in other nutritional supplements.

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 vitamin E, 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 vitamin E 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. There is other evidence for declining use of vitamin E. Within the U. S. military services, vitamin prescriptions written for active, reserve and retired military, and their dependents, were tracked over years 2007–2011. Vitamin E prescriptions decreased by 53% while vitamin C remained constant and vitamin D increased by 454%. A report on vitamin E sales volume in the USA documented a 50% decrease between 2000 and 2006, with a significant cause attributed to a well publicized meta analysis that had concluded that high dosage vitamin E increased all cause mortality.

A Cochrane review published in 2017 (updated in 2023) on antioxidant vitamin and mineral supplements for slowing the progression of age related macular degeneration (AMD) identified only one vitamin E clinical trial. That trial compared 500 IU/day of α tocopherol to placebo for four years and reported no effect on the progression of AMD in people already diagnosed with the condition. A large clinical trial known as AREDS compared β carotene (15 mg), vitamin C (500 mg), and α tocopherol (400 IU) to placebo for up to ten years, with a conclusion that the anti oxidant combination significantly slowed progression. However, because there was no group in the trial receiving only vitamin E, no conclusions could be drawn as to the contribution of the vitamin to the effect.

Proponents of megavitamin therapy and orthomolecular medicine advocate natural tocopherols. Meanwhile, clinical trials have largely concentrated on use of either a synthetic, all racemic d α tocopheryl acetate or synthetic dl α tocopheryl acetate.

Tocopherol is described as functioning as an antioxidant. A dose ranging trial was conducted in people with chronic oxidative stress attributed to elevated serum cholesterol. Plasma F2 isoprostane concentration was selected as a biomarker of free radical mediated lipid peroxidation. Only the two highest doses 1600 and 3200 IU/day significantly lowered F2 isoprostane.

Alzheimer's disease (AD) and vascular dementia are common causes of decline of brain functions that occur with age. AD is a chronic neurodegenerative disease that worsens over time. The disease process is associated with plaques and tangles in the brain. Vascular dementia may be caused by ischemic or hemorrhagic infarcts affecting multiple brain areas, including the anterior cerebral artery territory, the parietal lobes, or the cingulate gyrus. Both types of dementia may be present. Vitamin E status (and that of other antioxidant nutrients) is conjectured as having a possible impact on risk of Alzheimer's disease and vascular dementia. A review of dietary intake studies reported that higher consumption of vitamin E from foods lowered the risk of developing AD by 24%. A second review examined serum vitamin E levels and reported lower serum vitamin E in AD patients compared to healthy, age matched people. In 2017 a consensus statement from the British Association for Psychopharmacology included that until further information is available, vitamin E cannot be recommended for treatment or prevention of Alzheimer's disease.

From reviews of observational studies, diets higher in vitamin E content were associated with a lower relative risk of kidney cancer, bladder cancer, and lung cancer When comparisons were made between the lowest and highest groups for dietary vitamin E consumption from food, the average reductions in relative risk were in the range of 16 19%. For all of these reviews, the authors noted that the findings needed to be confirmed by prospective studies. In male tobacco smokers, 50 mg/day had no impact on developing lung cancer. A review of RCTs for colorectal cancer reported lack of a statistically significant reduction in risk. In male tobacco smokers, 50 mg/day reduced prostate cancer risk by 32%, but in a different trial, majority non smokers, 400 IU/day increased risk by 17%. In women who consumed either placebo or 600 IU of natural source vitamin E on alternate days for an average of 10.1 years there were no significant differences for breast cancer, lung cancer, or colon cancer. The U. S. Food and Drug Administration initiated a process of reviewing and approving food and dietary supplement health claims in 1993. A Qualified Health Claim issued in 2012 allows product label claims that vitamin E may reduce risk of renal, bladder, and colorectal cancers, with a stipulation that the label must include a mandatory qualifier sentence: “FDA has concluded that there is very little scientific evidence for this claim.” The European Food Safety Authority (EFSA) reviews proposed health claims for the European Union countries. As of March 2018, EFSA has not evaluated any vitamin E and cancer prevention claims.

