Vitamin E therapy beyond cancer: tocopherol versus tocotrienol.

Peh HY, Daniel Tan WS, Liao W, Fred Wong WS.

Pharmacol Ther. 2015 Dec 16. pii: S0163-7258(15)00229-6


The discovery of vitamin E (α-tocopherol) began in 1922 as a vital component required in reproduction. Today, there are eight naturally occurring vitamin E isoforms, namely α-, β-, γ- and δ-tocopherol and α-, β-, γ- and δ-tocotrienol. Vitamin E are potent antioxidants, capable of neutralizing free radicals directly by donating hydrogen from its chromanol ring. α-Tocopherol is regarded the dominant form in vitamin E as the α-tocopherol transfer protein in the liver binds mainly α-tocopherol, thus preventing its degradation. That contributed to the oversight of tocotrienols and resulted in less than 3% of all vitamin E publications studying tocotrienols. Nevertheless, tocotrienols have been shown to possess superior antioxidant and anti-inflammatory properties over α-tocopherol. In particular, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase to lower cholesterol, attenuating inflammation via downregulation of transcription factor NF-κB activation, and potent radioprotectant against radiation damage are some properties unique to tocotrienols, not tocopherols. Aside from cancer, vitamin E has also been shown protective in bone, cardiovascular, eye, nephrological and neurological diseases. In light of the different pharmacological properties of tocopherols and tocotrienols, it becomes critical to specify which vitamin E isoform(s) are being studied in any future vitamin E publications. This review provides an update on vitamin E therapeutic potentials, protective effects and modes of action beyond cancer, with comparison of tocopherols against tocotrienols. With the concerted efforts in synthesizing novel vitamin E analogues and clinical pharmacology of vitamin E, it is likely that certain vitamin E isoform(s) will be therapeutic agents against human diseases besides cancer.

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Suppression of NLRP3 inflammasome by gamma-tocotrienol ameliorates type 2 diabetes.

Kim Y, Wang W, Okla M, Kang I, Moreau , Chung S.

J Lipid Res. 2015 Dec 1


The Nod-like receptor 3 (NLRP3) inflammasome is an intracellular sensor that sets off the innate immune system in response to microbial-derived and endogenous metabolic danger signals. We previously reported that gamma-tocotrienol (γT3) attenuated adipose tissue inflammation and insulin resistance in diet-induced obesity, but the underlying mechanism remained elusive. Here, we investigated the effects of γT3 on NLRP3 inflammasome activation and attendant consequences on type 2 diabetes. γT3 repressed inflammasome activation, caspase-1 cleavage, and IL-1β secretion in murine macrophages, implicating the inhibition of NLRP3 inflammasome in the anti-inflammatory and anti-pyroptotic properties of γT3. Furthermore, supplementation of leptin-receptor KO mice with γT3 attenuated immune cell infiltration into adipose tissue, decreased circulating IL-18 levels, preserved pancreatic β-cells, and improved insulin sensitivity. Mechanistically, γT3 regulated the NLRP3 inflammasome via a two-pronged mechanism; 1) the induction of A20/TNFAIP3 leading to the inhibition of the TRAF6/NF-κB pathway, and 2) the activation of AMPK/autophagy axis leading to the attenuation of caspase-1 cleavage. Collectively, we demonstrated, for the first time, that γT3 inhibits the NLRP3 inflammasome thereby delaying the progression of type 2 diabetes. This study also provides an insight into the novel therapeutic values of γT3 for treating NLRP3 inflammasome-associated chronic diseases.

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Anti-inflammatory γ- and δ-tocotrienols improve cardiovascular, liver and metabolic function in diet-induced obese rats.

Wong WY, Ward LC, Fong CW, Yap WN, Brown L.

Eur J Nutr. 2015 Oct 8



This study tested the hypothesis that γ- and δ-tocotrienols are more effective than α-tocotrienol and α-tocopherol in attenuating the signs of diet-induced metabolic syndrome in rats.


Five groups of rats were fed a corn starch-rich (C) diet containing 68 % carbohydrates as polysaccharides, while the other five groups were fed a diet (H) high in simple carbohydrates (fructose and sucrose in food, 25 % fructose in drinking water, total 68 %) and fats (beef tallow, total 24 %) for 16 weeks. Separate groups from each diet were supplemented with either α-, γ-, δ-tocotrienol or α-tocopherol (85 mg/kg/day) for the final 8 of the 16 weeks.


