Bioavailability of tocotrienols: evidence in human studies.

Fu JY, Che HL, Tan DM, Teng KT.

As a minor component of vitamin E, tocotrienols were evident in exhibiting biological activities such as neuroprotection, radio-protection, anti-cancer, anti-inflammatory and lipid lowering properties which are not shared by tocopherols. However, available data on the therapeutic window of tocotrienols remains controversial. It is important to understand the absorption and bioavailability mechanisms before conducting in-depth investigations into the therapeutic efficacy of tocotrienols in humans. In this review, we updated current evidence on the bioavailability of tocotrienols from human studies. Available data from five studies suggested that tocotrienols may reach its target destination through an alternative pathway despite its low affinity for α-tocopherol transfer protein. This was evident when studies reported considerable amount of tocotrienols detected in HDL particles and adipose tissues after oral consumption. Besides, plasma concentrations of tocotrienols were shown to be higher when administered with food while self-emulsifying preparation of tocotrienols was shown to enhance the absorption of tocotrienols. Nevertheless, mixed results were observed based on the outcome from 24 clinical studies, focusing on the dosages, study populations and formulations used. This may be due to the variation of compositions and dosages of tocotrienols used, suggesting a need to understand the formulation of tocotrienols in the study design. Essentially, implementation of a control diet such as AHA Step 1 diet may influence the study outcomes, especially in hypercholesterolemic subjects when lipid profile might be modified due to synergistic interaction between tocotrienols and control diet. We also found that the bioavailability of tocotrienols were inconsistent in different target populations, from healthy subjects to smokers and diseased patients. In this review, the effect of dosage, composition and formulation of tocotrienols as well as study populations on the bioavailability of tocotrienols will be discussed.

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Novel liquid chromatography-mass spectrometry method shows that vitamin E deficiency depletes arachidonic and docosahexaenoic acids in zebrafish (Danio rerio) embryos.

To test the hypothesis that embryogenesis depends upon α-tocopherol (E) to protect embryo polyunsaturated fatty acids (PUFAs) from lipid peroxidation, new methodologies were applied to measure α-tocopherol and fatty acids in extracts from saponified zebrafish embryos. A solid phase extraction method was developed to separate the analyte classes, using a mixed mode cartridge (reverse phase, π-π bonding, strong anion exchange), then α-tocopherol and cholesterol were measured using standard techniques, while the fatty acids were quantitated using a novel, reverse phase liquid chromatography-mass spectrometry (LC-MS) approach. We also determined if α-tocopherol status alters embryonic lipid peroxidation products by analyzing 24 different oxidized products of arachidonic or docosahexaenoic (DHA) acids in embryos using LC with hybrid quadrupole-time of flight MS. Adult zebrafish were fed E- or E+ diets for 4 months, and then were spawned to obtain E- and E+ embryos. Between 24 and 72 hours post-fertilization (hpf), arachidonic acid decreased 3-times faster in E- (21 pg/h) compared with E+ embryos (7 pg/h, P<0.0001), while both α-tocopherol and DHA concentrations decreased only in E- embryos. At 36 hpf, E- embryos contained double the 5-hydroxy-eicosatetraenoic acids and 7-hydroxy-DHA concentrations, while other hydroxy-lipids remained unchanged. Vitamin E deficiency during embryogenesis depleted DHA and arachidonic acid, and increased hydroxy-fatty acids derived from these PUFA, suggesting that α-tocopherol is necessary to protect these critical fatty acids.

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Vitamin E-gene interactions in ageing and inflammatory age-related diseases: implications for treatment. A systematic review.

