© Whole Foods Magazine
Health Benefits Beyond Vitamin E Activity:
Solving the Tocotrienol Riddle:
An Interview with Dr. Barrie Tan
By Richard A. Passwater, Ph.D.
This month, we continue our chat with Dr. Barrie Tan about the newly discovered roles of the tocotrienol members of the vitamin E family of nutrients. In June, we discussed the basics of tocotrienols biochemistry with emphasis on their role in heart and artery health. This month, we will discuss the roles of tocotrienols in maintaining health by helping to prevent other diseases, including cancer and prediabetes.
Dr. Tan earned his Ph.D. at the University of Otago, New Zealand, and later became a professor at the University of Massachusetts/Amherst (chemistry and food science/nutrition). His research expertise includes lipid-soluble materials such as carotenoids, tocotrienols/tocopherols, coenzyme Q10, omega-3s and cholesterol. He was a pioneer in the discovery of the three major sources of tocotrienol, and introduced tocotrienol’s benefits to the nutrition industry. He founded American River Nutrition, Inc. in 1998.
Passwater: Tocotrienols have been implicated in the treatment or prevention of certain cancers. By what mechanism does tocotrienol work in this case?
Tan: There are several mechanisms that may be concurrently responsible. One of them is closely related to the cholesterol reduction theme we discussed last month. When we have excess cholesterol, a feedback mechanism is set up to tell the HMGR (3-hydroxy-3-methyl-glutaryl-CoA reductase, the enzyme responsible for cholesterol production) to make less. This feedback mechanism occurs in normal, healthy, albeit hypercholesterolemic, tissue. But, unfortunately, cholesterol production in tumor tissue is highly aberrant (or abnormal) because the HMGR is resistant to sterol feedback. However, the tumor HMGR retains high sensitivity to isoprenoid-mediated regulation (10), and tocotrienol, as an isoprenoid, reduces Ras (an oncogene responsible for cell growth), arrests cells in the G1 phase, and initiates cell death or apoptosis (11). Tumor HMGR is highly sensitive to tocotrienols (especially delta- and gamma-tocotrienol) and surprisingly, also GG (geranyl geraniol, another isoprenoid) (12, 13).
Another mechanism of tocotrienol’s effect on cancer has to do with direct induction of cancer cell death, also known as apoptosis activation. Here, tocotrienol may stimulate death receptors such as tumor necrosis factor (TNF) and Fas, which leads to the activation of caspases, including caspase-8, -9 and -3. Activation of these caspases mediates the various cytoplasmic and nuclear events associated with apoptosis (14). I would say that the jury is still out on the molecular biology of cancer-kill by tocotrienol.
Passwater: Very interesting mechanisms! Any animal studies?
Tan: Yes, I agree that mechanisms provide the rationale of how tocotrienol works on cancer. If tocotrienol inhibits cancer in the whole animal, we are observing an “organistic phenomenon,” which is one step closer to human. In animal studies, tocotrienols (especially delta- and gamma-tocotrienol) have been shown to inhibit tumors of the breast, prostate, lung, liver, pancreas and skin.
More recently, researchers have discovered that tocotrienol has anti-angiogenic properties. Angiogenesis is a mechanism tumors use to grow new vessels (arteries) from nearby arteries to feed themselves with much-needed nutrients and fuel their spectacular growth. Therefore, anti-angiogenesis is a strategy to block off nutrients to the voracious cancer, essentially starving the tumor to death. Tumors secrete vascular endothelial growth factor (VEGF) that triggers angiogenesis. Tocotrienol downregulates VEGF, therefore blocking intracellular signaling of VEGF and inhibiting angiogenesis. A study by Dr. Miyazawa and his colleagues at the Tohoku University and Nippon Medical School in Tokyo showed that tocotrienol inhibits the proliferation and formation of tubes by bovine aortic endothelial cells, and delta-tocotrienol had the strongest inhibitory activity (15, 16). Since angiogenesis is essential to tumor growth, its inhibition may likely prevent cancer metastasis. However, tocotrienol may also be applicable to other types of aberrant angiogenesis such as diabetic retinopathy, rheumatoid arthritis and psoriasis.
Passwater: What about the antioxidant role of tocotrienol in cancer?
