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Modern research on vitamin E tocotrienols.
By Brian Tanzer, MS, Reliance Private Label Supplements
Vitamin E is an essential lipid soluble nutrient that consists of eight naturally occurring isomers: four tocopherols (alpha, beta, gamma, and delta) and four tocotrienols (alpha, beta, gamma, and delta).
Until recently, most of the research on vitamin E focused on the tocopherols, mainly alpha-tocopherol. A review of the scientific literature on tocotrienols (via PubMed) shows that most of the literature on this form of vitamin E has been published on or after 2000. As a result, tocotrienol supplements have only recently become widely recognized as providing significant health benefits-and therefore only recently become more widely available.
The importance of consuming all eight vitamin E compounds is clearly demonstrated in numerous studies that show that vitamin E as found in food is typically more effective than alpha-tocopherol supplements in reducing risk of death from cardiovascular disease.1,2 The typical American diet contains more gamma-tocopherol and tocotrienols than alpha-tocopherol, which can offer greater antioxidant protection and cholesterol-lowering potential.
Palm oil is one of the most significant sources of tocotrienols (70%), particularly alpha- and gamma-tocotrienol, and has consistently been used as a source of supplemental tocotrienols. Other, less significant sources of tocotrienols include rice bran oil (mostly gamma) as well as wheat germ, oats, and barley.
Despite the presence of tocotrienols in these food sources, the amounts available would not be enough to be clinically significant. For example, it takes 1000 kg of crude palm oil to produce 1 kg of a specific brand of tocotrienols commonly used in dietary supplements. One would have to consume 100 to 200 g of palm oil-or about 3 kg of wheat germ, barley, or oat-to achieve doses that have been shown in the research to have clinically significant biological activity.
Research on tocotrienols is focused on three main areas: cardiovascular health, cancer, and neurological health.
Elevated total and low-density lipoprotein (LDL) cholesterol are established risk factors for cardiovascular disease. The cardioprotective effects of tocotrienols are mediated through their ability to influence the activity of HMGCoA-reductase, the rate-limiting enzyme involved in the biosynthesis of cholesterol.
Tocopherols don’t share tocotrienols’ ability to reduce elevated cholesterol. In fact, alpha-tocopherol may reduce or interfere with the cholesterol-lowering ability of tocotrienols.3 Several studies have demonstrated the ability of tocotrienols to reduce both total and LDL cholesterol levels.4-6
In addition, tocotrienols help protect the cardiovascular system via their ability to provide antioxidant support. These antioxidant activities are mediated through induction of antioxidant enzymes such as superoxide dismutase7,8 and glutathione peroxidase9. Studies also demonstrate the potent anti-inflammatory properties of tocotrienols, which involve the activation of NF-Kb, the suppression of TNF and COX-2.10-13Cancer
Several studies on cancer and vitamin E have demonstrated poor outcomes, mostly due to the use of a single compound, namely alpha-tocopherol. The synergism of the eight vitamin E family of compounds is such that when provided as a group, the benefits are more clear. In a recent study, researchers at Rutgers University reported that mice supplemented with a brand of mixed tocotrienols blended with alpha-tocopherol showed, after their study period, a significantly lower occurrence of prostate tumors compared to the control.14
Due to the presence of a unique structure containing a short isoprenoid tail with three unsaturated double bonds, tocotrienols are able to enter the cell more freely and carry out specific metabolic functions more efficiently compared with tocopherols.15 In addition, their structure gives them stronger anticancer activities than tocopherols, with gamma- and delta-tocotrienol having the greatest activity.16-18
The antitumor effect of tocotrienols is mediated, at least in part, through their ability to inhibit angiogenesis by attenuation of serum Vascular Endothelial Growth Factor (VEGF) levels. VEGF is regarded as one of the earliest and most important signals to stimulate angiogenesis, regulating key responses of endothelial cells such as proliferation, migration and differentiation, and protection from apoptosis (cell death).19Neurology
The dry weight of the brain is approximately 60% phospholipid. The majority of the phospholipid resides in the cell membrane, and it is here that vitamin E plays a significant role by helping protect the membrane against oxidative damage.
