Abstract

Vitamin E (α-, β-, γ- and δ-tocopherol and -tocotrienol) is an essential factor in the human diet and regularly taken as a dietary supplement by many people, who act under the assumption that it may be good for their health and can do no harm. With the publication of meta-analyses reporting increased mortality in persons taking vitamin E supplements, the safety of the micronutrient was questioned and interactions with prescription drugs were suggested as one potentially underlying mechanism. Here, we review the evidence in the scientific literature for adverse vitamin E-drug interactions and discuss the potential of each of the eight vitamin E congeners to alter the activity of drugs. In summary, there is no evidence from animal models or randomised controlled human trials to suggest that the intake of tocopherols and tocotrienols at nutritionally relevant doses may cause adverse nutrient-drug interactions. Consumption of high-dose vitamin E supplements ( ≥  300 mg/d), however, may lead to interactions with the drugs aspirin, warfarin, tamoxifen and cyclosporine A that may alter their activities. For the majority of drugs, however, interactions with vitamin E, even at high doses, have not been observed and are thus unlikely.

Delta-tocotrienol induces apoptotic cell death via depletion of intracellular squalene in ED40515 cells.

Yamasaki M, Nishimura M, Sakakibara Y, Suiko M, Morishita K, Nishiyama K

Food Funct. 2014 Oct 22;5 (11):2842-9

Abstract

Here, we examined the effect of tocotrienols (T3) on the growth of adult T-cell leukemia (ATL) cells. All three forms (β-, γ-, and δ-T3) inhibited cell proliferation in a dose-dependent manner; δ-T3 showed the strongest growth-inhibitory effect. δ-T3 increased the G1, G2/M, and subG1 populations and induced internucleosomal DNA fragmentation. δ-T3 treatment also increased the levels of cleaved caspase-3, -6, -7, -9, and poly-ADP ribose polymerase (PARP), and this was accompanied by downregulation of Bcl-2, Bcl-xL, and XIAP. Moreover, δ-T3 decreased nuclear p65 NF-κB levels, indicating downregulation of NF-κB activity. This cytotoxic effect of δ-T3 was abrogated by squalene (SQL) but not mevalonate (MVL), farnesyl diphosphate (FPP), geranylgeranyl diphosphate (GGPP), or cholesterol (CL). δ-T3 decreased intracellular SQL levels, and inhibition of de novo cholesterol synthesis did not affect the action of SQL. Furthermore, δ-T3 significantly decreased farnesyl-diphosphate farnesyltransferase 1 (FDFT1) expression. Taken together, it is evident that δ-T3, due to its ability to potently induce apoptosis via the depletion of intracellular SQL, shows the potential to be considered a therapeutic agent in patients with ATL.

Tocotrienol-rich fraction, [6]-gingerol and epigallocatechin gallate inhibit proliferation and induce apoptosis of glioma cancer cells.

Amirah Abdul Rahman, Suzana Makpol, Rahman Jamal, Roslan Harun, Norfilza Mokhtar and Wan Zurinah Wan Ngah

Molecules 2014, 19(9), 14528-14541

Abstarct

Plant bioactives [6]-gingerol (GING), epigallocatechin gallate (EGCG) and asiaticoside (AS) and vitamin E, such as tocotrienol-rich fraction (TRF), have been reported to possess anticancer activity. In this study, we investigated the apoptotic properties of these bioactive compounds alone or in combination on glioma cancer cells. TRF, GING, EGCG and AS were tested for cytotoxicity on glioma cell lines 1321N1 (Grade II), SW1783 (Grade III) and LN18 (Grade IV) in culture by the (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt) (MTS) assay. With the exception of AS, combinations of two compounds were tested, and the interactions of each combination were evaluated by the combination index (CI) using an isobologram. Different grades of glioma cancer cells showed different cytotoxic responses to the compounds, where in 1321N1 and LN18 cells, the combination of EGCG + GING exhibited a synergistic effect with CI = 0.77 and CI = 0.55, respectively. In contrast, all combinations tested (TRF + GING, TRF + EGCG and EGCG + GING) were found to be antagonistic on SW1783 with CI values of 1.29, 1.39 and 1.39, respectively. Combined EGCG + GING induced apoptosis in both 1321N1 and LN18 cells, as evidenced by Annexin-V FITC/PI staining and increased active caspase-3. Our current data suggests that the combination of EGCG + GING synergistically induced apoptosis and inhibits the proliferation 1321N1 and LN18 cells, but not SW1783 cells, which may be due to their different genetic profiles.

