Vitamin E Abstracts 2

© 2012

Opinion on mixed tocopherols, tocotrienol tocopherol and tocotrienols

            (European Food Safety Authority 2008) Download

Vitamin E tocotrienols: life beyond tocopherols

            (Aggarwal and Nesaretnam 2012) Download

High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability

            (Bailey, Dehnert et al. 2010) Download

High altitude (HA)-induced pulmonary hypertension may be due to a free radical-mediated reduction in pulmonary nitric oxide (NO) bioavailability. We hypothesised that the increase in pulmonary artery systolic pressure (PASP) at HA would be associated with a net transpulmonary output of free radicals and corresponding loss of bioactive NO metabolites. Twenty-six mountaineers provided central venous and radial arterial samples at low altitude (LA) and following active ascent to 4559 m (HA). PASP was determined by Doppler echocardiography, pulmonary blood flow by inert gas re-breathing, and vasoactive exchange via the Fick principle. Acute mountain sickness (AMS) and high-altitude pulmonary oedema (HAPE) were diagnosed using clinical questionnaires and chest radiography. Electron paramagnetic resonance spectroscopy, ozone-based chemiluminescence and ELISA were employed for plasma detection of the ascorbate free radical (A(.-)), NO metabolites and 3-nitrotyrosine (3-NT). Fourteen subjects were diagnosed with AMS and three of four HAPE-susceptible subjects developed HAPE. Ascent decreased the arterio-central venous concentration difference (a-cv(D)) resulting in a net transpulmonary loss of ascorbate, alpha-tocopherol and bioactive NO metabolites (P < 0.05 vs. LA). This was accompanied by an increased a-cv(D) and net output of A(.-) and lipid hydroperoxides (P < 0.05 vs. sea level, SL) that correlated against the rise in PASP (r = 0.56-0.62, P < 0.05) and arterial 3-NT (r = 0.48-0.63, P < 0.05) that was more pronounced in HAPE. These findings suggest that increased PASP and vascular resistance observed at HA are associated with a free radical-mediated reduction in pulmonary NO bioavailability.

Unleashing the untold and misunderstood observations on vitamin E

            (Gee 2011) Download

Paradoxically, meta-analysis of human randomized controlled trials revealed that natural but not synthetic alpha-tocopherol supplementation significantly increases all-cause mortality at 95% confidence interval. The root cause was that natural alpha-tocopherol supplementation significantly depressed bioavailability of other forms of vitamin E that have better chemo-prevention capability. Meta-analysis outcome demonstrated flaws in the understanding of vitamin E. Reinterpretation of reported data provides plausible explanations to several important observations. While alpha-tocopherol is almost exclusively secreted in chylomicrons, enterocytes secrete tocotrienols in both chylomicrons and small high-density lipoproteins. Vitamin E secreted in chylomicrons is discriminately repacked by alpha-tocopherol transfer protein into nascent very low-density lipoproteins in the liver. Circulating very low-density lipoproteins undergo delipidation to form intermediate-density lipoproteins and low-density lipoproteins. Uptake of vitamin E in intermediate-density lipoproteins and low-density lipoproteins takes place at various tissues via low-density lipoproteins receptor-mediated endocytosis. Small high-density lipoproteins can deliver tocotrienols upon maturation to peripheral tissues independent of alpha-tocopherol transfer protein action, and uptake of vitamin E takes place at selective tissues by scavenger receptor-mediated direct vitamin E uptake. Dual absorption pathways for tocotrienols are consistent with human and animal studies. alpha-Tocopherol depresses the bioavailability of alpha-tocotrienol and has antagonistic effect on tocotrienols in chemo-prevention against degenerative diseases. Therefore, it is an undesirable component for chemo-prevention. Future research directions should be focused on tocotrienols, preferably free from alpha-tocopherol, for optimum chemo-prevention and benefits to mankind.

Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans

            (Huang and Appel 2003) Download

Despite promising evidence from in vitro experiments and observational studies, supplementation of diets with alpha-tocopherol has not reduced the risk of cardiovascular disease and cancer in most large-scale clinical trials. One plausible explanation is that the potential health benefits of alpha-tocopherol supplements are offset by deleterious changes in the bioavailability and/or bioactivity of other nutrients. We studied the effects of supplementing diets with RRR-alpha-tocopheryl acetate (400 IU/d) on serum concentrations of gamma- and delta-tocopherol in a randomized, placebo-controlled trial in 184 adult nonsmokers. Outcomes were changes in serum concentrations of gamma- and delta-tocopherol from baseline to the end of the 2-mo experimental period. Compared with placebo, supplementation with alpha-tocopherol reduced serum gamma-tocopherol concentrations by a median change of 58% [95% CI = (51%, 66%), P < 0.0001], and reduced the number of individuals with detectable delta-tocopherol concentrations (P < 0.0001). Consistent with trial results were the results from baseline cross-sectional analyses, in which prior vitamin E supplement users had significantly lower serum gamma-tocopherol than nonusers. In view of the potential benefits of gamma- and delta-tocopherol, the efficacy of alpha-tocopherol supplementation may be reduced due to decreases in serum gamma- and delta-tocopherol levels. Additional research is clearly warranted.

Cancer-preventive activities of tocopherols and tocotrienols

            (Ju, Picinich et al. 2010) Download

The cancer-preventive activity of vitamin E has been studied. Whereas some epidemiological studies have suggested a protective effect of vitamin E against cancer formation, many large-scale intervention studies with alpha-tocopherol (usually large doses) have not demonstrated a cancer-preventive effect. Studies on alpha-tocopherol in animal models also have not demonstrated robust cancer prevention effects. One possible explanation for the lack of demonstrable cancer-preventive effects is that high doses of alpha-tocopherol decrease the blood and tissue levels of delta-tocopherols. It has been suggested that gamma-tocopherol, due to its strong anti-inflammatory and other activities, may be the more effective form of vitamin E in cancer prevention. Our recent results have demonstrated that a gamma-tocopherol-rich mixture of tocopherols inhibits colon, prostate, mammary and lung tumorigenesis in animal models, suggesting that this mixture may have a high potential for applications in the prevention of human cancer. In this review, we discuss biochemical properties of tocopherols, results of possible cancer-preventive effects in humans and animal models and possible mechanisms involved in the inhibition of carcinogenesis. Based on this information, we propose that a gamma-tocopherol-rich mixture of tocopherols is a very promising cancer-preventive agent and warrants extensive future research.

Going to altitude? Bring your vitamins!

            (Lundby 2010) Download

Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality

            (Miller, Pastor-Barriuso et al. 2005) Download

BACKGROUND: Experimental models and observational studies suggest that vitamin E supplementation may prevent cardiovascular disease and cancer. However, several trials of high-dosage vitamin E supplementation showed non-statistically significant increases in total mortality. PURPOSE: To perform a meta-analysis of the dose-response relationship between vitamin E supplementation and total mortality by using data from randomized, controlled trials. PATIENTS: 135,967 participants in 19 clinical trials. Of these trials, 9 tested vitamin E alone and 10 tested vitamin E combined with other vitamins or minerals. The dosages of vitamin E ranged from 16.5 to 2000 IU/d (median, 400 IU/d). DATA SOURCES: PubMed search from 1966 through August 2004, complemented by a search of the Cochrane Clinical Trials Database and review of citations of published reviews and meta-analyses. No language restrictions were applied. DATA EXTRACTION: 3 investigators independently abstracted study reports. The investigators of the original publications were contacted if required information was not available. DATA SYNTHESIS: 9 of 11 trials testing high-dosage vitamin E (> or =400 IU/d) showed increased risk (risk difference > 0) for all-cause mortality in comparisons of vitamin E versus control. The pooled all-cause mortality risk difference in high-dosage vitamin E trials was 39 per 10,000 persons (95% CI, 3 to 74 per 10,000 persons; P = 0.035). For low-dosage vitamin E trials, the risk difference was -16 per 10,000 persons (CI, -41 to 10 per 10,000 persons; P > 0.2). A dose-response analysis showed a statistically significant relationship between vitamin E dosage and all-cause mortality, with increased risk of dosages greater than 150 IU/d. LIMITATIONS: High-dosage (> or =400 IU/d) trials were often small and were performed in patients with chronic diseases. The generalizability of the findings to healthy adults is uncertain. Precise estimation of the threshold at which risk increases is difficult. CONCLUSION: High-dosage (> or =400 IU/d) vitamin E supplements may increase all-cause mortality and should be avoided.

