December 18, 2017
In the recent history of dietary supplements, vitamin E has been around forever. Discovered in 1922, it was once known only as tocopherol because the tocotrienol form had not yet been identified. The bulk of research was on tocopherols until recently, which may explain why alpha-tocopherol is the form used in most multivitamins and supplemented in foods today. Yet, a growing body of evidence suggests tocotrienols—which contain some exceptional benefits not shared by their “older” tocopherol siblings–deserve a closer look.
The term “vitamin E” covers eight compounds grouped into tocopherols and tocotrienols, each with different chemistries and biological effects. The eight separate, but related, molecules in the vitamin E family are four tocopherols (alpha, beta, gamma and delta) and four tocotrienols (alpha, beta, gamma and delta).
History and Sources
The first form of vitamin E discovered, alpha-tocopherol, was extensively researched between 1922 and 1940, covering isolation from plants,1 chemical identification,2,3 recognition of the antioxidant properties,4 and complete synthesis.5 In the 1950s, natural tocopherols derived from soy began to be commercialized. As demand for tocopherols grew, many companies moved away from soy- and corn-based tocopherols, which yield less than 20 percent alpha-tocopherol, searching for higher yield sources. Today, much “natural” alpha-tocopherol on the market is, in fact, semi-synthetic, with soy- and corn-based tocopherols synthesized to RRR- or d-alpha tocopherol via the addition of one methyl group to gamma-tocopherol and two methyl groups to delta-tocopherol.6 These methyl groups are petrochemically sourced.
Tocotrienols, initially mislabeled as tocopherols, were not discovered until the mid-1960s, 7,8 so the body of research into this form was understandably slower to develop. The ability of tocotrienols to lower lipids was first reported in the early 1980s. Then, in the 1990s, they were associated with inhibition of cancers and reduction of cardiovascular diseases (CVD).9 Even with expanding research on tocotrienols, they are still sometimes confused with tocopherols. “The Merck Index,” the encyclopedia of chemicals, drugs and biologicals, didn’t set it straight until 2001.10
While synthetic versions of tocopherols are common in the marketplace, tocotrienols are solely derived from natural sources. Tocotrienols are often present alongside tocopherols in various compositions. They are derived from three major sources: rice, palm and annatto. Palm and rice sources contain 25 to 50 percent alpha-tocopherol. Annatto is the only known source of tocotrienols with virtually no tocopherols present.
Research Uncovers Tocotrienol’s Heart Health, Anti-inflammatory Benefits
Tocopherol’s antioxidant effect is well-known, especially in the protection of lipids. Expecting more of tocopherols is unreasonable, as communicated by alpha-tocopherol expert Maret Traber in her review article, “Vitamin E, antioxidant and nothing more.”11 Tocotrienol goes further. Studies indicated tocotrienol–not tocopherol–can decrease total and low-density lipoprotein (LDL) cholesterol, which is partially responsible for the vitamin’s cardiovascular benefits.
The first study proposing that tocotrienols were more potent hypocholesterolemic agents, when administered with the lowest alpha-tocopherol content possible, was published in 1996.12 It concluded: for tocotrienols to affect cholesterol reduction, the alpha-tocopherol content should not be more than 15 percent. Four years later, another study confirmed these results.13 Additional research also found alpha-tocopherol compromises tocotrienol’s ability to reduce triglycerides, exacerbates stroke injury, inhibits tocotrienol absorption and prevents tocotrienol adipose storage.14,15,16,17,18 Many subsequent human trials have expanded understanding of tocotrienols’ effectiveness on heart health.19
Tocotrienol’s effect on inflammatory markers has also been established. In a 2015 study, C-reactive protein (CRP), which increases in the presence of inflammation, was reduced by 40 percent in subjects.20 Overall inflammation markers were down 35 to 60 percent.
Additional clinical studies showed that delta-tocotrienol, combined with antioxidant polyphenols, limit inflammation and manage dyslipidemia. One placebo-controlled study was conducted in two groups of elderly subjects over six weeks, one with elevated lipid levels, the other normal.21 The product formulation was composed of delta-tocotrienol from annatto along with a B vitamin (niacin) and polyphenols. Both groups showed a significant drop in CRP and γ-glutamyl-transferase (a predictor for fatal coronary heart disease and non-fatal myocardial infarction), while increasing total antioxidant status. LDL cholesterol (20 to 28 percent) and triglycerides (11 to 18 percent) also dropped in the hypercholesterolemic group. No adverse effects were observed with either group.
