Beyond α-Tocopherol: A Review of Natural Vitamin E’s Therapeutic Potential in Human Health and Disease: Part I
A widely reported meta-analysis, published in the Annals of Internal Medicine in 2005, found that, while doses of vitamin E < 200 IU had no negative effects, high-dose vitamin E, defined as ≥ 400 IU per day, resulted in a small but significant (4%) increase in all-cause mortality. Despite the uncritical press coverage given this meta-analysis, the conclusions promulgated are not only highly misleading regarding true vitamin E, but insupportable for a number of reasons discussed in this article. In addition to several methodological failings not only within the studies themselves, but in the choice of studies for review, the key issue is that (primarily synthetic) α-tocopherol was used, not the full complement of isomers that constitute vitamin E. Given alone, high dose α-tocopherol may become a pro-oxidant, dysregulate key detoxification enzymes and immune function, and promote inflammation. A negative result is the logical outcome of anything other than short-term high dose α-tocopherol supplementation. However, a robust and rapidly growing body of current research, discussed in here and in Part II of this article, indicates that supplementation with natural vitamin E (i.e., mixed tocopherols and tocotrienols) is not only safe, but offers significant therapeutic potential for human health.
Part I: In Defense of Vitamin E
Meta-Analysis Suggesting Vitamin E Increases All-Cause Mortality is, Itself, Fatally Flawed
A highly flawed, but widely reported meta-analysis, published in the Annals of Internal Medicine in 2005, found that, while doses of vitamin E < 200 IU had no negative effects, high-dose vitamin E, defined as ≥ 400 IU per day, resulted in a small but significant (4%) increase in all-cause mortality.1
Reverberations of the media frenzy sparked by this announcement continue to foster doubt among clinicians and the public about, not only vitamin E's capacity to benefit human health, but whether vitamin E supplementation is even safe. The most recent research, which this article will review, comprises a robust and rapidly growing body of data that indicates both vitamin E's significant therapeutic potential for human health and the safety of supplementation with natural vitamin E (i.e., mixed tocopherols and tocotrienols).
Despite the uncritical press coverage given to the 2005 Annals of Internal Medicine meta-analysis, the conclusions promulgated are not only highly misleading regarding true vitamin E, but insupportable for numerous reasons, including the following:
Vitamin E was not used
Most importantly, the clinical trials pooled for this study used only a single vitamin E isomer. Vitamin E, as found naturally in foods, is a family of eight structurally unique compounds (four tocopherols: α-, β-, γ-, δ- tocopherol and four tocotrienols: α-, β-, γ-, δ-tocotrienol), each of which has unique as well as complimentary biological actions. The clinical trials included in this meta-analysis, and virtually all research done on vitamin E until recently, have used only one fraction, α-tocopherol.
The authors reviewed 19 previously published clinical trials in which participants took α-tocopherol in doses ranging from 16.5 to 2,000 IU/day, either alone or, in the case of 61% of study participants, in combination with other vitamins and/or minerals. In addition, natural α-tocopherol was used only in the high-dose group in one trial, the HOPE study; all others used synthetic α-tocopherol.2
Synthetic α-tocopherol differs significantly from natural α-tocopherol
All natural vitamin E tocopherols are found in the RRR form (they have a saturated 16-carbon phytyl side chain with three chiral centers at carbons 2, 20 and 80, all of which are in the R configuration). Synthetic α-tocopherol is a mixture of 8 stereoisomers (molecules with the same molecular formula and same sequence of bonds but different spatial arrangements), only one of which has the same spatial arrangement as naturally occurring RRR α-tocopherol. Not only are the other seven stereoisomers not found in any food (i.e., they are new-to-nature, unnatural molecules), the racemic form (containing equal amounts of dextrorotatory and levorotatory molecules) in which they appear is potentially antagonistic to natural RRR α-tocopherol.3
In light of this fact, it is worth noting that only the RRR stereoisomer is biologically active (i.e., capable of affecting membrane-resident enzymes and cellular signaling). Synthetic α-tocopherol (properly referred to as all-rac-α-tocopherol since it is all racemic) may function as an antioxidant, but is composed of 7/8 (87.5%) otherwise non-biologically active compound.3