Tocotrienols have been shown to help reduce neurodegeneration by regulating key signalling processes involved in neurotoxicity. Activation of the signalling mediators c-SRC and 12-LOX (12-lipoxygenase) is a key step in the chemical cascade that leads to glutamate-induced neurotoxicity. This activation can be inhibited by alpha-tocotrienols.20,21 A recent study showed alpha-tocotrienol targets specific pathways to protect against neural cell death and rescues the brain after stroke injury.22
Tocotrienols are powerful protectors of healthy brain cells and, in conjunction with tocopherols and other important nutrients and cofactors, help provide a strong foundation for neurological health.
Like most other nutrients, the vitamin E family of compounds works synergistically to perform a myriad of biological functions. When looking for a vitamin E supplement, the days of just using alpha-tocopherol because that’s what was available are over.
In order to reap the full benefits of vitamin E, one must find and use a supplement that provides the full complement of tocopherols and tocotrienols. This is the only way to help ensure you’re giving your body what it needs to achieve optimal health and wellness.
1.Kushi LH, et al. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med1996 May 2;334:1156-62.
2.. Knekt P, et al. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol1994 Jun 15;139:1180-9.
3. Qureshi AA, et al. Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J Nutr. 1996. 126:389-94.
4. Qureshi AA, et al. Response of hypercholesterolemic subjects to administration of tocotrienols. Lipids 1995;30:1171-1177.
5. Bradlow BA, et al. Novel tocotrienols of rice bran modulate cardiovascular disease parameters of hypercholesterolemic humans. J Nutr Biochem 1997;8:290-298.
6. Gapor A, et al. Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee). Am J Clin Nutr 1991;53:1021S-1026S.
7. Lee SP, Mar GY, Ng LT. Effects of tocotrienol-rich fraction on exercise endurance capacity and oxidative stress in forced swimming rats. Eur J Appl Physiol 2009;107:587-595.
8. Newaz MA, Nawal NN. Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 1999;21:1297-1313.
9. Adam A, et al. Nitrofurantoin-induced hepatic and pulmonary biochemical changes in mice fed different vitamin E doses. Pharmacol Toxicol 1996;79:334-339.
10. Aggarwal BB, et al. Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK-1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis. J Biol Chem 2007;282:809-820.
11. Shirode AB, Sylvester PW. Synergistic anticancer effects of combined gamma-tocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling. Biomed Pharmacother 2010;64:327-332.
12. Kuhad A, Chopra K. Attenuation of diabetic neuropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci 2009;84:296-301.
13. Huang J, et al. Long-chain carboxychromanols, metabolites of vitamin E, are potent inhibitors of cyclooxygenases. Proc Natl Acad Sci USA 2008;105:20464-20469.
14. Sen C, et al. Mixed tocotrienols inhibit prostate carcinogenesis in TRAMP mice. Nutr Cancer 2010;62:789-799.
15. Das S, et al. Cardioprotection with palm tocotrienols: comparison of different isomers. Am J Physiol Heart Circ Physiol 2008;294:H970-H978.
16. Nasaretnam K, et al. Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Lipids 1995;30:1139-1143.
17. Sakai M, et al. Apoptosis induction by gamma-tocotrienol in human hepatoma Hep3B cells. J. Nutr Biochem 2006;17:672-676.
18. Sun W, et al. gamma-tocotrienol induces mitochondria-mediated apoptosis in human gastric Adenocarcinoma SGC-7901 cells. J Nutr Biochem 2009;20:276-284.
19. Nasaretnam K, et al. Suppression of tumor growth by palm tocotrienols via the attenuation of angiogenesis. Nutr Cancer 2009;61:367-373.
20. Khanna S, et al. Molecular basis of vitamin E action: tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 2003;278:43508-43515.
21. Sen CK, et al. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp-60 (c-SRC) kinase activation and death of HT4 neuronal cells. J Biol Chem;275:13049-13055.
22.Chandan CK, et al. Nanomolar vitamin E alpha-tocotrienol inhibits glutamate-induced activation of phospholipase A2 and causes neuroprotection. J Neurochem 2010;112:1249-1260.