Bone Health Benefits
A more recent area of investigation is the role of tocotrienols in bone health, with several animal studies published on the subject.22,23,24,25 In one in-vivo study, tocotrienol from annatto, both with and without lovastatin, increased bone formation and mineralization in rats.26 The tocotrienol, and tocotrienol and lovastatin groups increased expression of bone morphogenetic protein-2 (BMP-2) over the control group by 3.3 and 4.0 times, respectively. The authors concluded that “supplementation of tocotrienol in statin users can potentially protect them from osteoporosis.” This application may have broad utility because of widespread statin usage.
To confirm findings of pre-clinical settings, a clinical, double-blind, placebo-controlled trial, expected to publish by the end of 2017, set out to examine tocotrienol’s effect on bone health of 89 postmenopausal women using American River Nutrition’s DeltaGold Annatto Tocotrienol.27 Resulting data will fill an important gap in knowledge on tocotrienols in bone health.
While some have questioned the bioavailability of tocotrienols, one study showed, when taken with a meal, tocotrienol absorbed two- to three-fold better than when taken on an empty stomach.28 Pre-solubilized forms of vitamin E have popped up on the market, but are generally only useful when taken on an empty stomach. Major drawbacks of pre-solubilized or “bio-enhanced” formulations include unwanted added ingredients that are not natural and large capsule size, which may be unacceptable to consumers’ clean-label preferences. Clinical pharmacokinetic studies of a high-purity tocotrienol product have been performed and confirm the ingredient’s bioavailability, opening the door to increased consumer compliance of smaller capsule sizes without fillers or excipients, and allowing formulations with other ingredients.29,30 The take-home: consumers should take tocotrienols with a meal, and leave room for complementary platforms of synergistic combo products, including omega-3s, vitamin D, vitamin K and coenzyme Q10 (CoQ10).
A New Perspective on Vitamin E
Tocopherols and tocotrienols are important antioxidants, and fit well inside membranes and cell walls found throughout the human body, where they protect the 30 to 40 pounds of each person’s lipids from oxidation. This function was always there, and is a big deal.
Tocotrienols go further–they work to reverse chronic ills of the cardiometabolic, musculoskeletal and cellular systems. This is a unique proposition, scientifically star-powered, in tocotrienols. Some of these benefits have common platforms with other lipid nutrients, and therefore, novel combinations can be feasibly formulated. In today’s fast-paced market of ever-emerging ingredients, a new perspective on an old-fashioned staple—vitamin E—is in place. Here, tocotrienols deserve a closer look.
Evans HM et al., “The isolation from wheat germ oil of an alcohol alpha-tocopherol, having the properties of vitamin E,” The Journal of Biological Chemistry, vol. 113, no. 1 (February 1936):319-332
Fernholz E, “The thermal decomposition of alpha-tocopherol,” Journal of the American Chemical Society, vol. 59, no. 6 (July 1937):1154-1155
Fernholz E, “On the constitution of alpha-tocopherol,” Journal of the American Chemical Society, vol. 60, no. 3 (March 1938):700-705
Olcott HS et al., “Antioxidant and autoxidation of fats: the antioxidant properties of tocopherols,” Journal of the American Chemical Society, vol. 59, no. 6 (June 1937):1008-1009
Karrer P et al., “Synthese des alpha-tocopherol,” Hevetica Chimica Acta, vol. 21 (1938):820-825
Tan B, “Appropriate spectrum vitamin E and new perspectives on desmethyl tocopherols and tocotrienols,” Journal of the American Nutraceutical Association, vol. 8, no. 1 (2005):35-42
Pennock JF et al., “Reassessment of tocopherol in chemistry,” Biochemical and Biophysical Research Communications, vol. 17, no. 5 (November 30, 1964):542-548
Whittle KJ et al., “The isolation and properties of delta-tocotrienol from Hevea latex,” The Biochemical Journal, vol. 100, no. 1 (July 1966):138-145
Sylvester P et al., “Role of tocotrienols in the prevention of cardiovascular disease and breast cancer,” Current Topics in Nutraceutical Research, vol. 1, no. 2 (May 2003):121-136
Merck Index 13th ed. Tocols: 9570-9577. Rahway, NJ. Merck Publishing Group; 2001:1693-1694.
Traber MG, Atkinson J. Vitamin E, antioxidant and nothing more. Free Radic Biol Med. 2007;43(1):4-15.
