Vitamin E refers to a family of tocopherol and tocotrienol isomers discovered in 1922 as anti-infertility factor. Vitamin E deficiency causes infertility and delayed-onset ataxia in experimental animals, and it leads to neuronal dysfunctions in humans. However, based largely on its radical-scavenging antioxidant activity in vitro, vitamin E supplements are commonly thought to provide health benefits against diseases associated with oxidative damage, most notably cardiovascular diseases. Contrary to this belief, the outcome of recent large, prospective, randomized and placebo-controlled clinical studies does not encourage the use of vitamin E supplements. These overall disappointing results can be explained and substantiated by scientific data critically testing the strengths of evidence for many of the underlying assumptions and examining the possibility that in vivo vitamin E may have function(s) other than, or in addition to, acting as an antioxidant.

Tocotrienol levels in adipose tissue of benign and malignant breast lumps in patients in Malaysia

Nesaretnam, K., Gomez, P. A.,Selvaduray, K. R.,Razak, G. A.

Asia Pac J Clin Nutr, 2007;16(3):498-504

Data on dietary exposure to vitamin E by plasma or adipose tissue concentrations of alpha-tocopherol (alpha-T) in observational studies have failed to provide consistent support for the idea that alpha-T provides women with any protection from breast cancer. In contrast, studies indicate that alpha, gamma, and delta-tocotrienols but not alpha-T have potent anti-proliferative effects in human breast cancer cells. Our aim was to investigate whether there was a difference in tocopherol and tocotrienol concentrations in malignant and benign adipose tissue, in a Malaysian population consuming predominantly a palm oil diet. The study was undertaken using fatty acid levels in breast adipose tissue as a biomarker of qualitative dietary intake of fatty acids. The major fatty acids in breast adipose tissue of patients (benign and malignant) were oleic acid (45-46%), palmitic (28-29%) and linoleic (11-12%). No differences were evident in the fatty acid composition of the two groups. There was a significant difference (p=0.006) in the total tocotrienol levels between malignant (13.7 +/- 6.0 microg/g) and benign (20+/-6.0 microg/g) adipose tissue samples. However, no significant differences were seen in the total tocopherol levels (p=0.42) in the two groups. The study reveals that dietary intake influences adipose tissue fatty acid levels and that adipose tissue is a dynamic reservoir of fat soluble nutrients. The higher adipose tissue concentrations of tocotrienols in benign patients provide support for the idea that tocotrienols may provide protection against breast cancer.

Vitamin E and apoptosis

Sylvester PW.

Vitam Horm. 2007;76:329-56.

Vitamin E is a generic term that refers to a family of compounds that is further divided into two subgroups called tocopherols and tocotrienols. All natural forms of tocopherols and tocotrienols are potent antioxidants that regulate peroxidation reactions and controls free radical production within the body. However, it is now firmly established that many of the biological actions mediated by individual vitamin E isoforms are not dependent on their antioxidant activity. Furthermore, synthetic ether derivatives of vitamin E that no longer possess antioxidant activity also display a wide range of biological activities. One of the most intriguing therapeutic applications for natural vitamin E and vitamin E derivatives currently being investigated is their use as anticancer agents. Specific forms of vitamin E display potent apoptotic activity against a wide range of cancer cell types, while having little or no effect on normal cell function or viability. Experimental studies have also determined that the intracellular mechanisms mediating the apoptotic effects of specific vitamin E compounds display great diversity in different types of caner cells and has been found to restore multidrug resistant tumor cells sensitivity to chemotherapeutic agents. These findings strongly suggest that some natural and synthetic analogues of vitamin E can be used effectively as anticancer therapy either alone or in combination to enhance the therapeutic efficacy and reduce toxicity of other anticancer agents.

Tocotrienols are a group of natural vitamin E compounds with patent antitumoral effects, mostly based on their ability to induce apoptosis in cancer cells. In activated pancreatic stellate cells (PSCs) we have determined that tocotrienols elicit a dramatic mitochondrial destabilization followed by initiation of non-necrotic forms of programmed cell death, namely apoptosis and autophagy. PSCs are the main cell type involved in the generation of pancreatic fibrosis, and their removal is critical to limit the fibrogenic process. Noteworthy, tocotrienol death-promoting actions are exclusively directed to activated PSCs, but not to their quiescent counterparts nor to terminally differentiated acinar cells. Here, we hypothesize that the transformed phenotype of PSCs may include “activated” mitochondria, which can be used by tocotrienols to trigger autophagic and apoptotic signaling. We propose that mitochondria are the cornerstone of cell sensitivity to tocotrienols, and suggest possible mechanisms, that may be interconnected, on how tocotrienols may govern mitochondrial death pathways.

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Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects

James M. Roza, CN; Zheng Xian-Liu, PhD; Najla Guthrie

Altern Ther Health Med. 2007 Nov-Dec;13(6):44-8

Context • Preliminary studies have suggested that both citrus flavonoids and palm tocotrienols reduce cholesterol levels in laboratory animals.

Objective • To examine the effect of these nutrients in combination on blood levels of cholesterol and related cardiovascular disease risk factors.

Design • Two open-label studies and 1 double-blind study are reported.

Setting • Outpatient clinical research setting.

