© 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.
Certain members of the vitamin E family of nutrients called “tocotrienols” are emerging as having additional health benefits over “conventional” vitamin E family members, the tocopherols. Both tocotrienols and tocopherols are antioxidants, but only tocotrienols have been shown to reduce cholesterol, inhibit certain cancers and manage diabetes. It is very exciting to know that some nutrients can actually reverse atherosclerosis by removing so-called “cholesterol deposits.” There has been some confusion about the various forms of vitamin E, so I have asked Dr. Barrie Tan to bring us up-to-date.
One of the scientists that I look forward to chatting with at scientific meetings and tradeshows is Dr. Tan: He is dedicated and always working away at solving complex bio-organic synthesis or discovering better natural sources for hard-to-find nutrients. Years ago, our conversations were mostly about various carotenoids and somewhat about tocotrienols, but over the past few years, they have been almost entirely about tocotrienols. He has passionately pursued solving the biochemistry and sourcing of tocotrienols.
Figure 1: Dr. Barrie Tan poses with a photo of the annatto plant, which is an excellent source of tocotrienols.
Dr. Tan earned his B.S. (chemistry) and Ph.D. (analytical chemistry) 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 included lipid-soluble materials such as carotenoids, tocotrienols/tocopherols, CoQ10, omega-3s and cholesterol. He was a pioneer in the discovery of the three major sources of tocotrienol, and introduced tocotrienol’s benefits to our nutrition industry. He founded American River Nutrition, Inc. in 1998 and developed the first-ever tocopherol-free tocotrienol product derived from annatto beans. Today, the focus of his research is on phytonutrients that have an impact on chronic, degenerative and cancer diseases.
Passwater: Dr. Tan, why did you become interested in organic chemistry and biochemistry, and especially the structures and synthesis of complex nutrients such as carotenoids and tocotrienols?
Tan: I have always been fascinated by how nature makes organic compounds, invariably involving carbon atoms. After understanding the basis of organic chemistry, I became interested in how these organic compounds are assimilated by the body (i.e., the biochemical and biological functions). This began early in my graduate studies (in the 1970s) where I researched to solve enzymatic problems of biological molecules and hence received my Ph.D. in analytical biochemistry at the University of Otago, New Zealand. As to my special interest in compounds such as carotenoids and tocotrienols, I am fascinated by how these are derived from the last common synthesis step that the animal and plant kingdoms share.
Passwater: That’s an interesting thought.
Tan: Yes, I think so. This last common step is the compound geranyl geraniol (GG). In plants, GG produces lipid-soluble compounds such as carotenoids (e.g., beta-carotene, lycopene, astaxanthin, lutein, zeaxanthin), vitamin E (e.g., tocotrienols, tocopherols) and many other agro-based materials. In mammals, GG produces lipid-soluble compounds such as CoQ10 (e.g., ubiquinone, ubiquinol), sterols (e.g., cholesterol, hormones, vitamin D), heme, anchors for protein syntheses, dolichols and many other animal-based materials. Many of the agro-based and animal-based materials are carbon compounds. One may say that GG is indeed the endogenous nutrient that is the “great-grandfather” of organic compounds. For example, I can see the GG molecule embedded inside of CoQ10 (from animal), vitamin E (from plant) and vitamin K (from plant or animal).
Passwater: I see that two of my favorite nutrients diverge at this point, vitamin E in plants and the quasi vitamin CoQ10. This accounts for their structural similarities.
When we first met in the mid-1980s at a scientific meeting, weren’t you teaching and doing research at a university in the Northeast? What were you working on?
Tan: Yes, I worked in both the Chemistry and Food Science departments of the University of Massachusetts/Amherst, where I was studying carotenoids and tocotrienols. We were in the beginning stages of finding out more about the little known tocotrienol and worked on establishing analytical techniques for the identification of the various vitamin E isomers (1–3).
Passwater: Why did you become interested in tocotrienols?
Tan: Well, that is a long story…My first love was the colorful carotenoid family. As you know, palm contains relatively large amounts of carotenes. In 1984 I took a trip to my native Malaysia to visit an old friend. He took me to a palm oil manufacturer, where I had the privilege of observing the production process of palm oil. I noticed that the original material from palm prior to processing had a strong orange color, which immediately caught my interest. The manufacturer confirmed my suspicion that the orange color was carotenes, but unfortunately these would be destroyed during processing. I was astonished by such a waste of nutritious material and decided to put this production leftover to better use.