H rats developed visceral obesity, hypertension, insulin resistance, cardiovascular remodelling and fatty liver. α-Tocopherol, α-, γ- and δ-tocotrienols reduced collagen deposition and inflammatory cell infiltration in the heart. Only γ- and δ-tocotrienols improved cardiovascular function and normalised systolic blood pressure compared to H rats. Further, δ-tocotrienol improved glucose tolerance, insulin sensitivity, lipid profile and abdominal adiposity. In the liver, these interventions reduced lipid accumulation, inflammatory infiltrates and plasma liver enzyme activities.Tocotrienols were measured in heart, liver and adipose tissue showing that chronic oral dosage delivered tocotrienols to these organs despite low or no detection of tocotrienols in plasma.


In rats, δ-tocotrienol improved inflammation, heart structure and function, and liver structure and function, while γ-tocotrienolproduced more modest improvements, with minimal changes with α-tocotrienol and α-tocopherol. The most important mechanism of action is likely to be reduction in organ inflammation.

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Differentiation and apoptosis induction by lovastatin and γ-tocotrienol in HL-60 cells via Ras/ERK/NF-κB and Ras/Akt/NF-κB signaling dependent down-regulation of glyoxalase 1 and HMG-CoA reductase.

Chen CC, Liu TY, Huang SP, Ho CT, Huang TC.

Cell Signal. 2015 Nov;27(11):2182-90


Glyoxalase 1 (GLO1) and HMG-CoA reductase (HMGCR) are highly expressed in most tumor cells and little in normal cells. In this study, treatment of HL-60 cells with lovastatin induced characteristic apoptosis in a dose-dependent manner. We demonstrated that lovastatin treatment inhibited Ras and Raf protein translocation to cell membrane and eliminated the phosphorylation of the downstream effectors Akt and ERK, and the subsequent NF-κB translocation into nucleus. Specific inhibitors and γ-tocotrienol confirmed the Ras/Raf/ERK/NF-κB/GLO1 and Ras/Akt/NF-κB/GLO1 pathways. Data revealed that lovastatin induced HL-60 cell death was attenuated by mevalonate treatment. We demonstrated also that γ-tocotrienol showed its apoptotic effect on the HL-60 cell through the same pathway. γ-Tocotrienol enhanced the apoptotic effect of lovastatin through the down-regulation of GLO1 and HMGCR resulting in an increase of methylglyoxal and a decrease of cholesterol and led to the apoptosis of HL-60 cells. Data also revealed that both lovastatin and gamma-tocotrienol induced significant HL-60 cell differentiation. These results suggest that both lovastatin and gamma-tocotrienol could induce differentiation and followed by apoptosis.

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Effect of palm oil (Elaeis guineensis) tocotrienols on mesenteric adipose tissue deposition and the expression of 11β-hydroxysteroid dehydrogenase type 1 enzyme (11β-HSD1) in adrenalectomized rats treated with dexamethasone.

Azwan K, Farihah HS, Fairus A, Elvy MR.

Clin Ter. 2015;166(3):99-104.



A study was done to investigate the effect of palm oil (Elaeis guineensis) tocotrienols on (1) rats mesenteric adipose tissue deposition (2) and 11β-HSD1 enzyme expression in mesenteric adipocyte. There is a necessity to find an inhibitor for the 11β-HSD1 enzyme which enhances the proliferation of mesenteric adipocyte tissue therefore curbing the onset of metabolic syndrome.


A total of 35 male Spraque Dawley rats were divided into 5 different groups, i.e., a baseline control group (n=7), a sham operated group (n=7) and three experimental adrenalectomised groups (ADR) (n=21). Each of the experimental ADR group was given intramuscular dexamethasone (Dexa) with a dose of 120 μg/kg after 2 weeks post adrenalectomy and were divided into adrenalectomised control (n=7), Glycyrrhizic acid (GCA) treated (dose=120 mg/kg/day; n=7) and Palm Tocotrienol treated (dose=60 mg/kg/day; n=7) groups. These various treatments were given 6 days a week for 8 weeks via gastric gavage (following 2 weeks of adrenalectomy). Data is expressed as mean ± standard error mean (SEM), compared to each other using one-way analysis-of-variance (ANOVA) followed by Tukey’s post hoc test and then a t-test.