Qureshi AA et al., “Tocopherol attenuates the impact of gamma-tocotrienol on HMG-CoA reductase activity in chickens,” Journal of Nutrition, vol. 126, no. 2 (February 1996):389-394
Khor HT et al., “Effects of administration of alpha-tocopherol and tocotrienols on serum lipids and liver HMG CoA reductase activity,” International Journal of Food Sciences and Nutrition, vol. 51, suppl. 1(2000):S3-S11
Trias AM, Tan B. Alpha-Tocopherol: A Detriment to Tocotrienol Benefits. In: [ital] Tocotrienols: Vitamin E Beyond Tocopherols, 2nd ed. Tan B, Watson R, Preedy V, editors. Boca Raton, FL: CRC Press; 2013:61-78
Shibata A, Kawakami Y, Kimura T, Miyazawa T, Nakagawa K. alpha-Tocopherol Attenuates the Triglyceride- and Cholesterol-Lowering Effects of Rice Bran Tocotrienol in Rats Fed a Western Diet. J Agric Food Chem. 2016;64(26):5361-6. Epub 2016/06/14.
Khanna S, Heigel M, Weist J, Gnyawali S, Teplitsky S, Roy S, et al. Excessive alpha-tocopherol exacerbates microglial activation and brain injury caused by acute ischemic stroke. Faseb J. 2015;29(3):828-36. Epub 2014/11/21.
Ikeda S, Tohyama T, Yoshimura H, Hamamura K, Abe K, Yamashita K. Dietary alpha-tocopherol decreases alpha-tocotrienol but not gamma-tocotrienol concentration in rats. J Nutr. 2003;133(2):428-34.
Ikeda S, Uchida T, Abe C. Bioavailability of Tocotrienols and Interference of Their Bioavailability by Alpha-Tocopherol Supplementation. In: [ital] Tocotrienols: Vitamin E Beyond Tocopherols [ital], 2nd ed. Tan B, Watson R, Preedy V, editors. Boca Raton, FL: CRC Press; 2013:53-60.
Qureshi AA et al., “Dose-dependent modulation of lipid parameters, cytokines and RNA by delta-tocotrienols in hypercholesterolemic subjects restricted to AHA step-1 diet,” British Journal of Medicine & Medical Research, vol. 6, no. 4 (2015):351-366.
Qureshi AA, Khan DA, Mahjabeen W, Trias AM, Silswal N, Qureshi N. Impact of delta-tocotrienol on inflammatory biomarkers and oxidative stress in hypercholesterolemic subjects. Clin Exp Cardiology. 2015;6(4):1000367.
Qureshi AA et al., “Suppression of nitric oxide production and cardiovascular risk factors in healthy seniors and hypercholesterolemic subjects by a combination of polyphenols and vitamins,” Journal of Clinical & Experimental Cardiology. Published online June 7, 2012.
Chin KY, Abdul-Majeed S, Fozi NF, Ima-Nirwana S. Annatto tocotrienol improves indices of bone static histomorphometry in osteoporosis due to testosterone deficiency in rats. Nutrients. 2014;6(11):4974-83. Epub 2014/11/13.
Chin KY, Ima-Nirwana S. Effects of annatto-derived tocotrienol supplementation on osteoporosis induced by testosterone deficiency in rats. Clin Interv Aging. 2014;9:1247-59. Epub 2014/08/15.
Chin KY, Gengatharan D, Mohd Nasru FS, Khairussam RA, Ern SL, Aminuddin SA, et al. The Effects of Annatto Tocotrienol on Bone Biomechanical Strength and Bone Calcium Content in an Animal Model of Osteoporosis Due to Testosterone Deficiency. Nutrients. 2016;8(12). Epub 2016/12/17.
Shen CL, Klein A, Chin KY, Mo H, Tsai P, Yang RS, et al. Tocotrienols for bone health: a translational approach. Ann N Y Acad Sci. 2017;1401(1):150-65. Epub 2017/09/12.
Chin KY et al., “The effects of tocotrienol and Lovastatin co-supplementation on bone dynamic histomorphometry and bone morphogenetic protein-2 expression in rats with estrogen deficiency,” Nutrients. Published online February 15, 2017.
Shen CL, Mo H, Yang S, Wang S, Felton CK, Tomison MD, et al. Safety and efficacy of tocotrienol supplementation for bone health in postmenopausal women: protocol for a dose-response double-blinded placebo-controlled randomised trial. BMJ open. 2016;6(12):e012572. Epub 2016/12/25.
Qureshi AA, Khan DA, Saleem S, Silswal N, Trias AM, Tan B, et al. Pharmacokinetics and bioavailability of annatto delta-tocotrienol in healthy fed subjects. Journal of Clinical & Experimental Cardiology. 2015;6(11):1000411.
Qureshi AA, Khan DA, Silswal N, Saleem S, Qureshi N. Evaluation of Pharmacokinetics, and Bioavailability of Higher Doses of Tocotrienols in Healthy Fed Humans. Journal of Clinical & Experimental Cardiology. 2016;7(4). Epub 2016/08/06.
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