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Antioxidant activities of annatto and palm tocotrienol-rich fractions in fish oil and structured lipid-based infant formula emulsion.

Zou L, Akoh CC

Food Chem. 2015 Feb 1; 168:504-11

Abstract

The abilities of annatto and palm tocotrienol-rich fractions (TRFs), as natural antioxidants, to inhibit lipid oxidation in menhaden fish oil and structured lipid-based infant formula emulsion, were evaluated and compared. The peroxide and anisidine values of the bulk oil and oil-in-water emulsion samples stored at 37°C were measured over a 28-day period. The results showed that annatto TRF was a more effective antioxidant than palm TRF and α-tocopherol in both food systems at 0.02% and 0.05%. Factors, including structural differences in chromanol head and isoprenoid tail, polarity, concentration, oxidation time, and the method used to monitor lipid oxidation, were responsible for the different behaviours of tocopherols and tocotrienols. In contrast to the reported findings in vivo, addition of α-tocopherol (0-75%) did not interfere with the antioxidant activity of tocopherol-free annatto TRF in foods. Our findings may lead to the development of new natural antioxidant products for food applications.

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.

Fat-Soluble Bioactive Components in Colored Rice Varieties.

Minatel IO, Han SI, Aldini G, Colzani M, Matthan NR, Correa CR, Fecchio D, Yeum KJ.

Abstract Bioactive components in rice vary depending on the variety and growing condition. Fat-soluble components such as γ-oryzanol, tocopherols, tocotrienols, carotenoids, and fatty acids were analyzed in brown, sugary brown, red, and black rice varieties using established high-performance liquid chromatography (HPLC) and GC methodologies. In addition, these colored rice varieties were further analyzed using a high-resolution liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) (LTQ-Orbitrap XL) to identify the [M-H]- ions of γ-oryzanol, ranging from m/z 573.3949 to 617.4211. The highest content of tocopherols (α-, 1.5; γ-, 0.5 mg/100 g) and carotenoids (lutein 244; trans-β carotene 25 μg/100 g) were observed in black rice; tocotrienols (α-, 0.07; γ-, 0.14 mg/100 g) in red rice, and γ-oryzanol (115 mg/100 g) in sugary brown rice. In all colored rice varieties, the major fatty acids were palmitic (16:0), oleic (18:1n-9), and linoleic (18:2n-6) acids. When the γ-oryzanol components were further analyzed by LC-MS/MS, 3, 10, 8, and 8 triterpene alcohols or sterol ferulates were identified in brown, sugary brown, red, and black rice varieties, respectively. Such structural identification can lead to the elucidation of biological function of each component at the molecular level. Consumption of colored rice rich in beneficial bioactive compounds may be a useful dietary strategy for achieving optimal health.

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UPLC method for the determination of vitamin E homologues and derivatives in vegetable oils, margarines and supplement capsules using pentafluorophenyl column.

Foo Wong Y, Makahleh A, Saad B, Ibrahim MN, Abdul Rahim A, Brosse N.