The results show that palm tocotrienol tend to slightly increase mesenteric adipose tissue deposition in rats. However, palm tocotrienolwas also found to have potential in inhibiting the expression of 11β-HSD1 enzyme in mesenteric adipocytes.


This study suggests palm tocotrienol inhibits 11β-HSD1 enzyme expression and activity.

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Muscadine grape seed oil as a novel source of tocotrienols to reduce adipogenesis and adipocyte inflammation.

Zhao L1, Yagiz Y, Xu C, Lu J, Chung S, Marshall MR.

Food Funct. 2015 Jun 15.


Tocotrienols are unsaturated forms of vitamin E previously shown to reduce adipogenesis and adipose inflammation. In this study, muscadine grape seed oil (MGSO) was identified as a novel source of tocotrienols containing significant amounts of α- and γ-tocotrienol (T3) with minor seasonal changes. The aim of this study was to assess the anti-adipogenic and anti-inflammatory potential of MGSO by using primary human adipose-derived stem cells (hASCs). Differentiating hASCs were treated with MGSO and compared with rice bran and olive oil. Accumulation of triglyceride was significantly lower in MGSO-treated hASCs than rice bran and olive oils. A tocotrienol rich fraction (TRF) from MGSO was prepared by solid phase extraction and eluted with 15% 1,4-dioxane in hexane. The MGSO-derived TRF treatment significantly reduced mRNA and protein expression that are crucial to adipogenesis (e.g., PPARγ and aP2) in hASCs. Furthermore, TRF from MGSO markedly reduced LPS-induced proinflammatory gene expression in human adipocytes and cytokine secretion to the medium (IL-6 and IL-8). Collectively, our work suggests that MGSO is a stable and reliable natural source of T3 and MGSO may constitute a new dietary strategy to attenuate obesity and its associated adipose inflammation.

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A review of characterization of tocotrienols from plant oils and foods.

Ahsan H, Ahad A, Siddiqui WA.

J Chem Biol. 2015 Jan 20;8(2):45-59.


Tocotrienols, members of the vitamin E family, are natural compounds found in a number of vegetable oils, wheat germ, barley and certain types of nuts and grains. Vegetable oils provide the best sources of these vitamin E forms, particularly palm oil and rice bran oil contain higher amounts oftocotrienols. Other sources of tocotrienols include grape fruit seed oil, oats, hazelnuts, maize, olive oil, buckthorn berry, rye, flax seed oil, poppy seed oil and sunflower oil. Tocotrienols are of four types, viz. alpha (α), beta (β), gamma (γ) and delta (δ). Unlike tocopherols, tocotrienols are unsaturated and possess an isoprenoid side chain. A number of researchers have developed methods for the extraction, analysis, identification and quantification of different types of vitamin E compounds. This article constitutes an in-depth review of the chemistry and extraction of the unsaturated vitamin E derivatives, tocotrienols, from various sources using different methods. This review article lists the different techniques that are used in the characterization and purification of tocotrienols such as soxhlet and solid-liquid extractions, saponification method, chromatography (thin layer, column chromatography, gas chromatography, supercritical fluid, high performance), capillary electrochromatography and mass spectrometry. Some of the methods described were able to identify one form or type while others could analyse all the analogues of tocotrienolmolecules. Hence, this article will be helpful in understanding the various methods used in the characterization of this lesser known vitamin E variant.

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Location of α-tocopherol and α-tocotrienol to heterogeneous cell membranes and inhibition of production of peroxidized cholesterol in mouse fibroblasts.

Nakamura T, Noma A, Terao J

Springerplus. 2014 Sep 23;3:550.



α-Tocopherol (α-T) and α-tocotrienol (α-T3) are well recognized as lipophilic antioxidants. Nevertheless, there is limited knowledge on their location in heterogeneous cell membranes. We first investigated the distribution of α-T and α-T3 to the cholesterol-rich microdomains (lipid rafts and caveolae) of heterogeneous cell membranes by incubating these antioxidants with cultured mouse fibroblasts.


