Barrie Tan, Ph.D.; Anne Mueller, MSc
American River Nutrition, Inc.
Tocotrienols possess a more powerful ability to help maintain healthy cholesterol levels when compared to tocopherols.37 Research also shows that high levels of alpha tocopherol may limit the bioavailability and functional activity of other vitamin E isomers.4 While tocopherols and tocotrienols are both vital for a variety of cardiovascular and whole health goals, they ought to be taken individually, separated by several hours to optimize the body’s ability to process them appropriately.*
Desmethyl tocotrienols such as gamma- and delta tocotrienol were found to be much more bioactive than fully methylated tocotrienols and tocopherols. Gamma- and delta-tocotrienol are powerful heterogeneous antioxidants working at the surface of cells. They can support healthy vascular integrity, promote healthy coagulation, and provide significant antioxidant support, all of which contribute to cardiovascular and overall metabolic health including the maintenance of healthy blood glucose levels.38*
The following is an in-depth review of current research looking into the cardiovascular support provided by tocotrienols.*
Tocotrienol and tocopherol, the two forms of the vitamin E family, are similar in that both have the same head called chromanol nucleus, which is the site of their well-known antioxidant activities. Tocotrienol and tocopherol differ in the molecule’s tail. Tocotrienol has a shorter farnesyl tail containing double bonds that downregulate 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme of cholesterol synthesis. Tocopherol, on the other hand, has a longer phytyl tail without double bonds. Alpha, beta, gamma, and delta are among the isomers of tocotrienol as well as tocopherol. For tocotrienol, the isomers have a graduated ability to help maintain healthy cholesterol levels, as follows: delta>gamma >alpha>beta.*
The isomers of tocotrienols differ depending on the substitution and location of methyl groups at the head region of the molecule. Desmethyl tocotrienols (tocotrienols with less methyl groups) are more active, especially in the absence of a methyl group at C5 position on the chromanol ring system. Delta- and gamma-tocotrienol are the only two isomers that fit this molecular formula. Delta-tocotrienol is known to be monomethylated at C8 position of the chromanol ring system, making it the least substituted, and therefore the most potent isomer of the four tocotrienol compounds.
Compared to tocotrienols, tocopherols do not have the same ability to maintain healthy cholesterol levels. In fact, alpha-tocopherol has been shown to attenuate or interfere with this effect of tocotrienols.1 The majority of vitamin E supplements contain mostly tocopherols (and for that, mostly alpha-tocopherol) and only traces of tocotrienols, and large clinical studies on alpha-tocopherol’s support for cardiovascular health have been equivocal.*
Preparations effective in promoting healthy cholesterol levels consist of less than 15-20% alpha tocopherol and more than 60% gamma- and delta-tocotrienol, whereas less effective or ineffective preparations consist of more than 30% alpha-tocopherol and less than 45% of gamma- and delta-tocotrienol. This has been supported by clinical studies in which supplements with high alpha-tocopherol content did not contribute significant health-promoting effects related to maintaining healthy cholesterol levels2,3, whereas supplements containing low amounts of alpha-tocopherol and high amounts of gamma- and delta-tocotrienol led to a significant support for promoting healthy total cholesterol and LDL cholesterol levels.4,5*
In addition, tocotrienols absorbed better than tocopherols,6 and alpha-tocopherol (if present with other E vitamers) has been shown to prevent absorption of tocopherols and tocotrienols.7
Tocotrienols, although found in low amounts in the American diet (naturally in oils and fats, whole foods, and some processed foods) are most abundant in palm, rice, and annatto. Rice contains about 50% tocotrienols and 50% tocopherols, whereas palm contains approximately 75% tocotrienols and 25% tocopherols. Annatto ranks highest in tocotrienol content, since its tocotrienol content is 100%, and it is virtually tocopherol-free.
A.C. Grace’s tocotrienol product contains the wholesome rainforest annatto derived (not palm sourced) tocotrienols that have the highest concentration of the most effective component of tocotrienols – delta-tocotrienol – using a patented solvent-free extraction method. Annatto tocotrienol contains 90% delta-tocotrienol and 10% gamma-tocotrienol, and better yet, it is tocopherol-free.