Tan: Tocotrienol has superior antioxidant properties that may contribute to its effect on cancer and inflammation. Tocotrienol may alleviate redox imbalance, protecting against the deteriorating effects of oxidative stress. Therefore, it may reduce DNA damage that increases the risk of cancer (17). For example, tocotrienol may inhibit cancer by the quenching of free radicals or increase the efficacy of antitumor actions by strengthening the immune system (18). Interestingly, a mixture of tocopherol-free delta- and gamma-tocotrienol (annatto tocotrienols, DeltaGold®) had lipid Oxygen Radical Absorbance Capacity (L-ORAC) values that were many times greater than vitamin E tocopherols, high-grade vegetable oils, tocopherol-tocotrienol (TP-TT) mixtures, fish oils, and popular carotenoids (Figure 5). The L-ORAC of annatto tocotrienol is among the highest observed, about one-third higher than phospholipids-based krill oil and comparable to that of powerful lipid antioxidants resveratrol and EGCG. As a case in synergism, annatto TT-EGCG mixtures contained higher ORAC values than annatto tocotrienols (Figure 5).
Keep in mind that most ORAC readings with which we are familiar are the water-soluble or hydro-soluble ORAC (H-ORAC). We need high lipid-soluble L-ORAC to protect the lipid membranes of the approximate 75 trillion cells present in the human body.
Figure 5: Antioxidant potential expressed as lipid ORAC values of some important antioxidants. (Data adapted from Brunswick Laboratories, Wareham, MA).
Passwater: Are the tocopherol and tocotrienol forms of the vitamin E family complementary or competitive or both under varying conditions? Dr. Asaf Qureshi published his studies showing that tocotrienol–tocopherol in a particular range or ratio lower cholesterol, but they did not do so in other ranges or ratios.
Tan: Dr. Qureshi has done more research on tocotrienol than anyone I know of. He started in the early 1980s at the University of Wisconsin and USDA lab in Madison with the discovery of barley-based tocotrienol to lower cholesterol. He was also involved in the 1992 Bristol-Myers Squibb study that discovered tocotrienol’s cholesterol-lowering properties (6). In 1996, Dr. Qureshi showed that alpha-tocopherol interferes with tocotrienol’s ability to lower cholesterol and that alpha-tocopherol by itself actually upregulates HMGR (19). Other research groups found that alpha-tocopherol, the common vitamin E found in supplements, decreases the absorption of tocotrienol (20), increases its breakdown (21) and upregulates human Supernatant Protein Factor (22), which in turn will upregulate cholesterol synthesis. According to Dr. Qureshi, the less alpha-tocopherol is found in a tocopherol–tocotrienol preparation for cholesterol-lowering the better. Alpha-tocopherol content should be less than 15% (19), and in later experiments, Dr. Qureshi used less than 10% (23) or preferred tocopherol-free preparations.
Passwater: Since people consume various amounts of tocopherol in supplements such as multivitamins, what is your recommendation as far as tocotrienol supplementation in order to avoid interference?
Tan: Great question! I usually recommend that people take their tocopherols in the morning and take their tocotrienols in the evening with dinner. Remember that tocotrienol is not meant to replace tocopherol. Tocopherol was originally discovered to prevent fetal resorption (24), and later to protect red blood cells (25). Over the years, however, the amount of tocopherol in supplements has increased far beyond 22 IU (100% Dietary Reference Intakes; DRI) to the typical 200–400 IU as an antioxidant. It is important to note that although both tocopherol and tocotrienol are antioxidants, tocotrienol alone has the added benefits of cholesterol reduction, triglyceride reduction and anti-cancer properties, among others. Consumers with these types of conditions need to be aware that alpha-tocopherol interferes with tocotrienol benefits, and that the two should be taken apart.
At present, I am unable to reconcile the copious amounts of alpha-tocopherol (1,600–3,200 IU/day, or 1,100–2,100 mg/day) required to reduce oxidative stress in humans (26). This is 70–150x of the DRI, or approximately 4x the dosage of previous clinical studies. The study investigator, Dr. Roberts of Vanderbilt University said, “Vitamin E (alpha-tocopherol) is not the spiffy antioxidant everybody thinks it is.”
Passwater: Why is it that there are so many mixed tocotrienol–tocopherol products in the market?
Tan: Earlier studies on tocotrienol used palm or rice tocotrienol-rich fractions (TRF), which really means a mixture of tocopherols and tocotrienols (see Figure 3, Part 1). Therefore, “palm tocotrienol” and “rice tocotrienol” products are in fact mixtures of tocopherols and tocotrienols, typically with 20–50% tocopherols, of which alpha-tocopherol is the major component. At that time, palm and rice were the only known major sources of tocotrienol, and extracting pure tocotrienol from these would be prohibitively expensive. With early indications in cholesterol and atherosclerosis reduction, many companies adopted TRF products from palm and rice, and still carry them to this day. However, we now know of the alpha-tocopherol interference and the increased potency of tocopherol-free tocotrienol products such as those derived from annatto, and availability of these products is on the rise. Consumers and health professionals are becoming aware of the fact that palm and rice tocotrienols contain at least 100 times more tocopherol than annatto tocotrienol.
