Annatto Tocotrienol

The vitamin E family contains four tocotrienols and four tocopherols

Each has the designation of alpha, beta, gamma, and delta. The tocotrienols differ from the tocopherols in the chemical nature of the side chain or tail. Tocotrienols are fat-soluble, water-insoluble oils and modulate several mechanisms associated with the aging process and aging-related diseases.

Most of the vitamin E supplements sold commercially contain mostly alpha-tocopherol, a major form of vitamin E. Delta-tocotrienol (delta T3) has emerged with functions in health and disease that are clearly distinct from that of alpha-tocopherol.

The tocotrienols (T3s), especially delta tocotrienol has been shown to have the most potent cholesterol lowering, neuroprotective, anti-oxidant activity and anti-cancer effects that are often not exhibited by tocopherols.¹

Significantly, tocotrienols has been shown to offer dramatic cholesterol lowering only when tocopherols are not ingested simultaneously.

Tocotrienols are more valuable than tocopherols in protecting the interior cell membranes, such as those that surround the cell nucleus and mitochondria, because of their greater fluidity and ease in being incorporated into cellular membranes^{1, 2} One feature in the origin of disease and aging is the overproduction of reactive oxygen species (ROS). Tocotrienols possess excellent antioxidant activity and have been suggested to suppress ROS production more efficiently than tocopherols.

The tocotrienol concentration in Mito-GOLD™ consists of approximately 90% delta T3 and 10% gamma-tocotrienol, while most forms of tocotrienol on the market are predominantly alpha - and gamma-tocotrienols.

Annatto Tocotrienol is a natural, tocopherol-free, tocotrienol product and has the highest concentration of delta T3 commercially available.

Annatto Tocotrienol is naturally sourced and is extracted from annatto beans using a solvent free process. Annatto is the most commonly used carotenoid in foods, added for natural coloring.

Commercial sources of tocotrienols

There are 3 commercial sources of tocotrienols - rice bran oil, palm oil, and annatto bean.

The following table shows the ratios of tocotrienols and tocopherols from commercially available sources:

Cholesterol Reduction

Tocotrienols' ability to lower lipids was first reported in the early 1980s. The development of new cholesterol-lowering agents has been given more and more attention by pharmaceutical companies due to the strong relationship between cholesterol and atherosclerosis. Tocotrienols, especially ?- and ?-tocotrienols, were shown to be effective nutritional agents to treat high cholesterol in recent research studies. Specifically, these tocotrienols inhibit the liver enzyme HMG -CoA reductase - the same enzyme inhibited by the statin drugs without the toxic side effects.⁴ Tocopherols block the ability of delta- and gamma-tocotrienol to inhibit HMG -CoA reductase.

The significant differences in the results achieved in clinical trials on lowering cholesterol demonstrate the shortcomings of both rice bran oil and palm oil compared to annatto.

Notably, in the results of human clinical trials, the higher the level of tocopherols in a tocotrienol preparation, the less effective the product is at lowering cholesterol levels and oxidative indicators. Although tocopherols have shown no cholesterol lowering ability, tocotrienols do. Numerous clinical studies have shown that gamma and delta tocotrienols inhibit manufacture of cholesterol in the liver.³

In human studies, HDL increased with Annatto Tocotrienol supplementation. It was clearly documented that annatto extract tocotrienols effectively treated lipidemia of normal weight and overweight/obese subjects.

Subjects took tocopherol-free Annatto Tocotrienol (75 mg/day) consisting of 90% delta-tocotrienol and 10% gamma-tocotrienol.

On average, the total cholesterol and LDL-cholesterol dropped 13%, triglycerides dropped 23%, and HDL-cholesterol increased in all subjects (4-7%) after 2 months of supplementation, indicating a reduction in cardiovascular risk. The supplementation even raised HDL in overweight subjects.⁵

These studies are consistent with the mechanism of action and requirement of tocotrienol in order to modulate lipidemia.