The result was my founding of Carotech in 1988, which today is a major supplier of palm-derived products. Our initial research was the isolation of carotene from palm oil. When we isolated this material, we were left with a nearly colorless portion that seemed to have high antioxidant properties and very little rancidity. We ran an analytical procedure called high-performance liquid chromatography (HPLC) on the colorless material and noticed that some of the peaks were nearly identical with vitamin E tocopherol, and we confirmed these closely similar but unknown peaks to be tocotrienols. In literature from the 1950s, we found these compounds now known as tocotrienols identified, but they were erroneously named tocopherols (4). In the 1980s, the compounds were renamed to tocotrienols because of the three double bonds found in the tail of the molecule. We published a paper on our HPLC analysis techniques in 1989 (3) just to prove this fact, and a few years later I sold Carotech and returned to full-time research and development.
Shortly thereafter, my wife and I planned a vacation to the island of Phuket, a southern province of Thailand. The night before our flight departure I received an unexpected phone call: It was the chief counselor to the Prince of Thailand, who had heard of my background in carotenoids, and he wanted to set up a meeting between the Prince and me. I agreed, and we met a few days later. He had a business proposal for me, where he wanted to sponsor research dedicated to plant-based nutraceutical discoveries. We proceeded to found a company named after his great-grandfather, Rangsit Biotech, where we discovered that rice was a major source of tocotrienols. Unfortunately, due to the poor Asian economy in the late 1990s, we decided to dissolve the company. The most valuable part of the company, the technology of tocotrienol extraction from rice, was sold to Eastman-Kodak, and to this day Eastman sells rice-based tocotrienols. In 1998, I founded American River Nutrition, Inc., and was quite happy to return to my first love of carotenoids. I really didn’t want to have anything more to do with tocotrienols.
But, as irony has it, I had not seen the last of tocotrienol. I went on a “medicine man” exploratory trip to South America to check out some sources of sun-drenched marigold lutein (a carotenoid). There, I happened to stumble across the annatto plant (see Figure 1) with its beautiful, red-colored pods. The plant was named Bixa orellana after the Spanish discoverer Francisco de Orellana in the 1500s, and was first introduced to the United States as a food colorant about 150 years ago. Besides being amazed by the color (another carotenoid) of this unlikely plant, I noticed that the pods were phototrophic, following the sun. I was curious as to what was protecting the carotenoid from oxidation, and especially accelerated photo-oxidation, since carotenoids in general are very labile. My chemist and I took back a sample, analyzed it and found that the carotenoid’s protector was tocotrienol. Eureka! In addition, it was (and still is) the only known source of tocotrienol that is free of tocopherols. Interestingly, we found only two dominant peaks: delta-tocotrienol at about 90% and gamma-tocotrienol at about 10%. Right then, I knew we had stumbled onto the best-in-class tocotrienol that nature makes. To this day, I have never seen a similar composition in any other plant. We filed a patent on the extraction of tocotrienol from annatto, which was issued in 2002. Some of the latest research now supports the delta- and gamma-tocotrienol composition as the most potent for cholesterol reduction and cellular health.
Passwater: So, you really deserve to be called “Dr. Tocotrienol.” No wonder Dr. Stephen Sinatra referred to you as “The Tocotrienol King.”
Tan: In fact, Dr. Sinatra and I plan to write a book on tocotrienols and cardiovascular health, which is already in the works.
Passwater: That will be an important book. I can hardly wait to read it. When we saw each other in July 2007, you had exciting news that clarifies the tocotrienol picture as an important nutrient. I have wanted to chat with you about tocotrienols for our readers, but until then, I had considered the body of science regarding tocotrienols as too complex and perhaps a little murky.
In November 1997, we chatted with Dr. Maret Traber about the various members of the vitamin E family, including tocotrienols, in previous columns (www.drpasswater.com/nutrition_library/traber1.html) and in February 1998, we chatted with Drs. Marvin Bierenbaum and Tom Watkins (www.drpasswater.com/nutrition_library/bierenbaum.html) about how tocotrienols reversed arterial plaque. I have long wanted to follow these articles with an interview with you about the general biochemistry of the tocotrienol nutrients.
After all, vitamin E is not a specific compound, but a group of compounds having the same property of preventing resorption of the fetus in rats. The vitamin activity was first identified by Dr. Herbert Evans in a series of experiments with wheat germ extractions from 1922 through 1936 as being a dietary fertility factor in rats, it was given the name “tocopherol” from the Greek words “τοκος” [birth] and “φορειν” [to bear or carry] meaning in sum "to carry a pregnancy." The ending "-ol" signifying its status as a chemical alcohol.
Please give us a brief overview to get us started.