Very-high-dose alpha-tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke-prone spontaneously hypertensive rats

            (Miyamoto, Shiozaki et al. 2009) Download

Tocopherols and tocotrienols constitute the vitamin E family. Although alpha-tocotrienol is the most neuroprotective form of vitamin E proved to be effective against stroke, alpha-tocopherol is the most abundant in nature and is used most often for disease prevention/treatment. A recent metaanalysis of human studies suggested that alpha-tocopherol supplementation increases all-cause mortality. Therefore, we investigated the effects of alpha-tocopherol ( approximately 44 mg/kg body weight; equivalent to 2,600 mg/human/day) on the central nervous system (CNS) of stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP treated with high dose alpha-tocopherol had significantly higher blood pressure than untreated controls fed a basal diet that contained approximately 4 mg tocopherols/kg body weight, but neither group experienced a change in degree of lipid peroxidation in serum or CNS tissue. Biochemical/immunohistochemical analyses demonstrated that expressions of phosphorylated neurofilament H protein, glial fibrillary acidic protein and cathepsin D in the CNS tissue were significantly enhanced in alpha-tocopherol-supplemented rats, whereas expressions of SOD2 and Bcl-xL were diminished in response to alpha-tocopherol supplementation. Similarly, the frequency of cathepsin D-positive cells, corresponding mostly to microglial cells, was significantly increased in alpha-tocopherol-supplemented rats. Alpha-tocopherol supplementation also increased the number of lysosomes and lipofuscin granules in perikarya of both hippocampal pyramidal and Purkinje cells. Furthermore, alpha-tocopherol supplementation increased the frequency of glial filaments and lipofuscin granules in astrocytes and lysosomes in microglial cells that were frequently occupied with phagocytosed inclusion structures. The present results are the first to suggest that a very high dose of alpha-tocopherol supplementation increases blood pressure in SHRSP rats and influences the CNS tissue in a manner that seems adverse.

alpha-Tocopherol increased nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats

            (Newaz, Nawal et al. 1999) Download

Antioxidant protection provided by different doses of alpha-tocopherol was compared by determining nitric oxide synthase (NOS) activity in blood vessels of spontaneously hypertensive rats (SHR) treated with alpha-tocopherol. SHR were divided into four groups namely hypertensive control (C), treatment with 17 mg of alpha-tocopherol/kg diet (alpha1), 34 mg of alpha-tocopherol/kg diet (alpha2), and 170 mg of alpha-tocopherol/kg diet (alpha3). Wister Kyoto (WKY) rats were used as normal control (N). Blood pressure were recorded from the tail by physiography every other night for the duration of the study period of 3 months. At the end of the trial, animals were sacrificed. The NOS activity in blood vessels was measured by [3H]arginine radioactive assay and the nitrite concentration in plasma by spectrophotometry at wavelength 554 nm using Greiss reagent. Analysis of data was done using Student's t test and Pearson's correlation. The computer program Statistica was used for all analysis. Results of our study showed that for all the three alpha-tocopherol-treated groups, blood pressure was significantly (P < .001) reduced compared to the hypertensive control and maximum reduction of blood pressure was shown by the dosage of 34 mg of alpha-tocopherol/kg diet (C: 209.56 +/- 8.47 mm Hg; alpha2: 128.83 +/- 17.13 mm Hg). Also, NOS activity in blood vessels of SHR was significantly lower than WKY rats (N: 1.54 +/- 0.26 pmol/mg protein, C: 0.87 +/- 0.23 pmol/mg protein; P < .001). Although alpha-tocopherol in doses of alpha1, alpha2, and alpha3 increased the NOS activity in blood vessels, after treatment only that of alpha2 showed a statistical significance (P < .01). Plasma nitrite concentration was significantly reduced in SHR compared to normal WKY rats (N: 54.62 +/- 2.96 mol/mL, C: 26.24 +/- 2.14 mol/mL; P < .001) and accordingly all three groups showed significant improvement in their respective nitrite level (P < .001). For all groups, NOS activity and nitrite level showed negative correlation with blood pressure. It was significant for NOS activity in hypertensive control (r = -0.735, P = .038), alpha1 (r = -0.833, P = .001), and alpha2 (r = -0.899, P = .000) groups. For plasma nitrite, significant correlation was observed only in group alpha1 (r = -0.673, P = .016) and alpha2 (r = -0.643, P = .024). Only the alpha2 group showed significant positive correlation (r = 0.777, P = .003) between NOS activity and nitrite level. In conclusion it was found that compared to WKY rats, SHR have lower NOS activity in blood vessels, which upon treatment with antioxidant alpha-tocopherol increased the NOS activity and concomitantly reduced the blood pressure. There was correlation of lipid peroxide in blood vessels with NOS and nitric oxide, which implies that free radicals may be involved in the pathogenesis of hypertension.

Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon

            (Racasan, Braam et al. 2005) Download

The "programming hypothesis" proposes that an adverse perinatal milieu leads to adaptation that translates into cardiovascular disease in adulthood. The balance between nitric oxide (NO) and reactive oxygen species (ROS) is disturbed in cardiovascular diseases, including hypertension. Conceivably, this balance is also disturbed in pregnancy, altering the fetal environment; however, effects of perinatal manipulation of NO and ROS on adult blood pressure (BP) are unknown. In spontaneously hypertensive rats (SHR), NO availability is decreased and ROS are increased compared with normotensive Wistar-Kyoto rats, and, despite the genetic predisposition, the perinatal environment can modulate adult BP. Our hypothesis is that a disturbed NO-ROS balance in the SHR dam persistently affects BP in her offspring. Dietary supplements, which support NO formation and scavenge ROS, administered during pregnancy and lactation resulted in persistently lower BP for up to 48 wk in SHR offspring. The NO donor molsidomine and the superoxide dismutase mimic tempol-induced comparable effects. Specific inhibition of inducible nitric oxide synthase (NOS) reduces BP in adult SHR, suggesting that inducible NOS is predominantly a source of ROS in SHR. Indeed, inducible NOS inhibition in SHR dams persistently reduced BP in adult offspring. Persistent reductions in BP were accompanied by prevention of proteinuria in aged SHR. We propose that in SHR the known increase in ANG II type 1 receptor density during development leads to superoxide production, which enhances inducible NOS activity. The relative shortage of substrate and cofactors leads to uncoupling of inducible NOS, resulting in superoxide production, activating transcription factors that subsequently again increase inducible NOS expression. This vicious circle probably is perpetuated into adult life.

Tocotrienols: Vitamin E beyond tocopherols

            (Sen, Khanna et al. 2006) Download

In nature, eight substances have been found to have vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. Yet, of all papers on vitamin E listed in PubMed less than 1% relate to tocotrienols. The abundance of alpha-tocopherol in the human body and the comparable efficiency of all vitamin E molecules as antioxidants, led biologists to neglect the non-tocopherol vitamin E molecules as topics for basic and clinical research. Recent developments warrant a serious reconsideration of this conventional wisdom. Tocotrienols possess powerful neuroprotective, anti-cancer and cholesterol lowering properties that are often not exhibited by tocopherols. Current developments in vitamin E research clearly indicate that members of the vitamin E family are not redundant with respect to their biological functions. alpha-Tocotrienol, gamma-tocopherol, and delta-tocotrienol have emerged as vitamin E molecules with functions in health and disease that are clearly distinct from that of alpha-tocopherol. At nanomolar concentration, alpha-tocotrienol, not alpha-tocopherol, prevents neurodegeneration. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. An expanding body of evidence support that members of the vitamin E family are functionally unique. In recognition of this fact, title claims in manuscripts should be limited to the specific form of vitamin E studied. For example, evidence for toxicity of a specific form of tocopherol in excess may not be used to conclude that high-dosage "vitamin E" supplementation may increase all-cause mortality. Such conclusion incorrectly implies that tocotrienols are toxic as well under conditions where tocotrienols were not even considered. The current state of knowledge warrants strategic investment into the lesser known forms of vitamin E. This will enable prudent selection of the appropriate vitamin E molecule for studies addressing a specific need.