Proper dosage is important. Since tocotrienols can be converted to alpha-tocopherol in the body, taking too high a dosage of tocotrienols actually reduces their ability to lower cholesterol levels.⁶

Cardiovascular Benefits

Tocotrienols have been shown to exert additional benefits to the cardiovascular system, including an ability to decrease the amount of cholesterol plaque in arteries, lower the level of the extremely damaging lipoprotein, prevent the aggregation of platelets, and inhibit the expression of cellular adhesion molecules.^1,7 All of these factors are extremely important in the development and progression of atherosclerotic plaque.

Anticancer Effects of Tocotrienols

Cancer, still one of the leading causes of death, is tightly linked to the aging-process. Gamma and delta-tocotrienols, but not alpha- and gamma-tocopherols, have shown significant tumor-inhibition activity in several studies.

Tocotrienols are potent antioxidants, but anti-tumor activity is possibly independent of antioxidant activity. Part of the reason that tocotrienols are more potent than tocopherols is because of greater cellular accumulation and their ability to affect cell homeostasis.

The ability of the tocotrienols to inhibit the HMG -CoA reductase enzyme has also been the attributed basis for their apparent success in arresting cell proliferation. Recent studies showed that tocotrienol-induced programmed cell death (apoptosis) results from the activation of specific intracellular cysteine proteases (caspases) associated with death receptor activation and signal transduction.⁸

Tocotrienols and Breast Cancer

Tocotrienols may have potential health benefits in preventing and/or reducing the risk of breast cancer in women. Recent studies show that tocotrienols are responsible for growth inhibition in human breast cancer cells in vitro as well as in vivo through estrogen-independent mechanisms.⁹

Delta-tocotrienol is the most protective of breast cancer as far as being more potent at inducing apoptosis and inhibiting pre-neo and e-plastic and malignant cells.¹⁰ A daily dose of 30-50 mg of delta/gamma-tocotrienols can reduce breast cancer risk, with treatment for breast cancer at a higher dosage.

Similarities and differences found in the actions of lovastatins, (which have numerous negative side effects), and tocotrienols, support the notion that tocotrienols may be an anti-cancer agent.¹¹

Another anticancer mechanism involves inhibiting enzymes within cancer cells that stimulate them to replicate. Gamma-tocotrienols was shown to be three times more potent in inhibiting growth of human breast cancer cultured cells than chemotherapy drug tamoxifen.¹¹

A recent study also showed that tocotrienols also have an antiproliferative effect of in specific prostate cancer cells.¹²

Tocotrienols and skin cancer

Tocotrienols may also have a site-specific action with regard to skin cancer. This notion is substantiated by the fact that tocotrienols are preferentially deposited in the skin.^13,14

Tocotrienols and liver cancer

Studies in animals explored the effects of long term administration of tocotrienols on liver cancer. Supplementation of tocotrienols in rats induced with a potent liver cancer agent demonstrated that the tocotrienols prolonged the impact of the cancer agent. Cell damage to the liver was significant in the untreated group versus the tocotrienol treated group.¹⁵

Oral administration of tocotrienols has resulted in significant suppression of liver and lung carcinogenesis in mice. In human liver carcinoma cells, delta-tocotrienol exerted more significant antiproliferative effect than alpha-, beta-, and gamma-tocotrienols.¹⁶

Antioxidant activity

One characteristic in the origin of disease and aging is the overproduction of reactive oxygen species (ROS). Tocotrienols possess excellent antioxidant activity and have been suggested to suppress ROS production more efficiently than tocopherols.¹⁶

The benefits of tocotrienols reach from decreasing platelet aggregation (clumping of blood) to anti-inflammatory action and anti-cancer activity.