Mocchegiani E, Costarelli L, Giacconi R, Malavolta M, Basso A, Piacenza F, Ostan R, Cevenini E, Gonos ES, Franceschi C, Monti D

Aging is a complex biological phenomenon in which the deficiency of the nutritional state combined with the presence of chronic inflammation and oxidative stress contribute to the development of many age-related diseases. Under this profile, the free radicals produced by the oxidative stress lead to a damage of DNA, lipids and proteins with subsequent altered cellular homeostasis and integrity. In young-adult age, the cell has an complex efficient system to maintain a proper balance between the levels of free radicals and antioxidants ensuring the integrity of cellular components. In contrast, in old age this balance is poorly efficient compromising cellular homeostasis. Supplementation with Vitamin E can restore the balance and protect against the deteriorating effects of oxidative stress, progression of degenerative diseases, and ageing. Experiments in cell cultures and in animals have clearly shown that Vitamin E has a pivotal role as antioxidant agent against the lipid peroxidation on cell membranes preserving the tissue cells from the oxidative damage. Such a role has been well documented in immune, endothelial, and brain cells from old animals describing how the Vitamin E works both at cytoplasmatic and nuclear levels with an influence on many genes related to the inflammatory/immune response. All these findings have supported a lot of clinical trials in old humans and in inflammatory age-related diseases with however contradictory and inconsistent results and even indicating a dangerous role of Vitamin E able to affect mortality. Various factors can contribute to all the discrepancies. Among them, the doses and the various isoforms of Vitamin E family (α,β,γ,δ tocopherols and the corresponding tocotrienols) used in different trials. However, the more plausible gap is the poor consideration of the Vitamin E-gene interactions that may open new roadmaps for a correct and personalized Vitamin E supplementation in ageing and age-related diseases with satisfactory results in order to reach healthy ageing and longevity. In this review, this peculiar nutrigenomic and/or nutrigenetic aspect is reported and discussed at the light of specific polymorphisms affecting the Vitamin E bioactivity.

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Comparative effects of biodynes, tocotrienol-rich fraction, and tocopherol in enhancing collagen synthesis and inhibiting collagen degradation in stress-induced premature senescence model of human diploid fibroblasts.

Makpol S, Jam FA, Khor SC, Ismail Z, Mohd Yusof YA, Wan Ngah WZ.

Biodynes, tocotrienol-rich fraction (TRF), and tocopherol have shown antiaging properties. However, the combined effects of these compounds on skin aging are yet to be investigated. This study aimed to elucidate the skin aging effects of biodynes, TRF, and tocopherol on stress-induced premature senescence (SIPS) model of human diploid fibroblasts (HDFs) by determining the expression of collagen and MMPs at gene and protein levels. Primary HDFs were treated with biodynes, TRF, and tocopherol prior to hydrogen peroxide (H2O2) exposure. The expression of COL1A1, COL3A1, MMP1, MMP2, MMP3, and MMP9 genes was determined by qRT-PCR. Type I and type III procollagen proteins were measured by Western blotting while the activities of MMPs were quantified by fluorometric Sensolyte MMP Kit. Our results showed that biodynes, TRF, and tocopherol upregulated collagen genes and downregulated MMP genes (P < 0.05). Type I procollagen and type III procollagen protein levels were significantly increased in response to biodynes, TRF, and tocopherol treatment (P < 0.05) with reduction in MMP-1, MMP-2, MMP-3, and MMP-9 activities (P < 0.05). These findings indicated that biodynes, TRF, and tocopherol effectively enhanced collagen synthesis and inhibited collagen degradation and therefore may protect the skin from aging.

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Tocotrienol Supplementation Improves Lipid Profiles in Chronic Hemodialysis Patients

Scientists have found tocotrienol supplementation lower plasma triglyceride levels in patients undergoing chronic hemodialysis.

The study was conducted by Professor Pramod Khosla’s group in Wayne State University. End-stage renal disease patients on chronic (at least 3 months prior to the study) dialysis treatment were recruited from a local dialysis clinic in Detroit. 81 Patients were randomized to receive either 180 mg tocotrienol rich fraction or placebo daily for 16 weeks. The patient compliance was measured by pill counting. After 12 weeks supplementation, the group receiving tocotrienol supplementation have decreased plasma triglyceride levels from 144 ± 91mg/dL to 113± 47 mg/dL (p <0.05). The triglyceride levels remained low (103± 45 mg/dL) at week 16. In the control group, the plasma triglyceride levels were unchanged.

Triglycerides are produced from energy sources like carbohydrates. High plasma triglyceride levels (> 150 mg/dL) indicate increased risk of cardiovascular diseases. In end-stage renal disease patients, dyslipidemia is highly prevalent with elevated plasma triglyceride levels. This study indicated the lipid-regulation and potential cardio-protection effect of tocotrienol in these patients.