Of the ∼120 primary research studies published from 1973-2007 assessing vitamin E's (α-tocohperol's) effects in lipid structures (e.g., lipoproteins, cell membranes), 25% used natural RRR-α-tocopherol, 25% used all-racemic α-tocopherol, and the remaining 50% did not identify the form used. None used natural vitamin E containing the full complement of tocopherols and tocotrienols.4
Evidence is accumulating that vitamin E -- the entire family of inter-related tocopherols and tocotrienols – is involved in a myriad of other significant activities besides protecting polyunsaturated lipids by serving as chain-breaking inhibitors of lipid peroxidation. In addition to their antioxidant activities within HDL and LDL cholesterol, tocopherols reside in the lipid bilayers of cell membranes where they not only serve as antioxidants, but affect membrane-resident enzymes and other membrane-dependent cell signaling processes.5
Key Issues Resulting from the Use of High Dose (Primarily Synthetic) α-Tocopherol
α-tocopherol alone decreases plasma γ-tocopherol and can become a pro-oxidant
Key issues resulting from the use of high doses of α-tocopherol include the fact that supplementation with α-tocopherol alone decreases plasma γ-tocopherol concentrations by 30-60%. It is also well documented that, in illnesses where endogenous antioxidants are decreased (i.e., all chronic conditions in which inflammation plays a key role), α-tocopherol may itself become a pro-oxidant.6
The result is an increase in oxidative stress that promotes a functional decrease in antioxidant capacity leading to a functional increase in inflammation.7
Supplementation with α-tocopherol alone may promote inflammation
γ-tocopherol is a more potent anti-inflammatory agent than α-tocopherol. γ-tocopherol traps reactive nitrogen species more effectively than α-tocopherol. Supplementation with γ-tocopherol, but not α-tocopherol, significantly lowers C-reactive protein concentrations in hemodialysis patients (from 4.4 to 2.1 mg/L; P < .02)., and triples PPARγ mRNA levels within 24 hours in human colon cancer cells, an increase twice that produced by α-tocopherol. (PPARγ is one of a family of transcription factors—the peroxisome proliferator-activated receptors—which act as anti-inflammatory mediators by interfering with inflammatory signaling cascades such as the NFκB pathway.)6
Both α- and γ-tocopherol modulate eicosanoid synthesis, but γ-tocopherol's influence is significantly stronger since γ-tocopherol is a much more potent inhibitor of cyclooxygenase and lipoxygenase than α-tocopherol. Under most inflammatory conditions, cyclooxygenase 2 (COX-2) is upregulated and is the primary enzyme responsible for the formation of the pro-inflammatory prostaglandin E2 (PGE2); 5-lipoxygenase (5-LOX) is the rate-limiting enzyme involved in the formation of the pro-inflammatory eicosanoid, leukotriene B4 (LTB4).
Because of the central roles of PGE2 and LTB4 in inflammation, COX-2 and 5-LOX have been key targets for drug therapy in inflammatory diseases. (Reiter E, Jiang Q, Christen S. Anti-inflammatory properties of a- and γ-tocopherol. Mol Aspects Med 28 (2007) 668-691.) γ-tocopherol has been shown to be much more effective in reducing COX-2 synthesis of PGE2 than α-tocopherol, and to significantly inhibit lipoxygenase formation of LTB4, in contrast to α-tocopherol, which has no effect.8
Not only is γ-tocopherol more effective in inhibiting inflammation-associated disease than α-tocopherol, but, as noted above, supplementation with α-tocopherol alone significantly decreases γ-tocopherol levels, thus potentially increasing inflammation.
Supplementation with α-tocopherol alone may dysregulate key detoxification enzymes and immune function
Supplementation with high doses of α-tocopherol alone may also dysregulate the induction of key xenobiotic metabolizing enzymes and immune function
High dose α-tocopherol increases the expression of several cytochrome P450 (CYP) enzymes. In addition to metabolizing vitamin E, the hepatic CYP enzyme system is responsible for the Phase I metabolism of numerous endogenous and exogenous compounds, including the majority of pharmaceutical drugs.9 Specifically, members of the CYP3A, CYP2B, and CYP2C subfamilies are responsible for the metabolism of most pharmaceutical drugs.10 The CYP3A subfamily alone is responsible for the metabolism of 50% of all pharmaceutical drugs.11
While some compounds are completely detoxified by Phase I, the majority are altered into "activated intermediates" more toxic than the original compound, which are then detoxified by Phase II enzymes.