The mechanism of tocotrienol’s hypolipidemic action involves posttranscriptional suppression of HMG-CoA reductase,8 and specifically modulates the intracellular mechanism for controlled degradation of the reductase protein9 in charge of cholesterol synthesis.
Ubiquitination, the inactivation of a protein by attaching a ubiquitin to it is an important stage in the degradation of HMG-CoA reductase. As a ubiquitin is attached to the HMG-CoA reductase, the molecule is tagged for transport to the proteasome, a multi-protein complex where degradation occurs. Just recently it has been reported that only gamma- and delta-tocotrienol stimulate the ubiquitination and degradation of the HMG-CoA reductase. In addition, gamma- and delta-tocotrienol block processing of sterol regulatory element-binding proteins (SREBPs), membrane-bound transcription factors that modulate transcription of genes encoding cholesterol biosynthetic enzymes and LDL receptor. Blocking SREBP processing may have implications on the triglyceride synthesis with resulting implications for metabolic health and the maintenance of healthy blood glucose levels.*
Other forms of vitamin E (all four tocopherols and alpha- and beta-tocotrienols) do not degrade, down regulate, or block SREBP processing.10
1. Maintenance of Healthy Cholesterol Levels: Recently, animal studies supported results found in earlier cell line studies. Animals whose diet was supplemented with gamma- and delta-tocotrienols demonstrated the greatest support for healthy cholesterol levels, whereas alpha-tocopherol had no such effect. In this study, healthy HDL/LDL cholesterol ratios were dramatically supported. The safe dose of various tocotrienols for human consumption is estimated to be 200-1,000mg/day.11*
In humans, two open studies7 measured fasting blood lipids before and 2 months after supplementation with annatto tocotrienol (75mg/day) supplementation. In both groups, significant support was demonstrated for the maintenance of healthy cholesterol levels and healthy HDL/LDL ratios.12*
2. Metabolic Health: Supporting metabolic health is a growing health goal for an estimated 16% of US residents (47 million).13 Metabolic health is influenced by and related to weight management, triglyceride levels, blood pressure levels, and blood glucose metabolism. 14,15 Tocotrienols, especially gamma- and delta-tocotrienols, can provide support for vascular and cardiometabolic integrity and ultimately support metabolic health.*
In animal studies, tocotrienol supplementation has been shown to support cardiovascular health, promote healthy blood glucose levels, help maintain healthy cholesterol levels, and support overall metabolic health.16,17 Tocotrienols have been shown to provide a similar effect in human clinical studies.18,19,20 Supplementation of 75mg/day delta-tocotrienol in a small open study was found to promote metabolic health, while supporting the maintenance of healthy triglyceride levels.7*
3. Arterial Health: Tocotrienols have been shown to support the body’s natural ability to regulate cellular adhesion molecule expression and monocytic cell adherence.21 In particular, delta- tocotrienol showed the most profound effect on monocytic cell adherence as compared to tocopherols and other tocotrienol isomers.22 It has been suggested that this phenomenon occurs via inhibition of vascular cell adhesion molecule, VCAM-1 expression by delta-tocotrienol.23*
In a human double-blind cross over study, delta-tocotrienol was shown to be significantly more potent in supporting the body’s natural ability to regulate platelet aggregation than the other tocotrienol isomers.24 Similar support for arterial health has been shown in animal studies, showing stronger effects with tocotrienol supplementation than with tocopherols. Overall arterial health and vascular integrity was enhanced more significantly with desmethyl tocotrienols than with alpha-tocopherol.25,26 Fully methylated tocotrienols and tocopherols do not provide the cardiovascular benefits characteristic of desmethyl tocotrienols.27*
A 4-year placebo-controlled human study on arterial health, showed that tocotrienol supplementation provided significant support for arterial integrity. This study also showed significant support for maintenance of healthy cholesterol levels.28,29,30*