Tocotrienols show considerably superior antioxidant properties compared to dl-α-Tocopherol in clinical and experimental studies due to their better distribution in the fatty layers of the cell membrane. The tocotrienol unsaturated side chain allows for a more efficient penetration into saturated fatty layers of the brain and liver. Delta-tocotrienol counteracts cellular damage by protecting LDL from oxidation.

In addition to the free radical scavenging effect, the antioxidant function of tocotrienols is also associated with lowering tumor formation, DNA damage and cell damage^{18, 19}

Tocotrienols also penetrate rapidly through skin and efficiently combat oxidative stress induced by UV or ozone.

Nervous System

Reversing damage to the neurons and brain, whether acute or chronic is an important health issue.

Oxidative stress-induced programmed cell death, oxytosis, is one characteristic of neurodegenerative diseases. Elevated concentrations of extracellular glutamate inhibit the uptake of cystine and thus induce oxidative stress.

Vitamin E has a central role in maintaining neurological structure and function. Dietary supplementation studies have established that tocotrienols reach the cerebrospinal fluid and the brain and have shown to protect glutamate-induced neurotoxicity^{17, 18}

Neuroprotective properties of tocotrienols are much more potent than that of the widely studied tocopherols. At nanomolar concentration, tocotrienol, but not tocopherol, completely protected neurons by an antioxidant-independent mechanism.¹⁹

Brain cells are typically rich in omega-3 DHA and EPA, and hence they are very susceptible to oxidation. In studies with brain mitochondrial organelles, tocotrienols effectively prevented oxidative damages to both lipids as well as proteins.

Tocotrienols have been shown to effect acute nerve damage and repair, neural degenerative genetic disease, acute brain damage, chronic nerve/brain damage, brain trauma, neural toxicity, Alzheimer's, Parkinson's and Huntington's.²⁰

Anti-Atherogenic & Anti-inflammatory Effects

Delta-tocotrienol is the most effective member of the vitamin E family for reducing endothelial expression of adhesion molecules, thereby preventing the accumulation of inflammatory cells within the arterial wall.²¹

Delta-tocotrienol inhibits the excessive aggregation of blood platelets much more effectively than vitamin E or other tocotrienols.²²

Diabetes

Delta-tocotrienol significantly lowers triglyceride levels, reverses insulin resistance and decreases C-reactive protein (a risk index for cardiovascular inflammation). (23)

In type 2 diabetics, the progression of atherosclerosis is more rapid than the general population and 80% of these patients will die of an atherosclerotic event. Daily intake of dietary tocotrienols by type 2 diabetics has shown to be useful in the prevention and treatment of hyperlipidemia and atherogenesis. Tocotrienols showed a reduction of LDL-Cholesterol from an average of 179 mg/dl to 104 mg/dl.²⁴

Tocotrienols effectively prevented increase in AGE, and caused decrease in blood glucose in diabetic rats.²⁵

The same research also suggests that tocotrienols lower both cardiovascular risk and metabolic syndrome risk ratios.

Bone Mineral Density

Gamma tocotrienols, but not alpha-tocopherols were shown to prevent the loss of bone mineral density, reduce osteoporosis, reduce body fat mass and improve the bone calcium content of rats^{26, 27}

Unfortunately, delta tocotrienol is expensive to isolate and not rich in many common foods.

Dosage

Proper dosage is important. Since tocotrienols can be converted to alpha-tocopherol in the body, taking too high a dosage of tocotrienols actually reduces their ability to lower cholesterol levels.

Two capsules of Mito-GOLD™ daily delivers 82 mg of annatto tocotrienol (90% delta and 10% gamma), was shown to have the maximum effect on reducing triglycerides and cholesterol and may prove more effective than higher dosages.²⁸

Contraindications

There are no known contraindications to the use of this supplement and no adverse reactions have been reported in the PDR for nutritional supplements. It may slightly potentate the effects of anti platelet medication such as Coumadin and Ticlid and it should not be taken with iron supplements.