A sensitive and rapid reversed-phase ultra performance liquid chromatographic (UPLC) method for the simultaneous determination of tocopherols (α-, β-, γ-, δ-), tocotrienols (α-, β-, γ-, δ-), α-tocopherol acetate and α-tocopherol nicotinate is described. The separation was achieved using a Kinetex pentafluorophenyl (PFP) column (150×2.1mm, 2.6µm) with both photodiode array (PDA) and fluorescence (FL) detectors that were connected in series. Column was thermostated at 42°C. Under a gradient system consisting of methanol and water at a constant flow rate of 0.38mLmin(-1), all the ten analytes were well separated in less than 9.5min. The method was validated in terms of linearity, limits of detection and quantitation, precision and recoveries. Calibration curves of the ten compounds were well correlated (r(2)>0.999) within the range of 100 to 25,000μgL(-1) for α-tocopherol acetate and α-tocopherol nicotinate, 10 to 25,000μgL(-1) for α-tocotrienol and 5 to 25,000μgL(-1) for the other components. The method is simple and sensitive with detection limits (S/N, 3) of 1.0 to 3.0μgL(-1) (FL detection) and 30 to 74μgL(-1) (PDA detection). Relative standard deviations for intra- and inter-day retention times (<1%) and peak areas (≤4%) were obtained. The method was successfully applied to the determination of vitamin E in vegetable oils (extra virgin olive, virgin olive, pomace olive, blended virgin and refined olive, sunflower, soybean, palm olein, carotino, crude palm, walnut, rice bran and grape seed), margarines and supplements.

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

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

Background: 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.

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Antioxidant activities of annatto and palm tocotrienol-rich fractions in fish oil and structured lipid-based infant formula emulsion.

Zou L, Akoh CC.

The abilities of annatto and palm tocotrienol-rich fractions (TRFs), as natural antioxidants, to inhibit lipid oxidation in menhaden fish oil and structured lipid-based infant formula emulsion, were evaluated and compared. The peroxide and anisidine values of the bulk oil and oil-in-water emulsion samples stored at 37°C were measured over a 28-day period. The results showed that annatto TRF was a more effective antioxidant than palm TRF and α-tocopherol in both food systems at 0.02% and 0.05%. Factors, including structural differences in chromanol head and isoprenoid tail, polarity, concentration, oxidation time, and the method used to monitor lipid oxidation, were responsible for the different behaviours of tocopherols and tocotrienols. In contrast to the reported findings in vivo, addition of α-tocopherol (0-75%) did not interfere with the antioxidant activity of tocopherol-free annatto TRF in foods. Our findings may lead to the development of new natural antioxidant products for food applications.

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δ-Tocotrienol Oxazine Derivative Antagonizes Mammary Tumor Cell Compensatory Response to CoCl 2 -Induced Hypoxia.

Ananthula S, Parajuli P, Behery FA, Alayoubi AY, Nazzal S, El Sayed K, Sylvester PW.

In response to low oxygen supply, cancer cells elevate production of HIF-1α, a hypoxia-inducible transcription factor that subsequently acts to stimulate blood vessel formation and promote survival. Studies were conducted to determine the role of δ-tocotrienol and a semisynthetic δ-tocotrienol oxazine derivative, compound 44, on +SA mammary tumor cell hypoxic response. Treatment with 150 µM CoCl2 induced a hypoxic response in +SA mammary tumor cells as evidenced by a large increase in HIF-1α levels, and combined treatment with compound 44 attenuated this response. CoCl2-induced hypoxia was also associated with a large increase in Akt/mTOR signaling, activation of downstream targets p70S6K and eIF-4E1, and a significant increase in VEGF production, and combined treatment with compound 44 blocked this response. Additional in vivo studies showed that intralesional treatment with compound 44 in BALB/c mice bearing +SA mammary tumors significantly decreased the levels of HIF-1α, and this effect was associated with a corresponding decrease in Akt/mTOR signaling and activation of downstream targets p70S6kinase and eIF-4E1. These findings demonstrate that treatment with the δ-tocotrienol oxazine derivative, compound 44, significantly attenuates +SA mammary tumor cell compensatory responses to hypoxia and suggests that this compound may provide benefit in the treatment of rapidly growing solid breast tumors.

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