4. Healthy Blood Pressure: Antioxidants play an important role in supporting healthy blood pressure levels and blood vessel integrity and tone through antioxidant effects. Vitamin E is widely known for its antioxidant properties.31 The antioxidant efficiency of tocotrienols was evaluated as the ability of the compounds to help the body regulate lipid peroxidation, reactive oxygen species (ROS) production, and heat shock protein expression. Delta-tocotrienol was found to have the greatest antioxidant properties among the tocotrienol isomers,32 which is due to the decreased methylation of the chromanol ring that allows the molecule to be more easily incorporated into cell membranes.7 A comparative in vitro study showed that gamma- and delta-tocotrienol was 4-fold more efficient as scavenger of peroxyl radicals than other tocotrienol isomers.33*
Blood pressure can ultimately affect arterial integrity, which can influence the natural oxidative processes on arterial walls. In recent animal studies tocotrienols were shown to promote healthy blood pressure levels. When rats were treated with gamma-tocotrienol for three months, plasma and blood vessel lipid peroxides were maintained at healthy levels even in the presence of risk factors, and support for healthy antioxidant status was demonstrated.34 Gamma tocotrienol was shown to significantly support healthy systolic blood pressure, and promoted healthy nitric oxide synthase activity (NOS), both of which play a critical role in maintenance of healthy blood pressure.35 Tocotrienol’s impact on blood pressure levels was confirmed in humans, where tocotrienol-rich vitamin E supplementation resulted in significant support for their aortic systolic blood pressure, as well as significant support for total antioxidant status.36*
1 Qureshi, A. A., B. C. Pearce, R. M. Nor, A. Gapor, D. M. Peterson, and C. E. Elson. 1996. Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J Nutr 126:389-94.
2 Mensink, R. P., A. C. van Houwelingen, D. Kromhout, and G. Hornstra. 1999. A vitamin E concentrate rich in tocotrienols had no effect on serum lipids, lipoproteins, or platelet function in men with mildly elevated serum lipid concentrations. Am J Clin Nutr 69:213-9.
3 Mustad, V. A., C. A. Smith, P. P. Ruey, N. K. Edens, and S. J. DeMichele. 2002. Supplementation with 3 compositionally different tocotrienol supplements does not improve cardiovascular disease risk factors in men and women with hypercholesterolemia. Am J Clin Nutr 76:1237-43.
4 Qureshi, A. A., S. A. Sami, W. A. Salser, and F. A. Khan. 2002. Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Atherosclerosis 161:199-207.
5 Tan, D. T., H. T. Khor, W. H. Low, A. Ali, and A. Gapor. 1991. Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans. Am J Clin Nutr 53:1027S-1030S.
6 Schaffer, S., W. E. Muller, and G. P. Eckert. 2005. Tocotrienols: constitutional effects in aging and disease. J Nutr 135:151-4.
7 Tan, B. 2005. Appropriate spectrum vitamin E and new perspectives on desmethyl tocopherols and tocotrienols. JANA 8:35-42.
8 Pearce, B. C., R. A. Parker, M. E. Deason, A. A. Qureshi, and J. J. Wright. 1992. Hypocholesterolemic activity of synthetic and natural tocotrienols. J Med Chem 35:3595-606.
9 Parker, R. A., B. C. Pearce, R. W. Clark, D. A. Gordon, and J. J. Wright. 1993. Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 268:11230-8.
10 Song, B. L., and R. A. DeBose-Boyd. 2006. Insig-dependent ubiquitination and degradation of 3-hydroxy-3-methylglutaryl coenzyme a reductase stimulated by delta- and gamma-tocotrienols. J Biol Chem 281:25054-61.
11 Yu, S.G., A.M. Thomas, A. Gapor, B. Tan, N. Qureshi, and A.A. Qureshi. Dose-response impact of various tocotrienols on serum lipid parameters in 5-week-old female chickens. 2006. Lipids 41 (5): 453-461.
12 Qureshi, A.A., and N. Qureshi. 1993. Tocotrienols: Novel hypocholesterolemic agents with antioxidant properties. In L. Packer and J. Fuchs (ed.), Vitamin E in Health and Disease. Marcel Dekker, New York.
13 American Heart Association. 2006.
14 Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 2001. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on the Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486-2497.
15 World Health Organization. 1999. Definition, diagnosis, and classification of diabetes mellitus and its complications: report of a WHO consultation. Geneva, World Health Organization.
16 Wan Nazaimoon, W. M., and B. A. Khalid. 2002. Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats. Malays J Pathol 24:77-82.