A meta analysis from 2015 reported that for studies that reported serum tocopherol, higher serum concentration was associated with a 23% reduction in relative risk of age related cataracts (ARC), with the effect due to differences in nuclear cataract rather than cortical or posterior subcapsular cataract the three major classifications of age related cataracts. However, this article and a second meta analysis reporting on clinical trials of α tocopherol supplementation reported no statistically significant change to risk of ARC when compared to placebo.

Research on the effects of vitamin E on cardiovascular disease has produced conflicting results. An inverse relation has been observed between coronary heart disease and the consumption of foods high in vitamin E, and also higher serum concentration of α tocopherol. In one of the largest observational studies, almost 90,000 healthy nurses were tracked for eight years. Compared to those in the lowest fifth for reported vitamin E consumption (from food and dietary supplements), those in the highest fifth were at a 34% lower risk of major coronary disease. Diet higher in vitamin E also may be higher in other, unidentified components that promote heart health, or people choosing such diets may be making other healthy lifestyle choices. The results were not consistent for all of the individual trials incorporated into the meta analysis. For example, the Physicians' Health Study II did not show any benefit after 400 IU every other day for eight years, for heart attack, stroke, coronary mortality, or all cause mortality. The effects of vitamin E supplementation on incidence of stroke were summarized in 2011. There were no significant benefits for vitamin E versus placebo for risk of stroke, or for subset analysis for ischaemic stroke, haemorrhagic stroke, fatal stroke, or non fatal stroke. In 2001 the U. S. Food and Drug Administration rejected proposed health claims for vitamin E and cardiovascular health. The U. S. National Institutes of Health also reviewed the literature and concluded there was not sufficient evidence to support the idea that routine use of vitamin E supplements prevents cardiovascular disease or reduces its morbidity and mortality.

Antioxidant vitamins as dietary supplements have been proposed as having benefits if consumed during pregnancy. For the combination of vitamin E with vitamin C supplemented to pregnant women, a Cochrane review of 21 clinical trials concluded that the data do not support vitamin E supplementation majority of trials α tocopherol at 400 IU/day plus vitamin C at 1000 mg/day as being efficacious for reducing risk of stillbirth, neonatal death, preterm birth, preeclampsia, or any other maternal or infant outcomes, either in healthy women or those considered at risk for pregnancy complications. The review identified only three small trials in which vitamin E was supplemented without co supplementation with vitamin C. None of these trials reported any clinically meaningful information.

The U. S. Food and Nutrition Board set a Tolerable upper intake level (UL) at 1,000 mg (1,500 IU) per day derived from animal models that demonstrated bleeding at high doses. The European Food Safety Authority reviewed the same safety question and set a UL at 300 mg/day. Another meta analysis reported a non significant 1% increase in all cause mortality when α tocopherol was the only supplement. Subset analysis reported no difference between natural (plant extracted) or synthetic α tocopherol, or whether the amount used was less than or more than 400 IU/day. There are reports of vitamin E induced allergic contact dermatitis from use of vitamin E derivatives such as tocopheryl linoleate and tocopherol acetate in skin care products. Incidence is low despite widespread use.

The amounts of α tocopherol, other tocopherols and tocotrienols that are components of dietary vitamin E, when consumed from foods, do not appear to cause any interactions with drugs. Consumption of α tocopherol as a dietary supplement in amounts in excess of 300 mg/day may lead to interactions with aspirin, warfarin, tamoxifen, and cyclosporine A in ways that alter function. For aspirin and warfarin, high amounts of vitamin E may potentiate anti blood clotting action. One small trial demonstrated that vitamin E at 400 mg/day reduced blood concentration of the anti breast cancer drug tamoxifen. In multiple clinical trials, vitamin E lowered blood concentration of the immuno suppressant drug, cyclosporine A. 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.

During feeding experiments with rats Herbert McLean Evans concluded in 1922 that besides vitamins B and C, an unknown vitamin existed. Although every other nutrition was present, the rats were not fertile. This condition could be changed by additional feeding with wheat germ. It took several years until 1936 when the substance was isolated from wheat germ and the formula C29H50O2 was determined. Evans also found that the compound reacted like an alcohol and concluded that one of the oxygen atoms was part of an OH (hydroxyl) group. As noted in the introduction, the vitamin was given its name by Evans from Greek words meaning "to bear young" with the addition of the ol as an alcohol. The structure was determined shortly thereafter in 1938.