High doses of α-tocopherol, which have been shown to upregulate CYP3A, CYP2B, and CYP2C (as well as P-glycoprotein, which is involved in biliary xenobiotic excretion) in animal models, may thus not only alter drug efficacy, but produce a significant increase in highly toxic activated intermediate compounds.9 12
In humans, high doses of α-tocopherol have been shown to exacerbate respiratory infections in the elderly and to attenuate the protective increase in HDL with simvastatin plus niacin.13 While the reasons for these adverse effects are not yet clear, researchers have proposed they may be due to imbalances resulting from high dose α-tocopherol, which significantly depresses plasma, and eventually tissue concentrations, of γ-tocopherol and also inhibits protein kinase C (PKC), an important signaling pathway for the regulation of inflammation related to immune function as well as other processes. High doses of γ-tocopherol do not have these effects.6
α-tocopherol may become a pro-oxidant
As noted above, another major concern regarding the use of α-tocopherol alone is its potential to become a pro-oxidant. While α-tocopherol's ability to maintain cellular membrane integrity by quenching free radicals is well recognized, it becomes a tocopheryl radical in the process and must be reduced to restore its antioxidant capacity.
This reduction is primarily enabled by vitamin C, although coenzyme Q10 and reduced glutathione (GSSH) can serve as alternate reducing agents. When vitamin C reduces any of the tocopherols, it, in turn, is oxidized and must be regenerated. Two molecules of GSSH (which requires selenium and riboflavin [vitamin B2] to move through its own redox pathway) can restore vitamin C's antioxidant status, but this leaves two molecules of oxidized glutathione (GSSG), which must be converted back to GSSH via an electron-donation from NADPH, a niacin-containing complex.
In short, it's a relay team effort in which depletion or absence of any team player decreases the cell's capacity to reduce the tocopherol radical, which will, as a result, increase, increasing oxidative stress.2
Negative outcomes are a logical result of high dose (primarily synthetic) α-tocopherol supplementation
Given the above issues, it is clear that the use of high dose α-tocopherol could account for the non-significant increase in mortality reported in the widely publicized Annals of Internal Medicine 2005 meta-analysis. The SPACE trial, one of the studies included, exemplifies key reasons why.
Subjects in the SPACE trial not only had cardiovascular disease, but were on hemodialysis for end-stage renal failure. A prior study of dialysis patients with end-stage renal disease had shown that supplementation with γ-enriched tocopherols, but not α-tocopherols, lowered median C-reactive protein (CRP) significantly (4.4 to 2.1 mg/L). Subjects in the SPACE trial had severe end-stage renal failure, yet even in patients with moderate renal failure, total GSSH and plasma glutathione peroxidase activity have been shown to be significantly lowered.14 These patients were already depleted of the endogenous antioxidants needed to reduce high doses of α-tocopherol.
Finally, as previously noted, supplementing with α-tocopherol alone significantly reduces γ-tocopherol, which also promotes an increase in inflammation and a concurrent reduction in antioxidant recycling capacity. Supplementation of healthy non-smokers with 400 IU/day RRR-α-tocopherol for a period of 2 months reduced serum γ-tocopherol concentrations an average of 58%, a finding consistent with other trials in which prior vitamin E supplement users had significantly lower serum γ-tocopherol than nonusers.15
Therefore, in the SPACE trial subjects, the logical outcome of high dose α-tocopherol supplementation would be decreased levels of γ-tocopherol, increasing levels of oxidized (pro-oxidant) α-tocopherol, and an escalation in oxidative stress.2
Annals of Internal Medicine 2005 Meta-analysis' Methodological Failings
In addition to the issues raised above concerning the use, not of true vitamin E, but (primarily synthetic) α-tocopherol, a number of methodological failings render the conclusions drawn in this meta-analysis highly suspect.