In topical applications however, tocopherol does not interfere with tocotrienol, and the two may be used synergistically. No interference has been reported for dermatological application.
Passwater: There is an understanding that many studies have used palm tocotrienol. How does annatto fit into the picture?
Tan: There is a popular misunderstanding that when science is interpreted, it must not use “borrowed science.” In my three decades as a scientist, I have always understood that any good scientist stands on the shoulders of other great scientists who have built up a vast reservoir of research from the past.
In most of the studies, and especially the original studies, pure tocotrienol isomers were used. Therefore, the material source of tocotrienols was rendered irrelevant. In earlier studies, tocotrienols were ranked in order of potency (most pronounced for cardiovascular disease and cancer) from highest to lowest potency as follows: delta-tocotrienol > gamma-tocotrienol >> alpha-tocotrienol. Alpha-tocopherol did not work. These studies were followed by research using tocotrienol-rich fraction (TRF) from palm, because at this point, palm was the plant with the greatest availability of natural tocotrienols, and annatto tocotrienol was undiscovered. The potency of this TRF in cardiovascular disease and cancer was found to be somewhere between gamma- and alpha-tocotrienol, and therefore less potent than pure delta- or gamma-tocotrienol. Since palm TRF had a high content of gamma-tocotrienol and a fairly low content of delta-tocotrienol, the gamma isomer was deemed the “magic bullet” during this period. Even with this understanding, Dr. Qureshi and scientists at BMS clearly delineated the most potent effect of delta-tocotrienol in their earliest published works in the 1990s (6). More recently, studies in 2006 (27, 7) used pure isomers, and once again unequivocally proved that delta- followed by gamma-tocotrienol were the most potent isomers.
Passwater: You mentioned that desmethyl tocotrienols such as delta- and gamma-tocotrienol may have increased activity due to their superior mobility in membranes. Is there scientific evidence that these tocotrienol isomers work better for various functions?
Tan: We have found that delta- and gamma-tocotrienol in small dosages (75–100 mg) reduced total cholesterol, LDL and triglycerides by 15–20%, while cardiovascular risk (TC/HDL) and metabolic syndrome ratios (TG/HDL) dropped by 15–20% and 20–30%, respectively.
Passwater: These findings also have important implications for those with metabolic syndrome and diabetes. The number of diabetics in the United States has been increasing, with approximately 21 million diabetics in 2005 as compared with 18.2 million in 2003 (National Diabetes Fact Sheet, CDC). In addition, there are about 60 million pre-diabetics in the United States. For more information on diagnosis and prevalence of prediabetes/diabetes, readers are advised to visit the American Diabetes Association (ADA) Web site (www.diabetes.org/CMR).
Dr. Tan, what are some indicators of metabolic syndrome/prediabetes and diabetes, and what are the associated risks?
Tan: I have been an ADA member and have attended annual meetings for about 10 years. Aside from the obvious risk factors such as increased waist circumference, elevated blood pressure and reduced HDL cholesterol, elevated fasting glucose and triglyceride levels are good indicators for prediabetes or metabolic syndrome. Other descriptors of these conditions are “insulin resistance” and “insulin dysfunction.” Let me illustrate. Prediabetics have moderately elevated triglycerides and glucose, but not high enough to be “diabetics” (see Figure 6). Elevated triglycerides precede elevated glucose in prediabetes. The US Government and the American Heart Association identify “Metabolic Syndrome” condition as the presence of three or more of the five risk factors listed above. With Metabolic Syndrome defined, we have a handle on prediabetes; it has a name and a measurement.
Metabolic Syndrome and moderately high triglyceride levels independently increase the risk of cardiovascular disease (28–30). Because of this, the ADA has recently preferred the more encompassing term “cardiometabolic syndrome” to describe this prediabetic condition. Prediabetes sits between “diabetes” and “normal” (Figure 6), and this field is still evolving.
Figure 6: Prediabetes is marked by high “normal level” of blood glucose and triglycerides.
Passwater: Have there been other tocotrienol studies on this important topic?
Tan: In fact, several research groups have shown that tocotrienol may be beneficial for prediabetics and diabetics. For example, in animal studies, scientists saw a significant decrease in cardiometabolic events, including increased insulin sensitivity, lower plasma and hepatic triglyceride levels, and lower LDL cholesterol levels (31, 32).