The triglyceride-lowering effect of tocotrienol observed in this clinical study agrees with a previous publication by Davos Life Science, in which supplementation with 120 mg γδ-tocotrienol in 10 hypercholesterolemic subjects for 8 weeks led to a 28% reduction in plasma triglyceride levels.

Both the tocotrienol supplementation group and the control group have decreased levels of total cholesterol, higher levels of high density lipoprotein cholesterol (HDLC) and decreased levels of low-density lipoprotein cholesterol (LDLC) at week 16. This could be due to the effect of the cholesterol-lowering drug statin of which 30-40% of the patients were taking concurrently.

This study reinforced the cardiovascular benefits of palm-derived tocotrienols in lowering triglyceride levels in subjects with mild to moderate dyslipidemia.

Tocotrienols for normalisation of hepatic echogenic response in nonalcoholic fatty liver: a randomised placebo-controlled clinical trial.

Magosso E, Ansari MA, Gopalan Y, Shuaib IL, Wong JW, Khan NA, Abu Bakar MR, Ng BH, Yuen KH.

Nonalcoholic fatty liver disease (NAFLD) is one of the commonest liver disorders. Obesity, insulin resistance, lipid peroxidation and oxidative stress have been identified amongst the possible hits leading to the onset and progression of this disease. Nutritional evaluation of NAFLD patients showed a lower-than-recommended intake of vitamin E. Vitamin E is a family of 8 isoforms, 4 tocopherols and 4 tocotrienols. Alpha-tocopherol has been widely investigated in liver diseases, whereas no previous clinical trial has investigated tocotrienols for NAFLD. Aim of the study was to determine the effects of mixed tocotrienols, in normalising the hepatic echogenic response in hypercholesterolaemic patients with ultrasound-proven NAFLD.

METHODS:

Eighty-seven untreated hypercholesterolaemic adults with ultrasound-proven NAFLD were enrolled and randomised into control group (n = 44) and tocotrienols group (n = 43). The treatment, either mixed tocotrienols 200 mg twice daily or placebo, had a 1-year duration.Normalisation of hepatic echogenic response, being the trial primary aim, was used in sample size calculations. The data were assessed according to intention to treat principle as primary outcome. Per protocol analysis was also carried out as secondary outcome measurement.

RESULTS:

Thirty and 34 participants concluded the study in the tocotrienols and placebo group respectively. Alpha-tocopherol levels were within the normal range for all subjects. As primary outcome, the normalisation of hepatic echogenic response was significantly higher for the tocotrienols treated group compared to the placebo group in the intention to treat analysis (P = 0.039; 95% CI = 0.896-6.488). As secondary objective, the per protocol assessment also showed significant rate of remission (P = 0.014; 95% CI = 1.117-9.456). Worsening of NAFLD grade was recorded in two patients in the placebo group, but none in the group treated with tocotrienols. No adverse events were reported for both groups.

CONCLUSION:

This is the first clinical trial that showed the hepatoprotective effects of mixed palm tocotrienols in hypercholesterolemic adults with NAFLD.

TRIAL REGISTRATION:

Clinicaltrials.gov, NCT00753532.

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Vitamin E ‘beneficial’ in dementia

A daily dose of vitamin E could help people with dementiabrain

A study in the journal JAMA found people with mild to moderate Alzheimer’s disease on high doses of vitamin E had a slower rate of decline than those given a dummy pill.

They were able to carry out everyday tasks for longer and needed less help from carers, say US researchers.

The Alzheimer’s Society said the dosage was very high and might not be safe.

In the study, 613 people with mild to moderate Alzheimer’s disease received either a daily dose of vitamin E, a dementia drug treatment known as memantine, a combination of vitamin E and memantine, or placebo.

Changes in their ability to carry out everyday tasks – such as washing or dressing – were measured over an average of two years.

The study found participants receiving vitamin E had slower functional decline than those receiving placebo, with the annual rate of decline reduced by 19%.

Dysken MW, Sano M, Asthana S, et al. Effect of Vitamin E and Memantine on Functional Decline in Alzheimer Disease: The TEAM-AD VA Cooperative Randomized Trial. JAMA.2014;311(1):33-44. 

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