Dose dependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E

Rasool AH, Yuen KH, Yusoff K, Wong AR, Rahman AR.

J Nutr Sci Vitaminol (Tokyo). 2006 Dec;52(6):473-8.

Tocotrienols are a class of vitamin E reported to be potent antioxidants, besides having the ability to inhibit the HMG-CoA reductase enzyme. This study assessed the effects of 3 doses of tocotrienol-rich vitamin E (TRE) on plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in healthy males.

Methodology: This randomised, blinded end-point, placebo-controlled clinical trial with a parallel design involved 36 healthy male subjects who took either an oral placebo or TRE at doses of 80, 160 or 320 mg daily for 2 mo. Baseline and end-of-treatment measurements of vitamin E concentration, arterial compliance [assessed by aortic femoral pulse wave velocity (PWV) and augmentation index (AI)], ASBP, plasma TAS, serum TC and LDL-C were taken.

Results: Baseline tocotrienol isomer concentrations were low and not detectable in some subjects. Upon supplementation, all TRE-treated groups showed significant difference from placebo for their change in alpha, gamma and delta tocotrienol concentrations from baseline to end of treatment. There was a linear dose and blood level relationship for all the isomers. There was no significant difference between groups for their change in PWV, AI, plasma TAS, ASBP, TC or LDL-C from baseline to end of treatment. Groups 160 mg (p = 0.024) and 320 mg (p = 0.049) showed significant reductions in their ASBP. Group 320 mg showed a significant 9.2% improvement in TAS.

Conclusion: TRE at doses up to 320 mg daily were well tolerated. Treatment significantly increased alpha, delta, and gamma tocotrienol concentrations but did not significantly affect arterial compliance, plasma TAS, serum TC or LDL-C levels in normal subjects.

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More than 80 years after the discovery of the essentiality of vitamin E for mammals, the molecular basis of its action is still an enigma. From the eight different forms of vitamin E, only alpha-tocopherol is retained in the body. This is in part due to the specific selection of RRR-alpha-tocopherol by the alpha-tocopherol transfer protein and in part by its low rate of degradation and elimination compared with the other vitamers. Since the tocopherols have comparable antioxidant properties and some tocotrienols are even more effective in scavenging radicals, the antioxidant capacity cannot be the explanation for its essentiality, at least not the only one. In the last decade, a high number of so-called novel functions of almost all forms of vitamin E have been described, including regulation of cellular signalling and gene expression. alpha-Tocopherol appears to be most involved in gene regulation, whereas gamma-tocopherol appears to be highly effective in preventing cancer-related processes. Tocotrienols appear to be effective in amelioration of neurodegeneration. Most of the novel functions of individual forms of vitamin E have been demonstrated in vitro only and require in vivo confirmation. The distinct bioactivities of the various vitamers are discussed, considering their metabolism and the potential functions of metabolites.

Dose dependent elevation of plasma tocotrienol levels and its effect on arterial compliance, plasma total antioxidant status, and lipid profile in healthy humans supplemented with tocotrienol rich vitamin E

Rasool AH, Yuen KH, Yusoff K, Wong AR, Rahman AR.

J Nutr Sci Vitaminol (Tokyo). 2006 Dec;52(6):473-8.

Published

Objectives: To assess the effects of 3 doses of tocotrienol-rich vitamin E (TRE) on plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) in healthy males.

Study design: Randomised, blinded end-point, placebo-controlled

Subjects: Healthy male volunteers

Intervention: Tocotrienol-rich Vitamin E at 80 mg, 160 mg or 320 mg versus placebo

Primary outcome: Plasma tocotrienol isomer concentration, arterial compliance, plasma total antioxidant status (TAS), aortic systolic blood pressure (ASBP), serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C)

Methodology: This randomised, blinded end-point, placebo-controlled clinical trial with a parallel design involved 36 healthy male subjects who took either an oral placebo or TRE at doses of 80, 160 or 320 mg daily for 2 mo. Baseline and end-of-treatment measurements of vitamin E concentration, arterial compliance [assessed by aortic femoral pulse wave velocity (PWV) and augmentation index (AI)], ASBP, plasma TAS, serum TC and LDL-C were taken.