Individuals on warfarin should be cautious in using doses of tocotrienols greater than 100 milligrams daily and, if they do so, they should have their INRs carefully monitored and their warfarin dose appropriately adjusted if indicated.

Likewise, individuals with vitamin K deficiencies, such as those with liver failure, should be cautious in using doses of tocotrienols greater than 100 milligrams daily. Tocotrienols should also be used with caution in those with lesions with a propensity to bleed (e.g., bleeding peptic ulcers), those with a history of hemorrhagic stroke and those with inherited bleeding disorders (e.g., hemophilia).

Tocotrienol supplementation (greater than 100 milligrams daily) should be stopped about one month before surgical procedures and may be resumed following recovery from the procedure.

Those taking iron supplements should not take tocotrienols and iron at the same time as iron can oxidize tocotrienols to their pro-oxidant forms if taken together.

Drug Interactions

Antiplatelet drugs, such as aspirin, dipyridamole, eptifibatide, clopidogrel, ticlopidine, tirofiban and abciximab: Tocotrienol supplementation may potentiate the effects of these antiplatelet drugs.

• Cholestyramine: may decrease tocotrienol absorption.
• Colestipol: may decrease tocotrienol absorption.
• Isoniazid: may decrease tocotrienol absorption.
• Mineral oil: may decrease tocotrienol absorption.
• Neomycin: may impair utilization of tocotrienols.
• Orlistat: is likely to inhibit tocotrienol absorption.
• Statins: atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin: The possible cholesterol-lowering action of tocotrienols may be additive to that of the statins.
• Sucralfate: may interfere with tocotrienol absorption.
• Warfarin: Tocotrienol doses greater than 100 milligrams daily may enhance the anticoagulant response of warfarin. Monitor INRs and appropriately adjust warfarin dose if necessary.

Nutritional Supplements, Food and Herbs

• Desiccated ox bile: may increase the absorption of tocotrienols.
• Medium-chain triglycerides: may enhance absorption of tocotrienols if taken together (as in Mito-GOLD).
• Phytosterols and phytostanols, including beta-sitosterol and beta-sitostanol: may lower plasma tocotrienol levels.
• Olestra: is likely to inhibit the absorption of tocotrienols. Alpha-tocopherol is the only member of the vitamin E family that is added to olestra.
• Some herbs, including ginkgo and garlic, possess antithrombotic activity, and tocotrienols, if taken together with these herbs, may enhance their antithrombotic activity.