Heterogeneous populations and protocols
For meaningful results, a meta-analysis must analyze data that compares apples to apples, i.e., studies included should involve homogenous populations using similar study protocols. But the clinical trials pooled for this meta-analysis involved widely heterogeneous populations following highly divergent protocols. Subjects included individuals "at substantial 5-year risk of death from coronary heart disease, other occlusive arterial disease, or diabetes mellitus"; individuals being treated for hypertension; people with CVD who also had end-stage renal failure and were on dialysis; subjects with age-related cataracts; Alzheimer's; Parkinson's; and recent history of bowel adenoma. It's worth noting that all these conditions involve significant inflammation, which would deplete endogenous antioxidants, increasing the likelihood of α-tocopherol becoming a pro-oxidant.2
As noted earlier, 61% of the subjects in these studies were given α-tocopherol in conjunction with other supplements. While nutrients can work synergistically together (e.g., the relay team needed to restore α-tocopherol's antioxidant capacity), an excessively high dose of one biologically active compound can disrupt the balance necessary for normal function. Perhaps the most blatant example of the potential such imbalance has to impact study outcomes is the Age-Related Eye Disease Study (AREDS) clinical trial, which comprised 18% of the total high-dose "vitamin E" participants in the meta-analysis.
AREDs subjects were given 400 IU of "vitamin E" (synthetic α-tocopherol), 500 mg vitamin C, 15 mg beta-carotene, 80 mg of zinc, and 2 mg copper per day. Not only did this regimen include a dose of zinc that is twice the upper limit (UL) of safety for zinc, but in addition to depressing immunity, excessive zinc consumption can cause copper deficiency. Copper was given as cupric oxide, a form in which it is insoluble and thus unable to be absorbed, but even had it been absorbed, the dose was so low it could not have begun to remediate the loss caused by such an excessively high dose of zinc. This inappropriate supplementation could, by itself, account for the non-significant increase in mortality in the AREDs trial.2
Synthetic beta-carotene, used in 4 of the high-dose trials, could also have contributed. Synthetic beta-carotene is not structurally the same as naturally occurring beta-carotene and, as the Finnish smokers study clearly demonstrated, can have adverse effects.2 16
When the risk of all-cause mortality noted in Annals of Internal Medicine 2005 meta-analysis was reviewed17 in terms of "vitamin E" (α-tocopherol) dose and adjusted for other vitamin and mineral supplements, it was found that the increased risk of death was only statistically significant at a dose of 2,000 IU/day, which is double the adult UL (tolerable upper intake level) for α-tocopherol established by the Food and Nutrition Board for the Institute of Medicine. According to the Board, 1,000 mg/day of α-tocopherol, whether synthetic or natural (equivalent to 1,500 IU/day of RRR-α-tocopherol or 1,100 IU/day of all-rac-α-tocopherol), would be the highest dose unlikely to result in hemorrhage in almost all adults.18
Finally, three other recent meta-analyses combining the results of randomized controlled trials designed to evaluate the efficacy of vitamin E supplementation for the prevention or treatment of cardiovascular disease found no evidence that vitamin E (α-tocopherol) supplementation up to 800 IU/day significantly increased or decreased cardiovascular disease mortality or all-cause mortality.19 20 21
Epidemiological Data Consistently Finds Dietary Vitamin E Beneficial
Epidemiological findings regarding dietary intake of vitamin E—i.e., regular intake of the full complement of tocopherols and tocotrienols—have been unanimously positive.
A substantial body of epidemiologic evidence links dietary intake of vitamin E with reduced risk of coronary disease. The largest studies include:
The Nurses' Health Study, involving 87,245 female nurses who were followed for 8 years, in which relative risk (RR) of CHD was found to be 0.66 for women in the highest quintile of vitamin E intake compared with those in the lowest.22
The Health Professionals' Follow-up Study, involving 39,910 men followed for 4 years, which revealed a similar risk reduction. RR of CHD was 0.64 among men in the highest quintile of dietary vitamin E intake compared to those in the lowest quintile.23
A Finnish longitudinal population study, which revealed a substantial inverse association between vitamin E derived from food and coronary mortality. In this 14-year prospective study of 5,133 healthy individuals, RR was 0.68 for men and 0.34 for women in the highest compared to the lowest tertile of dietary vitamin E intake.24
The Alpha-Tocopherol, Beta-Carotene Cancer Prevention study, in which, among the 29,092 Finnish men participating, those in the highest compared with the lowest quintile of serum α-tocopherol at baseline had significantly lower incidences of total and cause-specific mortality. Men in the highest quintile of serum α-tocopherol had a RR of 0.82 for total mortality, and 0.79, 0.81, and 0.70 for deaths due to cancer, cardiovascular disease, and other causes, respectively. Since only 10% of participants reported vitamin E supplement use, and this was adjusted for as a confounding factor, serum concentrations of α-tocopherol served as an indirect measure of full vitamin E status, reflecting dietary intake, i.e., mixed tocopherols and tocotrienols.25