Levels of cellular uptake for α-T and α-T3 were adjusted to the same order, as that of the latter was much more efficient than that of the former in the cultured cells. After ultracentrifugation, α-T and α-T3 were partitioned to the microdomain fractions. When the distribution of α-T and α-T3 was further confirmed by using methyl-β-cyclodextrin (which removes cholesterol from membranes), α-T was suggested to be distributed to the microdomains (approx. 9% of the total uptake). The same treatment did not affect α-T3 content in the microdomain fractions, indicating that α-T3 is not located in these cholesterol-rich domains. However, α-T and α-T3 significantly inhibited the production of peroxidized cholesterol when cells were exposed to ultraviolet-A light.


These results suggest that α-T and α-T3 can act as membranous antioxidants against photo-irradiated cholesterol peroxidation irrespective of their distribution to cholesterol-rich microdomains.

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Tocotrienols have a nephroprotective action against lipid-induced chronic renal dysfunction in rats

Rashid Khan M, Ahsan H, Siddiqui S, Siddiqui WA

Ren Fail. 2014 Sep 18:1-8


Abstract Vitamin E is the generic term for a group of tocopherols and tocotrienols (T3). Hyperlipidemia has been known to cause progressive chronic renal dysfunction (CRD). Several investigators have reported that T3 have hypolipidemic and nephroprotective activity against free radical-related diseases. This study was conducted to determine if T3 as tocotrienol-rich fraction (TRF) from palm oil would protect against lipid-induced CRD in rats. For the induction of atherosclerosis and hyperlipidemia, Wistar male rats were fed an atherogenic diet containing 1.25% cholesterol, 0.5% cholic acid and 21% beef tallow (42.6% calories from fat). The atherogenic diet was given for 14 weeks to induce atherosclerosis. The control rats were given normal rat chow and drug control animals treated with TRF (100 mg/kg bw; orally). The first group was taken as disease control in which the animals were left untreated and given normal rat chow for six weeks, while the second group was treated with 100 mg TRF/kg bw. Atherosclerosis and renal functions were evaluated after six weeks of TRF treatment. Feeding an atherogenic diet to rats for 14 weeks resulted in dyslipidemia and impaired renal functions with decreased glomerular filtration rate. The treatment with TRF significantly reduced dyslipidemia and inhibited the development of CRD caused by atherogenic factors. These findings show that low-dose treatment of TRF may provide significant health benefits in the prevention of lipid-induced CRD. The study suggests that TRF is effective in preventing lipid-induced CRD.

Distribution of Tocopherols and Tocotrienols in Guinea Pig Tissues Following Parenteral Lipid Emulsion Infusion.

Xu Z, Harvey KA, Pavlina TM, Zaloga GP, Siddiqui RA

J Parenter Enteral Nutr. 2014 Aug 28

Abstract:  Tocopherols and tocotrienols possess vitamin E activity and function as the major lipid-soluble antioxidants in the human body. Commercial lipid emulsions are composed of different oils and supply different amounts of vitamin E. The objective of this study was to measure all 8 vitamin E homologs within 4 different commercial lipid emulsions and evaluate their distribution in guinea pig tissues. Materials and Methods: The distribution of vitamin E homologs within plasma and guinea pig tissues was determined using a high-performance liquid chromatography (HPLC) system. Lipid hydroperoxides in lipid emulsions were determined using a commercial kit (Cayman Chemical Company, Ann Arbor, MI), and malondialdehyde tissue levels were determined using an HPLC system. Results: The lipid emulsions contained variable amounts of tocopherols, which were significantly different between emulsions. Tocotrienols were present at very low concentrations (≤0.3%). We found no correlation between the amount of vitamin E present in the lipid emulsions and lipid peroxidation. Hydroperoxides were the lowest with an olive oil-based emulsion and highest with a fish oil emulsion. The predominant vitamin E homolog in guinea pig tissues was α-tocopherol. No tissues had detectable levels of tocotrienols. Vitamin E levels (primarily α-tocopherol and γ-tocopherol) were highly variable among organ tissues. Plasma levels were a poor reflection of most tissue levels. Conclusion: Vitamin E levels within different lipid emulsions and plasma/tissues are highly variable, and no one tissue or plasma sample serves as a good proxy for levels in other tissues. All study emulsions were well tolerated and did not significantly increase systemic lipid peroxidation.