Precautions In The Use Of Alpha-Tocopherol In The Treatment Of Hypertensive Heart Disease

            (Shute 1949) Download

Chemopreventive Activity of Vitamin E in Breast Cancer: A Focus on gamma- and delta-Tocopherol

            (Smolarek and Suh 2011) Download

VITAMIN E CONSISTS OF EIGHT DIFFERENT VARIANTS: alpha-, beta-, gamma-, and delta-tocopherols (saturated phytyl tail) and alpha-, beta-, gamma-, and delta-tocotrienols (unsaturated phytyl tail). Cancer prevention studies with vitamin E have primarily utilized the variant alpha-tocopherol. To no avail, a majority of these studies focused on variant alpha-tocopherol with inconsistent results. However, gamma-tocopherol, and more recently delta-tocopherol, have shown greater ability to reduce inflammation, cell proliferation, and tumor burden. Recent results have shown that gamma-enriched mixed tocopherols inhibit the development of mammary hyperplasia and tumorigenesis in animal models. In this review, we discuss the possible differences between the variant forms, molecular targets, and cancer-preventive effects of tocopherols. We recommend that a gamma-enriched mixture, gamma- and delta-tocopherol, but not alpha-tocopherol, are promising agents for breast cancer prevention and warrant further investigation.

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

            (Viola, Pilolli et al. 2012) Download

The selective constraint of liver uptake and the sustained metabolism of tocotrienols (T3) demonstrate the need for a prompt detoxification of this class of lipophilic vitamers, and thus the potential for cytotoxic effects in hepatic and extra-hepatic tissues. Hypomethylated (gamma and delta) forms of T3 show the highest in vitro and in vivo metabolism and are also the most potent natural xenobiotics of the entire vitamin E family of compounds. These stimulate a stress response with the induction of detoxification and antioxidant genes. Depending on the intensity of this response, these genes may confer cell protection or alternatively they stimulate a senescence-like phenotype with cell cycle inhibition or even mitochondrial toxicity and apoptosis. In cancer cells, the uptake rate and thus the cell content of these vitamers is again higher for the hypomethylated forms, and it is the critical factor that drives the dichotomy between protection and toxicity responses to different T3 forms and doses. These aspects suggest the potential for marked biological activity of hypomethylated "highly metabolized" T3 that may result in cytoprotection and cancer prevention or even chemotherapeutic effects. Cytotoxicity and metabolism of hypomethylated T3 have been extensively investigated in vitro using different cell model systems that will be discussed in this review paper as regard molecular mechanisms and possible relevance in cancer therapy.