17 Chen, C.W., and H.H. Cheng. 2006. A rice bran oil diet increases LDL-receptor and HMG-CoA reductase mRNA expressions and insulin sensitivity in rats with streptozotocin/nicotinamide-induced type 2 diabetes. J Nutr 136(6):1472-6.
18 Qureshi, A. A., S. A. Sami, and F. A. Khan. 2002. Effects of stabilized rice bran, its soluble and fiber fractions on blood glucose levels and serum lipid parameters in humans with diabetes mellitus Types I and II. J Nutr Biochem 13:175-187.
19 Montonen, J., P. Knekt, R. Jarvinen, and A. Reunanen. 2004. Dietary antioxidant intake and risk of type 2 diabetes. Diabetes Care 27:362-6.
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22 Chao, J. T., A. Gapor, and A. Theriault. 2002. Inhibitory effect of delta-tocotrienol, a HMG CoA reductase inhibitor, on monocyte-endothelial cell adhesion. J Nutr Sci Vitaminol (Tokyo) 48:332-7.
23 Naito, Y., M. Shimozawa, M. Kuroda, N. Nakabe, H. Manabe, K. Katada, S. Kokura, H. Ichikawa, N. Yoshida, N. Noguchi, and T. Yoshikawa. 2005. Tocotrienols reduce 25-hydroxycholesterol-induced monocyte-endothelial cell interaction by inhibiting the surface expression of adhesion molecules. Atherosclerosis 180:19-25.
24 Holub, B. 1989. Inhibition of Platelet Aggregation by Tocotrienols. University of Guelph, Ontario, Canada. Internal Publication.
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26 Black, T.M., P. Wang, N. Maeda, and R.A. Coleman. 2000. Palm tocotrienols protect ApoE +/- mice from diet-induced atheroma formation. J Nutr 130(10):2420-6.
27 Suarna, C., B. J. Wu, K. Choy, T. Mori, K. Croft, O. Cynshi, and R. Stocker. 2006. Protective effect of vitamin E supplements on experimental atherosclerosis is modest and depends on preexisting vitamin E deficiency. Free Radic Biol Med 41:722-30.
28 Tomeo, A. C., M. Geller, T. R. Watkins, A. Gapor, and M. L. Bierenbaum. 1995. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Lipids 30:1179-83.
29 Kooyenga, D.K., T.R. Watson, M. Geller, M. L. Bierenbaum. 2001. Micronutrients and Health: Antioxidants modulate the course of carotid atherosclerosis: A four-year report. Nesaretnam, K., L. Packer (Eds). Illinois: AOCS Press. 366-375.
30 Watkins, T. R., M. Geller, D. K. Kooyenga, and M. Bierenbaum. 1999. Hypocholesterolemic and antioxidant effect of rice bran oil non-saponifiables in hypercholesterolemic subjects. Env & Nutr Int 3:115-122.
31 Traber, M.G., and J. Atkinson. 2007. Vitamin E, antioxidant and nothing more. Free Rad Biol & Med 43:4-15.
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33 Qureshi, A. A., H. Mo, L. Packer, and D.M. Peterson. 2000. Isolation and structural identification of novel tocotrienols from rice bran with hypocholesterolemic, antioxidant and antitumor properties. J Agric Food Chem48 (8):3130-3140.
34 Newaz, M. A., and N. N. Nawal. 1999. Effect of gamma-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 21:1297-313.
35 Newaz, M. A., Z. Yousefipour, N. Nawal, and N. Adeeb. 2003. Nitric oxide synthase activity in blood vessels of spontaneously hypertensive rats: antioxidant protection by gamma-tocotrienol. J Physiol Pharmacol 54:319-27.
36 Rasool, A.h.g., K.H. Yuen, K. Yusoff, A.R. Wong, and A. R. Rahman. 2006. 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. J Nutr Sci Vitaminol 52:473-478.
37 Sen, C. K., S. Khanna, and S. Roy. 2006. Tocotrienols: Vitamin E beyond tocopherols. Life Sci 78:2088-98.
38 Spinler, S.A. 2006.Challenges associated with metabolic syndrome. Pharmacotherapy 26:209S-17S.