The Iowa Women's Study, which followed 34,486 postmenopausal women for 7 years, also found that dietary vitamin E intake, but not supplemental "vitamin E" (i.e., α-tocopherol), was inversely associated with the risk of death from CHD. Women in the highest quintile of dietary vitamin E consumption had a RR of 0.38 compared to those in the lowest.26
The WHO/MONICA study, in which both the blood levels of RRR--tocopherol and the tocopherol/cholesterol ratio were inversely, and dramatically, correlated with mortality rates. Essential antioxidant plasma levels were determined in ~100 middle-aged men representing 16 European study populations, which differed six-fold in age-specific mortality from ischemic heart disease (IHD). Plasma cholesterol and blood pressure, both classical risk factors, lacked significant correlations to IHD mortality, but absolute levels of vitamin E (plasma α-tocopherol was used as a maker of vitamin E status) showed a strong inverse correlation (RR = 0.63). (Pre-supplementation, serum α-tocopherol serves as an indirect measure of full vitamin E status, whereas after high-dose supplementation with serum α-tocopherol alone, its serum levels may correlate with lowered levels of γ-tocopherol.)27
Type 2 Diabetes
A systematic review and meta-analysis identified 9 cohort studies examining the association between antioxidant intake and RR of diabetes. Pooled data incorporated 139,793 participants with a mean follow-up of 13 years. A 13% reduction in risk among those with the highest compared to the lowest antioxidant intake was attributed primarily to vitamin E.28
Three case-control studies from distinct countries (Yugoslavia, Greece, and Uruguay), each involving ~300 - 500 subjects, have noted inverse associations between dietary vitamin E and prostate cancer risk with statistically significant reductions of 40% or greater.29 30 31 32
A review of 37 prospective cohort and four intervention studies on potential dietary risk factors for prostate cancer indicates that a diet rich in vitamin E may play a protective role in the etiology of prostate cancer.33
Researchers randomly selected 100 incident prostate cancer case patients and matched 200 control subjects from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort of 29,133 Finnish men, 50-69 years old. Participants with higher circulating concentrations of α-tocopherol and γ-tocopherol, an indirect measure of consumption of vitamin E-rich foods, had a 51% and 43% lower risk, respectively, of prostate cancer. This suggests that α-tocopherol may provide significant benefit when properly balanced by the full complement of vitamin E isomers.34
Researchers involved in the Chicago Health and Aging Project examined whether food intakes of vitamin E, individual tocopherols or supplemental vitamin E (α-tocopherol) would protect against incidence of Alzheimer's disease and cognitive decline in 1,041 subjects > or=65 over a 6 year period. Higher dietary intake of vitamin E, but not supplemental "vitamin E" (α-tocopherol), was associated with a significant reduction in risk, specifically, a 26% reduction in risk (RR) per 5 mg/d increase in vitamin E intake. Dietary α-, γ-, and δ-tocopherols were each significantly and inversely associated with incidence of Alzheimer's disease, with RRs of 34% per 5 mg/d increase in α-tocopherol, 40% per 5 mg/d increase in γ-tocopherol, and 25% per 1 mg/d increase in δ-tocopherol.
Presenting this data, the researchers concluded, "These findings suggest that the combined intake of the tocopherol forms, particularly α-tocopherol equivalents (a measure of the relative biologic activity of tocopherols and tocotrienols), may be more important than α-tocopherol alone in the protective relations with Alzheimer disease and cognitive decline. This may explain the absence of association reported in some studies between Alzheimer's disease and use of vitamin E supplements, which have traditionally contained only α-tocopherol."35
The epidemiological research summarized above clearly indicates that this line of reasoning should not be limited to Alzheimer's disease, but extends to vitamin E's therapeutic potential in all forms of chronic degenerative disease and aging.
Why has the research been focused, not on natural vitamin E, but on α-tocopherol?
Vitamin E, first referred to as "Factor X," was discovered in 1922, by Evans and Bishop who found that diets lacking certain plant oils would support growth but not reproduction in rats. In 1936, α-tocopherol (from the Greek "tokos" meaning "offspring" and "phero" meaning “to bear" because its presence was necessary to prevent rat fetal resorption), was isolated from wheat germ oil.36 37
Since then the biological activity of vitamin E has traditionally been determined using the rat fetal resorption assay, and α-tocopherol has been considered the most bioactive vitamin E isoform in humans. Why?