Patients • Three groups (n=10, n=10, n=120) of hypercholesterolemic men and women (cholesterol levels >230 mg/dL) between the ages of 19 and 65 years were recruited.

Intervention • Subjects were randomized to consume either 270 mg citrus flavonoids plus 30 mg tocotrienols (S) or placebo (P) daily for a period of 4 weeks (group 1 [G1] and group 2[G2]) or 12 weeks (group 3 [G3]).

Main Outcome Measures • Measurements of fasting levels of blood cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides were made at baseline and 4 weeks (all groups) and at 8 weeks and 12 weeks (G3).

Results • Daily treatment with S significantly improved cardiovascular parameters compared to P in all groups. Significant reductions were shown in total cholesterol (20%-30%), LDL (19%-27%), apolipoprotein B (21%), and triglycerides (24%-34%). HDL levels remained unchanged in G1 and G2 but increased 4% (nonsignificant) in G3 and was accompanied by a significant increase in apolipoprotein A1 (5%).

Protection of cerebellar granule cells by tocopherols and tocotrienols against methylmercury toxicity

Shichiri M, Takanezawa Y, Uchida K, Tamai H, Arai H.

Brain Res. 2007 Nov 28;1182:106-15.

Excessive free radical formation has been implicated as one of the causative factors in neurotoxic damage associated with variety of metals, including methylmercury (MeHg). Although the mechanisms associated with MeHg-dependent neurotoxicity remains are unclear, it is known that MeHg leads to neurotoxicity in cerebellar granule cells (CGCs). In vitro exposure of murine CGC primary cultures to MeHg resulted in time- and concentration-dependent cell death. The present study was designed to assess the effect of fat-soluble antioxidant tocopherols and tocotrienols (unsaturated vitamin E) on MeHg-induced neurotoxicity using cultured CGCs. Significant protection from MeHg-induced neuronal cell death was observed with both tocopherols and tocotrienols. Moreover, we observed that tocotrienols are multi-fold more potent than tocopherols in protecting CGCs against MeHg neurotoxicity. At micromolar concentration, tocotrienols, but not tocopherols, showed complete protection by an antioxidant mechanism. Similarly, tocopherols and tocotrienols showed a protective effect on CGCs migration against MeHg-toxicity. These results suggested that oxidative events may contribute to MeHg toxicity in isolated cerebellar granule neurons, and that tocotrienols are potent supplements for pharmacological protection of the developing brain exposed to MeHg.

Vitamin E and mast cells

Zingg JM.

Vitam Horm. 2007;76:393-418.

Mast cells play an important role in the immune system by interacting with B and T cells and by releasing several mediators involved in activating other cells. Hyperreactivity of mast cells and their uncontrolled accumulation in tissues lead to increased release of inflammatory mediators contributing to the pathogenesis of several diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and allergic disorders such as asthma and allergic rhinitis. Interference with mast cell proliferation, survival, degranulation, and migration by synthetic or natural compounds may represent a preventive strategy for the management of these diseases. Natural vitamin E covers a group of eight analogues-the alpha-, beta-, gamma-, and delta-tocopherols and the alpha-, beta-, gamma-, and delta-tocotrienols, but only alpha-tocopherol is efficiently retained by the liver and distributed to peripheral tissues. Mast cells preferentially locate in the proximity of tissues that interface with the external environment (the epithelial surface of the skin, the gastrointestinal mucosa, and the respiratory system), what may render them accessible to treatments with inefficiently retained natural vitamin E analogues and synthetic derivatives. In addition to scavenging free radicals, the natural vitamin E analogues differently modulate signal transduction and gene expression in several cell lines; in mast cells, protein kinase C, protein phosphatase 2A, and protein kinase B are affected by vitamin E, leading to the modulation of proliferation, apoptosis, secretion, and migration. In this chapter, the possibility that vitamin E can prevent diseases with mast cells involvement by modulating signal transduction and gene expression is evaluated.

Vitamin E: Inflammation And Atherosclerosis

U. Singh and S. Devaraj

Vitam Horm. 2007;76:519-49

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the western world with its incidence increasing lately in developing countries. Several lines of evidence support a role for inflammation in atherogenesis. Hence, dietary micronutrients having anti-inflammatory properties may have a potential beneficial effect with regard to CVD. Vitamin E is a potent antioxidant with anti-inflammatory properties. It comprises eight diferent isoforms: four tocopherols (T) (α, β, γ, and δ) and four tocotrienols (T3) (α, β, γ, and δ). A wealth of data is available for the preventive efficacy of  alpha-T. alpha-T supplementation in human subjects and animal models has been shown to be antioxidant and antiinflammatory in terms of decreasing C-reactive protein (CRP) and release of proinflammatory cytokines, the chemokine IL-8 and PAI-1 levels especially at high doses. Gamma-T is effective in decreasing reactive nitrogen species and also appears to have antiinflammatory properties; however, there are scanty data examining pure gamma-T preparations. Furthermore, tocotrienols (α and γ) also have implications for prevention of CVD; however, there are conflicting and insuffcient data in the literature with regards to their potency. In this chapter, we have gathered recent emerging data on alpha T specifically and also have given a composite view of gamma-T and tocotrienols especially with regards to their effect on inflammation as it relates to CVD.

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