In clinical studies with metabolic syndrome patients and diabetics, tocotrienol reduced the symptoms associated with the disease. Dr. Montonen from the National Public Health Institute in Finland showed that tocotrienol reduced hyperglycemia and hyperlipidemia, and increased insulin levels (33). In another study, Dr. Baliarsingh of Jawaharlal Nehru Medical College in India confirmed the therapeutic effects of tocotrienol on type 2 diabetics, where total lipids, total cholesterol and LDL cholesterol were reduced by 23%, 30% and 42%, respectively (34). These and other research projects are reviewed in my chapter of a comprehensive tocotrienol book that will be available this summer, called Tocotrienols: Vitamin E Beyond Tocopherols (9), edited by Dr. Ron Watson of the University of Arizona/Tucson and Dr. Victor Preedy of King’s College/London.
Passwater: That sounds interesting. There have not been too many compilations on tocotrienols until now.
Tan: That is correct. The compilation will contain some of the latest research on tocotrienols. In the same book, we studied tocotrienol’s effect on chlamydial infections with Dr. Stuart of the University of Massachusetts/Amherst (35). Chlamydia trachomatis is the most prevalent sexually transmitted disease in this country, but few people know of its sister strain Chlamydia pneumoniae, which sometimes causes chronic respiratory infections (36). More importantly, Chlamydia pneumoniae has been found in atherosclerotic tissue, and is believed to aggravate the progression of atherosclerosis (37). In our cell line studies, tocotrienol reduced chlamydial infection, and delta-tocotrienol worked far better than the other isomers.
Passwater: The Chlamydia link to atherosclerosis is certainly an interesting angle. This reminds me of Dr. Bierenbaum’s clinical study on tocotrienol and atherosclerosis using palm and rice tocotrienols. Do you think that a tocopherol-free tocotrienol supplement would work even better in reducing atherosclerosis?
Tan: Yes, I believe so. An early step of atherogenesis is fatty streak formation in arteries, which begins with the adherence of circulating monocytes tethering onto the endothelium, perhaps prompted by oxidized cholesterol and/or Chlamydia. Let me illustrate. The pathogenic/diseased artery changes from the “non-stick frying pan” to a “Velcro” situation. Previously, Dr. Theriault of the University of Hawaii/Manoa showed that tocotrienols reduce cellular adhesion molecule expression and monocytic cell adherence (38). In particular, delta-tocotrienol showed the most profound inhibitory effect on monocytic cell adherence as compared with tocopherols and other tocotrienol isomers (39). This is an exceptional finding because delta-tocotrienol was many-fold more potent than the other tocotrienols, which is likely due to its increased bioavailability (see Figure 7). The potency of tocotrienols (from greatest to least) is delta-tocotrienol > gamma-tocotrienol >> alpha-tocotrienol > beta-tocotrienol. Dr. Naito of the Kyoto Prefectural University of Medicine confirmed this finding and suggested that this bioavailability phenomenon occurs via inhibition of vascular cell adhesion molecule, VCAM-1 expression by delta-tocotrienol (40). In effect, tocotrienol “de-velcronized” the artery!
Figure 7: Tocotrienols are much more bioavailable to cell uptake than tocopherols.
Passwater: Is the order of potency of various tocotrienol isomers in atherosclerosis similar to that in anti-cancer properties?
Tan: Yes. In 2000, Dr. Sylvester of the University of Louisiana/Monroe showed that delta-tocotrienol was the most potent isomer in reducing proliferation and inducing cell death (apoptosis) of mammary cancer cells, followed by gamma-tocotrienol as a close second (41). TRF worked less well and alpha-tocopherol did not work at all. This superior effect of delta- and gamma-tocotrienol was also shown in melanoma (42), breast (43), prostate (44) and colorectal cancers (45).
Most recently, Dr. Malafa and his group at the Moffitt Cancer Center and Research Institute of the University of Southern Florida/Tampa, for whom we provided the initial annatto delta-tocotrienol material, tested tocotrienol’s effect on pancreatic cancer, one of the most deadly of all cancers. About 35,000 Americans get pancreatic cancer each year, and 95% do not survive beyond 6–12 months following diagnosis. Among the famous, singer Luciano Pavarotti succumbed to it, actor Patrick Swayze and professor Randy Pausch (who wrote The Last Lecture) are currently infirmed by it, and entrepreneur Steve Jobs (of Apple Computer/Pixar) escaped it. In cell line and animal studies, the Tampa researchers found that delta-tocotrienol inhibits pancreatic tumor growth, blocks malignant transformation, induces apoptosis in vitro, and accumulates in the pancreas 10 times more than the liver and tumor. Their preferred composition was a preparation consisting of delta- and/or gamma-tocotrienol, without alpha- and beta-tocotrienol. In addition, the preparation should preferably be tocopherol-free (46). Coincidentally, annatto tocotrienol fits this preferred composition.