α-tocopherol has the highest concentrations in plasma
One reason is that α- tocopherol has the highest plasma concentrations of all the vitamin E isomers in humans. This is largely due to the fact that transport mechanisms within the body display significant preference for α-tocopherol.3
Along with dietary fat, the vitamin E isomers are taken up without preference by the intestine and secreted in chylomicron particles together with triacylglycerol and cholesterol. Lipoprotein lipase–mediated catabolism of chylomicron particles results in some chylomicron-bound vitamin E being transported to muscle, adipose and brain tissue, while the remaining chylomicron remnants go to the liver, where α-tocopherol is selectively differentiated from the other vitamin E isomers by α-tocopherol transfer protein (α-TTP) and used to enrich very low density lipoproteins (VLDL). Subsequently, approximately half the VLDL is transformed to LDL, the major carrier for α-tocopherol in blood, enabling its further distribution throughout the body.38 39
The strong preference of α-TTP for α-tocopherol is demonstrated by the fact that α-TTP's affinities for β‐, γ‐, and δ-tocopherols and for α-tocotrienol are 38, 9, 2, and 11% of that for α-tocopherol.40 In addition, α-TTP has been shown to play a critical role in regulating plasma concentrations of vitamin E.3
γ-tocopherol concentration higher in tissues
γ-tocopherol represents 31% of the vitamin E stored in human adipose tissue, 38% in muscle tissue, and 53% in the skin. Such high tissue concentrations of γ-tocopherol are highly suggestive of the potential physiological importance of this under-investigated tocopherol.41
γ-tocopherol more prevalent as CEHC metabolite
However, in addition to incorporation in lipoproteins via α-TTP (the primary metabolic route for α-tocopherol), vitamin E isomers are also metabolized into products discovered in the 1980s: the family of carboxyethyl hydroxychromans (CEHCs). In humans, γ-tocopherol is significantly more prone to hepatic catabolism to its CEHC metabolite than α- tocopherol. Only 1–3% of ingested α-tocopherol appears in the human urine as α-CEHC, and the concentration of α-CEHC in serum is a striking 1000-fold lower than the α-tocopherol. In contrast, γ-tocopherol is metabolized into its CEHC metabolite three times more rapidly than α-tocopherol, and ~50% of ingested γ-tocopherol is eliminated as γ-CEHC.40
Also of interest is the fact that high-dose administration of α-tocopherol has been reported to increase γ-tocopherol metabolism into γ-CEHC. This may be one reason for the drop in plasma γ-tocopherol seen with high-dose α-tocopherol.15
Protective biological actions of γ-CEHC metabolites
These differences in the body's utilization of vitamin E isomers suggest that γ-tocopherol plays physiological roles for which transformation to its CEHC metabolite is not a mechanism for disposal of unnecessary vitamin E forms, but a bio-activation process.
In support of this hypothesis, exploration of the biological activities of CEHC metabolites in cell cultures have shown that γ-CEHC inhibits COX‐2 activity.38 In animal models, γ-CEHC has demonstrated protective effects against metal-induced nephrotoxicity, indicating γ-CEHC has antioxidant capacities. In cancer cell lines, γ-CEHC has been shown to exert much stronger anti-proliferative activity than α-CEHC, via inhibition of cyclin signaling causing subsequent cell cycle arrest. Furthermore, hypomethylated forms of tocotrienols, which are extensively metabolized to CEHCs, are more effective anti-proliferative agents than tocopherols in different cancer cell lines.40
Is α-tocopherol a more powerful antioxidant?
A second reason α-tocopherol has been considered the key vitamin E isomer is that it is a more potent chain-breaking antioxidant for inhibiting lipid peroxidation. The tocopherols' capacity to neutralize reactive oxygen species (ROS) is rooted in their ability to donate phenolic hydrogens (electrons) to lipid radicals, and a-tocopherol has one more electron-donating methyl groups on the chromanol ring than γ-tocopherol.