Results: Baseline tocotrienol isomer concentrations were low and not detectable in some subjects. Upon supplementation, all TRE-treated groups showed significant difference from placebo for their change in alpha, gamma and delta tocotrienol concentrations from baseline to end of treatment. There was a linear dose and blood level relationship for all the isomers. There was no significant difference between groups for their change in PWV, AI, plasma TAS, ASBP, TC or LDL-C from baseline to end of treatment. Groups 160 mg (p = 0.024) and 320 mg (p = 0.049) showed significant reductions in their ASBP. Group 320 mg showed a significant 9.2% improvement in TAS.

Conclusion: TRE at doses up to 320 mg daily were well tolerated. Treatment significantly increased alpha, delta, and gamma tocotrienolconcentrations but did not significantly affect arterial compliance, plasma TAS, serum TC or LDL-C levels in normal subjects.

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Proposed mechanisms for red palm oil induced cardioprotection in a model of hyperlipidaemia in the rat

Esterhuyse JS, van Rooyen J, Strijdom H, Bester D, du Toit EF.

Prostaglandins Leukot Essent Fatty Acids. 2006 Dec;75(6):375-84.

High-cholesterol diets alter myocardial and vascular NO-cGMP signaling and have been implicated in ischaemic/reperfusion injury. We investigated the effects of dietary red palm oil (RPO) containing fatty acids, carotonoids, tocopherols and tocotrienols on myocardial ischaemic tolerance and NO-cGMP pathway function in the rat. Wistar rats were fed a standard rat chow+/-RPO, or a standard rat chow+cholesterol+/-RPO diet. Myocardial mechanical function and NO-cGMP signaling pathway intermediates were determined before, during and after 25 min ischaemia. RPO-supplementation improved aortic output recovery and increased myocardial ischaemic cGMP concentrations. Simulated ischaemia (hypoxia) increased cardiomyocyte nitric oxide levels in the two RPO supplemented groups, but not in control non-supplemented groups. RPO supplementation also increased hypoxic nitric oxide levels in the control diet fed, but not the cholesterol fed rats. These data suggest that dietary RPO may improve myocardial ischaemic tolerance by increasing bioavailability of NO and improving NO-cGMP signaling in the heart.

Gamma-Tocotrienol inhibits ErbB3-dependent PI3K/Akt mitogenic signalling in neoplastic mammary epithelial cells

Samant GV, Sylvester PW.

Cell Prolif. 2006 Dec;39(6):563-74.

The antiproliferative effects of gamma-tocotrienol are associated with suppression in epidermal growth factor (EGF)-dependent phosphatidylinositol-3-kinase (PI3K)/PI3K-dependent kinase-1 (PDK-1)/Akt mitogenic signalling in neoplastic mammary epithelial cells. Studies were conducted to investigate the direct effects of gamma-tocotrienol treatment on specific components within the PI3K/PDK-1/Akt mitogenic pathway. +SA cells were grown in culture and maintained in serum-free media containing 10 ng/ml EGF as a mitogen. Treatment with 0-8 microm gamma-tocotrienol resulted in a dose-responsive decrease in the +SA cell growth and a corresponding decrease in phospho-Akt (active) levels. However, gamma-tocotrienol treatment had no direct inhibitory effect on Akt or PI3K enzymatic activity, suggesting that the inhibitory effects of gamma-tocotrienol occur upstream of PI3K, possibly at the level of the EGF-receptor (ErbB1). Additional studies were conducted to determine the effects of gamma-tocotrienol on ErbB receptor activation. Results showed that gamma-tocotrienol treatment had little or no effect on ErbB1 or ErbB2 receptor tyrosine phosphorylation, a prerequisite for substrate interaction and signal transduction, but did cause a significant and progressive decrease in the ErbB3 tyrosine phosphorylation. Because ErbB1 or ErbB2 receptors form heterodimers with the ErbB3 receptor, and ErbB3 heterodimers have been shown to be the most potent activators of PI3K, these findings strongly suggest that the antiproliferative effects of gamma-tocotrienol in neoplastic +SA mouse mammary epithelial cells are mediated by a suppression in ErbB3-receptor tyrosine phosphorylation and subsequent reduction in PI3K/PDK-1/Akt mitogenic signalling.

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