References

1. Tocotrienol: a review of its therapeutic potential. Theriault A, et al. Clin Biochem 1999;32:309-19.
2. Pharmacokinetics and bioavailability of alpha-, gamma- and delta-tocotrienols under different food status. Yap SP, Yuen KH, Wong JW. J Pharm Pharmacol 2001;53:67-71.
3. Dietary Alpha-Tocopherol Attenuates the Impact of Gamma-Tocotrienol on HMG -CoA Reductase Activity in Chickens. Qureshi, A. A. Pearce, B. C.et al. J. Nutr. 126: 389-394, 1996.
4. Hypocholesterolemic Activity of Synthetic and Natural Tocotrienols. Pearce, B.C., et al. J. Med. Chem. 35: 3595-3606, 1992.
5. Appropriate Spectrum Vitamin E and New Perspectives on Desmethyl Tocopherols and Tocotrienols. Barrie Tan. Jana 35 Vol. 8, No. 1, 2005.
6. Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Qureshi AAet al. Atherosclerosis 2002;161:199-207.
7. Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Theriault A, Chao JT, Gapor A, et al. Atherosclerosis 2002:160:21-30.
8. Mechanisms mediating the antiproliferative and apoptotic effects of vitamin E in mammary cancer cells. Sylvester PW, Shah SJ. Front Biosci. 2005 Jan 1;10:699-709.
9. Tocotrienol-rich fraction from palm oil and gene expression in human breast cancer cells. Nesaretnam K, Ambra R, Selvaduray KR, et al(year 2004). ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1031: 143-157.
10. Role of Tocotrienols in the Prevention of Cardiovascular Disease and Breast Cancer. Sylvester, P. W., Theriault, A. Curr. Topics in Nutra. Res. 1:121-136, 2003.
11. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Thibault, A, et al. Clin. Can. Res. 2: 483-491, 1996.
12. Gamma-Tocotrienol metabolism and antiproliferative effect in prostate cancer cells. Conte C, Floridi A, Aisa C, et al(year 2004). ANNALS OF THE NEW YORK ACADEMY OF SCIENCES 1031: 391-394.
13. Efficacy of Topically Applied Tocopherols and Tocotrienols in Protection of Murine Skin From Oxidative Damage Induced by UV-irradiation. Weber, C., Podda, M., et al.Free Radic. Biol. Med. 22(5): 761-769, 1997.
14. Diet derived topically applied tocotrienols accumulate in skin and protect the tissue against uv light-induced oxidative stress. Traber, MG., Podda, N., Weber, C., et al. Asia Pacific J. Clin. Nutr. 6: 63-67, 1997.
15. Long-term administration of tocotrienols and tumor-marker enzyme activities during hepatocarcinogenesis in rats. Rahmat A, Ngah WZ, Shamaan NA, et al. Nutrition. 1993 May-Jun;9(3):229-32.
16. Tocotrienols: constitutional effects in aging and disease. Schaffer S, Muller WE, Eckert GP. J Nutr. 2005 Feb;135(2):151-4.
17. Tocotrienol: the natural vitamin E to defend the nervous system? Sen CK, Khanna S, Roy S. Ann N Y Acad Sci. 2004 Dec;1031:127-42.
18. Tocotrienols: constitutional effects in aging and disease. Schaffer S, Muller WE, Eckert GP. 1: J Nutr. 2005 Feb;135(2):151-4.
19. Tocotrienols: Vitamin E beyond tocopherols. Sen CK, Khanna S, Roy S. Life Sci. 2006 Feb 2; US Patent 20050037102.
20. Palm-tocotrienol Rich Fraction (TRF) Is a More Effective Inhibitor of LDL Oxidation and Endothelial Cell Lipid Peroxidation than a-tocopherol In Vitro. Sokhini, M., Mutalib, A., et al. Food Research Internal 36: 405-413, 2003Â.
21. The therapeutic impacts of tocotrienols in type 2 diabetic patients with hyperlipidemia. Baliarsingh S, Beg ZH, Ahmad J. Atherosclerosis. 2005 Oct;182(2):367-74.
22. Inhibitory Effect of Delta-Tocotrienol, a HMG CoA Reductase Inhibitor, on Monocyte-Endo Thelial Cell Adhesion. Chao, J. T., et al. Sci. Vitaminol 48:332-337, 2002.
23. Antioxidants Modulate the Course of Carotid Atherosclerosis: A Four-Year Report. Kooyenga, D., et al. Micronutrients and Health. Molecular and Biological Mechanisms by Nesaretnam and Packer. AOCS Press 366-375, 2001.
24. Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats. Wan Nazaimoon WM, Khalid BA. Malays J Pathol. 2002 Dec;24(2):77-82.
25. Effects of tocopherols and tocotrienols on body composition and bone calcium content in adrenalectomized rats replaced with dexamethasone. Ima-Nirwana S, Suhaniza S. J Med Food. 2004 Spring;7(1):45-51.
26. Tocotrienols are needed for normal bone calcification in growing female rats. Norazlina M, Ima-Nirwana S, et al. Asia Pac J Clin Nutr. 2002;11(3):194-9.
27. Dose-dependent suppression of serum cholesterol by tocotrienol-rich fraction (TRF25) of rice bran in hypercholesterolemic humans. Qureshi AAet al. Atherosclerosis 2002;161:199-207.