However, γ-tocopherol's unsubstituted C-5 position makes it better able to trap lipophilic electrophiles, such as reactive nitrogen oxide species (RNOS), whose excessive generation is associated with chronic inflammation-related diseases such as cancer, CVD, and neurodegenerative disorders.38
In addition, recent in vitro and in vivo studies have suggested that tocotrienols are much more potent antioxidants in preventing breast cancer initiation due to E2 epoxidation. E2 (17 β-estradiol) can be activated by epoxide-forming oxidants, gaining the ability to bind to DNA and form DNA adducts that may cause mutation leading to carcinogenesis. While γ-tocotrienol was most effective, reducing formation of E2 epoxide to near zero, α-tocotrienol and δ-tocotrienol were also far superior to α-tocopherol against the oxidative formation of E2 epoxide.44
A growing body of research indicates that not only has supplementation with α-tocopherol been ineffective in reducing risk of cardiovascular disease and cancer, but the use of high-dose α-tocopherol alone may result in a decrease in antioxidant capacity and exacerbation of inflammation, due to deleterious imbalances resulting from a corresponding lack of other bioactive vitamin E isomers. The complementary therapeutic actions of all 8 vitamin E isomers are discussed in Part II of this review.
Miller ER, 3rd, Pastor-Barriuso R, Dalal D, et al. Meta-Analysis: high-dosage Vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005 Jan 4; 142(1):37-46. Epub 2004 Nov 1. ↑
Pizzorno J, Neustadt J. Commentary: vitamin E & all cause mortality. IMCJ. 4(1): February/March 2005, p. 14-17. ↑
Sylvester PW. Vitamin E and apoptosis. Vitam Horm. 2007;76:329-56.Review. ↑
Atkinson J, Epand R, Epand R. Tocopherols and tocotrienols in membranes: a critical review. Free Rad Biol & Med. 44(2008)739-764. ↑
Atkinson J, Epand R, Epand R. Tocopherols and tocotrienols in membranes: a critical review. Free Rad Biol & Med. 44(2008)739-764. ↑
Reiter E, Jiang Q, Christen S. Anti-inflammatory properties of a- and γ-tocopherol. Mol Aspects Med . 28 (2007) 668-691. ↑
Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. J Nutr. 1985;115(6):807-813. ↑
Jiang Q, Ames BN. Gamma-tocopherol, but not alpha-tocopherol, decreases proinflammatory eicosanoids and inflammation damage in rats. FASEB J. 2003 May;17(8):816-22. ↑
Mustacich D, Bruno R, Traber M. Vitamin E. Vitam Horm . 2007;76:1-21.Review. ↑
Guengerich FP. Cytochromes P450, drugs, and diseases. Mol Interv. 2003 Jun;3(4):194-204. ↑
Kliewer, S. A., Goodwin, B., Willson, T. M. The nuclear pregnane X receptor: A key regulator of xenobiotic metabolism. Endocr. Rev. 2002 Oct;23(5):687-702. ↑
Mustacich DJ, Leonard SW, Devereaux MW, et al. Alpha-tocopherol regulation of hepatic cytochrome P450s and ABC transporters in rats. Free Radic Biol Med. 2006 Oct 1;41(7):1069-78. ↑
Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001 Nov 29;345(22):1583-92. ↑
Ceballos-Picot I, Witko-Sarsat V, Merad-Boudia M, et al. Glutathione antioxidant system as a marker of oxidative stress inchronic renal failure. Free Rad Biol Med. 1996;21(6):845-853. ↑
Huang HY, Appel LJ. Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans. J Nutr. 2003 Oct;133(10):3137-40. ↑
The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. N Engl J Med. 1994 Apr 14;330(15):1029-35. ↑
Linus Pauling Institute, Oregon State University. Vitamin E, Safety, Vitamin E supplementation and all-cause mortality. ↑
Food and Nutrition Board, Institute of Medicine. Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington D.C.: National Academy Press. 2000:186-283. ↑
Shekelle PG, Morton SC, Jungvig LK, et al. Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen Intern Med. 2004;19(4):380-389. ↑
Eidelman RS, Hollar D, Hebert PR, et al. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med. 2004;164(14):1552-1556. ↑
Vivekananthan DP, Penn MS, Sapp SK, et al. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361(9374):2017-2023. ↑