Research on the anti-angiogenic properties of tocotrienol also favors delta-tocotrienol as the most potent of the isomers (15). Since angiogenesis is important in tumor growth, diabetic retinopathy, rheumatoid arthritis, and psoriasis, the anti-angiogenic delta-tocotrienol may have significant therapeutic implications beyond cancer.
Passwater: Are there cases in which alpha-tocotrienol would have benefits?
Tan: Dr. Sen of the Ohio State University/Columbus convincingly showed that alpha-tocotrienol is an important neuroprotector (47, 48). I conversed with Dr. Sen in a Seattle meeting this past May and he is conducting clinical studies with alpha-tocotrienol on stroke patients. In familial dysautonomia (FD; i.e., a genetic disease primarily causing dysfunction of the autonomic and sensory nervous systems), gamma- and delta-tocotrienol had the greatest effect by raising cellular levels of functional IKAP (49). This protein is largely non-functional in this neurodegenerative disease, which results in autonomic crises characterized by hypertension, tachycardia, diaphoresis and vomiting. Children with FD take tocotrienols on a daily basis to reduce the symptoms of the disease. They also regularly take EGCG from green tea, which was shown to correct aberrant splicing of the IKAP mRNA (50). Drs. Rubin and Anderson of Fordham University/Bronx (discoverers of this nerve activity of the two ingredients) applied these ingredients to FD children with consequent reduction of episodic crises. In short, I believe the jury is still out as to which tocotrienol isomer is best for neuroprotection. Perhaps the tocotrienol isomers all work to varying degrees in neuroprotection.
In general, tocotrienol and EGCG is a great combination to support healthy arteries, cells and nerves. Together, they have the highest L-ORAC values and therefore are a formidable antioxidant team (see Figure 5). A resveratrol and tocotrienol combination should work similarly.
Passwater: What other supplement ingredients work well in combination with tocotrienols?
Tan: One of my favorite combinations is tocotrienol with fish oil/algal omega-3. Both work synergistically to support healthy arteries and red blood cells while maintaining healthy lipid levels, especially triglycerides. In addition, tocotrienol would help the omega-3 takers keep the LDL from increasing, especially among diabetics.
Another good combination is tocotrienol with either sterol or red yeast rice. All of these ingredients have cholesterol-lowering properties and they would work synergistically to maintain healthy cholesterol levels.
Sesame and flaxseeds contain lignans, which have been shown to decrease or inhibit cytochrome P-450. This decreased cytochrome P-450 activity slows down tocotrienol metabolism (51). This means that the lignan given along with tocotrienol may potentiate tocotrienol and increase its blood levels, making it another great combo.
Tocotrienol would also be an excellent combination with CoQ10, since both have been shown to lower systolic blood pressure and reduce hypertension (52, 53).
Passwater: Is it safe to take tocotrienols with statin drugs? Have you seen cases of people being able to reduce their statin drug dosage as a result of taking tocotrienols?
Tan: A study done by Dr. Qureshi in which tocotrienol is synergistic with lovastatin (54) and it is suggested that the dosage of statin may be reduced when tocotrienol is added. Anecdotally, Dr. A.P. Chieng (Irvine, CA) saw these effects, where annatto tocotrienol worked synergistically with red yeast rice in hypercholesterolemic and diabetic patients of his.
Passwater: Where can we read and learn more about tocotrienols?
Tan: As I mentioned before, a very comprehensive book (Tocotrienols: Vitamin E Beyond Tocopherols) on tocotrienols will be published in August. Those who are interested to hear more about the science behind tocotrienols can view a recent webinar I presented (www.naturalproductsinsider.com/webinars/).
Passwater: What are you working on now?
Tan: I am focusing on writing a tocotrienol book with Dr. Stephen Sinatra. We are also setting up to do some research on the essential endogenous nutrient, geranyl geraniol. For example, we are studying geranyl geraniol’s effect on melanoma, and tocotrienol’s effect on prostate cancer.
Passwater: Thank you Dr. Tan. I am so glad you could put all the pieces of the tocotrienol puzzle together for us. It was worth the wait!
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