The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial

(Ward, Wu et al. 2007) Download

OBJECTIVE: Oxidative stress has been suggested to play a role in the development of diabetes, hypertension and vascular dysfunction. Vitamin E, a major lipid-soluble dietary antioxidant, has two major dietary forms, alpha-tocopherol and gamma-tocopherol. The potential importance of gamma-tocopherol has largely been overlooked. Our aim was to investigate the effect of alpha-tocopherol and gamma-tocopherol supplementation on 24-h ambulatory blood pressure (BP) and heart rate, vascular function and oxidative stress in individuals with type 2 diabetes. METHOD: Fifty-eight individuals with type 2 diabetes were randomized in a double-blind, placebo-controlled trial. Participants were randomized to a daily dose of 500 mg/day RRR-alpha-tocopherol, 500 mg/day mixed tocopherols (60% gamma-tocopherol) or placebo for 6 weeks. Primary endpoints were 24-h ambulatory BP and heart rate, endothelium-dependent and independent vasodilation and plasma and urinary F2-isoprostanes. RESULTS: Treatment with alpha-tocopherol significantly increased systolic BP [7.0 (5.2, 8.8) mmHg, P < 0.0001], diastolic BP [5.3 (4.0, 6.5) mmHg, P < 0.0001], pulse pressure [1.8 (0.6, 3.0) mmHg, P < 0.005] and heart rate [2.0 (0.6, 3.3) bpm, P < 0.005] versus placebo. Treatment with mixed tocopherols significantly increased systolic BP [6.8 (4.9, 8.6) mmHg, P < 0.0001], diastolic BP [3.6 (2.3, 4.9) mmHg, P < 0.0001], pulse pressure [3.2 (2.0, 4.4) mmHg, P < 0.0001] and heart rate [1.8 (0.5, 3.2) bpm, P < 0.01] versus placebo. Treatment with alpha-tocopherol or mixed tocopherols significantly reduced plasma F2-isoprostanes versus placebo, but had no effect on urinary F2-isoprostanes. Endothelium-dependent and independent vasodilation was not affected by either treatment. CONCLUSION: In contrast to our initial hypothesis, treatment with either alpha- or mixed tocopherols significantly increased BP, pulse pressure and heart rate in individuals with type 2 diabetes.

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

            (Wright, Lawson et al. 2006) Download

BACKGROUND: A meta-analysis of 19 trials suggested a small increase in the risk of all-cause mortality with high-dose vitamin E supplementation. Little is known, however, about the relation between mortality and circulating concentrations of vitamin E resulting from dietary intake, low-dose supplementation, or both. OBJECTIVE: We examined whether baseline serum alpha-tocopherol concentrations are associated with total and cause-specific mortality. DESIGN: A prospective cohort study of 29 092 Finnish male smokers aged 50-69 y who participated in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study was carried out. Fasting serum alpha-tocopherol was measured at baseline by using HPLC. Only 10% of participants reported vitamin E supplement use at baseline, and thus serum concentrations of vitamin E mainly reflected dietary intake and other host factors. Risks of total and cause-specific mortality were estimated by using proportional hazards models. RESULTS: During up to 19 y of follow-up, 13 380 deaths (including 4518 and 5776 due to cancer and cardiovascular disease, respectively) were identified. Men in the higher quintiles of serum alpha-tocopherol had significantly lower risks of total and cause-specific mortality than did those in the lowest quintile [relative risk (RR) = 0.82 (95% CI: 0.78, 0.86) for total mortality and 0.79 (0.72, 0.86), 0.81 (0.75, 0.88), and 0.70 (0.63, 0.79) for deaths due to cancer, cardiovascular disease, and other causes, respectively; P for trend for all < 0.0001]. Cubic regression spline analysis of continuous serum alpha-tocopherol values indicated greater risk reductions with increasing concentrations up to approximately 13-14 mg/L, after which no further benefit was noted. CONCLUSION: Higher circulating concentrations of alpha-tocopherol within the normal range are associated with significantly lower total and cause-specific mortality in older male smokers.

Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol

            (Yu, Jia et al. 2009) Download

Two naturally occurring dietary sources of vitamin E (i.e. RRR-alpha-tocopherol (alphaT) and RRR-gamma-tocopherol (gammaT)), the manufactured synthetic form of vitamin E, all-racemic-alpha-tocopherol (all-rac-alphaT), as well as a potent antitumor analog of vitamin E, RRR-alpha-tocopherol ether-linked acetic acid analog (alpha-TEA), were assessed for anticancer actions. Data showed that gammaT, all-rac-alphaT, and alpha-TEA but not alphaT or alphaT+gammaT significantly inhibited tumor burden of human MDA-MB-231 cells in nude mice. Immunohistochemical analyses of tumor tissue showed that all-rac-alphaT and alpha-TEA increased apoptosis and decreased proliferation in tumor cells while gammaT was associated with increased tumor cell apoptosis only. In vitro data showed alpha-TEA and gammaT but not all-rac-alphaT or alphaT to inhibit colony formation and induce apoptosis. Anticancer actions of alpha-TEA and gammaT involved death receptor 5 protein upregulation, Survivin protein downregulation and poly (ADP-ribose) polymerase cleavage, all of which were blocked by co-treatment with alphaT. In summary, both gammaT and alpha-TEA exhibited promising anticancer properties in vivo and in vitro, whereas all-rac-alphaT exhibited promising anticancer properties in vivo only. Importantly, alphaT not only failed to exhibit anticancer properties but it also reduced anticancer actions of gammaT in vivo and gammaT and alpha-TEA in vitro.


Aggarwal, B. and K. Nesaretnam (2012). "Vitamin E tocotrienols: life beyond tocopherols." Genes Nutr 7(1): 1.

Bailey, D. M., C. Dehnert, et al. (2010). "High-altitude pulmonary hypertension is associated with a free radical-mediated reduction in pulmonary nitric oxide bioavailability." J Physiol 588(Pt 23): 4837-47.

Gee, P. T. (2011). "Unleashing the untold and misunderstood observations on vitamin E." Genes Nutr 6(1): 5-16.

Huang, H. Y. and L. J. Appel (2003). "Supplementation of diets with alpha-tocopherol reduces serum concentrations of gamma- and delta-tocopherol in humans." J Nutr 133(10): 3137-40.

Ju, J., S. C. Picinich, et al. (2010). "Cancer-preventive activities of tocopherols and tocotrienols." Carcinogenesis 31(4): 533-42.

Lundby, C. (2010). "Going to altitude? Bring your vitamins!" J Physiol 588(Pt 23): 4603-4.

Miller, E. R., 3rd, R. Pastor-Barriuso, et al. (2005). "Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality." Ann Intern Med 142(1): 37-46.

Miyamoto, K., M. Shiozaki, et al. (2009). "Very-high-dose alpha-tocopherol supplementation increases blood pressure and causes possible adverse central nervous system effects in stroke-prone spontaneously hypertensive rats." J Neurosci Res 87(2): 556-66.

Newaz, M. A., N. N. Nawal, et al. (1999). "alpha-Tocopherol increased nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats." Am J Hypertens 12(8 Pt 1): 839-44.

Racasan, S., B. Braam, et al. (2005). "Programming blood pressure in adult SHR by shifting perinatal balance of NO and reactive oxygen species toward NO: the inverted Barker phenomenon." Am J Physiol Renal Physiol 288(4): F626-36.

Sen, C. K., S. Khanna, et al. (2006). "Tocotrienols: Vitamin E beyond tocopherols." Life Sci 78(18): 2088-98.

Shute, E. V. (1949). "Precautions In The Use Of Alpha-Tocopherol In The Treatment Of Hypertensive Heart Disease." Ann NY Academy of Sciences 52: 354–357.

Smolarek, A. K. and N. Suh (2011). "Chemopreventive Activity of Vitamin E in Breast Cancer: A Focus on gamma- and delta-Tocopherol." Nutrients 3(11): 962-86.

Viola, V., F. Pilolli, et al. (2012). "Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E." Genes Nutr 7(1): 29-41.

Ward, N. C., J. H. Wu, et al. (2007). "The effect of vitamin E on blood pressure in individuals with type 2 diabetes: a randomized, double-blind, placebo-controlled trial." J Hypertens 25(1): 227-34.

Wright, M. E., K. A. Lawson, et al. (2006). "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 84(5): 1200-7.

Yu, W., L. Jia, et al. (2009). "Anticancer actions of natural and synthetic vitamin E forms: RRR-alpha-tocopherol blocks the anticancer actions of gamma-tocopherol." Mol Nutr Food Res 53(12): 1573-81.