Stampfer MJ, Hennekens CH, Manson JE, et al. E consumption and the risk of coronary disease in women. N Engl J Med . 1993;328:1444–9. ↑
Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med . N Engl J Med . ↑
Knekt P, Reunanen A, Jarvinen R, et al. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol . 1994;139:1180–9. ↑
Wright ME, Lawson KA, Weinstein SJ, et al. Higher baseline serum concentrations of vitamin E are associated with lower total and cause-specific mortality in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Am J Clin Nutr. 2006 Nov;84(5):1200-7. ↑
Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med . 1996;334:115–62. ↑
Gey KF, Puska P, Jordan P, et al. Inverse correlation between plasma vitamin E and mortality from ischemic heart disease in cross-cultural epidemiology. Am. J. Clin. Nutr. 53 (1991), pp. 326S–334S. ↑
Hamer M, Chida Y. Intake of fruit, vegetables, and antioxidants and risk of type 2 diabetes: systematic review and meta-analysis. J Hypertens. 2007 Dec;25(12):2361-9. ↑
Chan JM, Giovannucci EL. Vegetables, fruits, associated micronutrients, and risk of prostate cancer. Epidemiol Rev. 2001;23(1):82-6. Review. ↑
Vlajinac HD, Marinkovic JM, Ilic MD, et al. Diet and prostate cancer: a case-control study. Eur J Cancer . 1997;33:101-7. ↑
Deneo-Pellegrini H, De Stefani E, Ronco A, et al. Foods, nutrients and prostate cancer: a case-control study in Uruguay. Br J Cancer . 1999;80:591-7. ↑
Tzonou A, Signorello LB, Lagiou P, et al. Diet and cancer of the prostate: a case-control study in Greece. Int J Cancer . 1999,80:704-8. ↑
Dagnelie PC, Schuurman AG, Goldbohm RA, et aL. Diet, anthropometric measures and prostate cancer risk: a review of prospective cohort and intervention studies. BJU Int. 2004 May;93(8):1139-50. ↑
Weinstein SJ, Wright ME, Pietinen P, et al. Serum alpha-tocopherol and gamma-tocopherol in relation to prostate cancer risk in a prospective study. J Natl Cancer Inst. 2005 Mar 2;97(5):396-9. ↑
Morris MC, Evans DA, Tangney CC, et al. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. Am J Clin Nutr. 2005 Feb;81(2):508-14. ↑
Evans HM, Bishop KS. On the existence of a hitherto unrecognized dietary factor essential for reproduction. Science. 1922 Dec 8;56(1458):650-651. ↑
Bell EF. History of vitamin E in infant nutrition. Am J Clin Nutr. 1987 Jul;46(1 Suppl):183.6. ↑
Jiang Q, Christen S, Shigenaga M, Ames B. γ-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74:714–22. ↑
Kline K, Lawson K, Yu W et al. Vitamin E and cancer. Vitam Horm. 2007;76:435-61. Review. ↑
Galli F, Cristina Polidori M, Stahl W, et al. Vitamin E biotransformation in humans. Vitam Horm. 2007;76:263-80. Review. ↑
Saldeen K, Saldeen T. Importance of tocopherols beyond a-tocopherol: evidence from animal and human studies. Nutrition Research . 25 (2005) 877–889. ↑
Campbell SE, Stone WL, Lee S, et al. Comparative effects of RRR-alpha- and RRR-gamma-tocopherol on proliferation and apoptosis in human colon cancer cell lines. BMC Cancer. 2006 Jan 17;6:13. ↑
Hensley K, Benaksas EJ, Bolli R, et al. New perspectives on vitamin E: gamma-tocopherol and carboxyelthylhydroxychroman metabolites in biology and medicine. Free Radic Biol Med. 2004 Jan 1;36(1):1-15. ↑
Fu-Li Y, Gapor A, Bender W. Evidence for the preventive effect of the polyunsaturated phytol side chain in tocotrienols on 17β-estradiol epoxidation. Cancer Detection and Prevention . 29 (2005) 383–388. ↑
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Lara Pizzorno is a member of the American Medical Writers Association with 25+ years of experience writing for physicians and the public, Lara is Editor for Longevity Medicine Review as well as Senior Medical Editor for SaluGenecists, Inc. Read more...
Lara Pizzorno, MDiv, MA, LMT
John Morgenthaler has been active in the field of nutritional medicine since 1986. Today, John travels the world looking for breakthrough nutraceuticals and anti-aging therapies. He also continues to publish cutting-edge nutrition and medical science books and periodicals. Read more...
John Morgenthaler, Publisher