Tan: You put this so aptly, Dr. Passwater. This is why vitamin E was discovered as the “birth vitamin”. I think there is still a lot of confusion about vitamin E as an entity, and more importantly, there is lack of familiarity with tocotrienol among consumers. Vitamin E is a collective term for a molecule with a 6-hydroxychroman moiety (chromanol head) and a lipid-soluble side chain (tail), such as tocopherols and tocotrienols.
Passwater: Whoa there, Professor Tan, that may be just a little too much biochemical nomenclature for some of our readers. Let’s use a figure to show the molecular structures and point out that the “ring-like” structure in the molecule can be thought of the “head” of the molecule and the fairly straight chain of atoms coming from this ring (head) can be thought of as the “tail” of the molecule. (please see figure 2)
Figure 2: Molecular structures of tocotrienol and tocopherol.
Tan: Yes, the chromanol head of tocopherols and tocotrienols is the same, and hence they are both good antioxidants. On a molecular level, tocopherols and tocotrienols differ because of their lipid-soluble tails. Tocopherol has a longer saturated phytyl tail, embedding it in cell membranes and causing it to be less mobile. Tocotrienol, on the other hand, has a shorter unsaturated (three double bonds) farnesyl tail that increases its mobility in cell membranes. The increased mobility of tocotrienols allows them to move faster and cover a larger area of the membrane.
Passwater: So, tocopherols, relative to tocotrienols, have a longer, stiffer tail that acts more like an anchor holding the molecule in place in the membrane, whereas, tocotrienols, relative to tocopherols, have a more flexible and shorter tail that acts more like a flipper that enables them to move around more in the membrane.
Tan: Yes, I always like to illustrate this by giving the example of the local policeman versus a state trooper. In this example, tocopherol is the local policeman (guarding city-wide), while tocotrienol is the state trooper (guarding state-wide). The bad guys are the free radicals. The local policeman and the state trooper both go after the bad guys, but the state trooper has a much greater area of jurisdiction than the local policeman, whose jurisdiction is confined to the town boundaries. In the same way, as antioxidants, both the tocopherol and tocotrienol go after the free radicals, but tocotrienol is anchored less deeply into the membrane and therefore, with its increased mobility, can hunt down free radicals across a much larger area. This concept is shown in the oft-quoted work of University of California/Berkeley’s Dr. Lester Packer, where tocotrienol is a 50 times more potent antioxidant than tocopherol.
While both tocotrienol and tocopherol are antioxidants, tocotrienol has added benefits, including cholesterol lowering, maintenance and reduction of triglyceride levels, and anti-cancer properties, to mention a few. Research is yielding that these features are unshared by tocopherols.
Passwater: We will go over the benefits of tocotrienol in detail later, and we will also cover how alpha-tocopherol might interfere with tocotrienol’s beneficial effects. Tell us a little bit more about the different isomers of tocotrienol.
Tan: In addition to its shorter tail, the substitution of methyl groups on the chromanol head of the tocotrienol molecule also plays an important role in its efficiency. Tocotrienol isomers (as well as tocopherol isomers) are designated by the substitution of methyl groups on the chromanol head. If the chromanol head contains three methyl substitutes (trimethylated) at position C-5, -7, and -8, we have alpha-tocotrienol. Substitution with two methyl groups (dimethylated) is either beta-tocotrienol (substitution at position C-5 and -8) or gamma-tocotrienol (substitution at position C-7 and -8). Delta-tocotrienol has only one methyl group (monomethylated) at position C-8. In general, less methylated tocotrienols are more active than fully methylated tocotrienols, especially when C-5 is left vacant or unsubstituted. Most recent studies show that delta- and gamma-tocotrienol, which I have collectively named “desmethyl tocotrienols” (Des T3) (5), are the most potent in their effects. This is most likely due to the lack of stearic hindrance with less methylated tocotrienols, which allows them to penetrate deeper into damaged membrane, and at the same time regenerate (or recharge) the spent (or oxidized) tocotrienol faster (or efficiently). Translated, desmethyl tocotrienols can have easier access to action, and treat damaged membranes faster.
Passwater: What are some sources of tocotrienol, and what is the composition of these sources?
Tan: Some of the more readily available sources of tocotrienol in the diet include oils and fats, grains (such as barley, wheat and corn), certain fruits, nuts, meat and eggs. However, the percentages in these are quite small. To date, the major sources of tocotrienol are rice, palm and annatto. This is my rule of thumb: Rice is composed of 50% tocotrienol and 50% tocopherol, while palm contains about 75% tocotrienol and 25% tocopherol. Annatto is the only known source containing 100% tocotrienol without tocopherol (see Figure 3).
Figure 3: Sources of tocotrienols.
Passwater: You said that the shorter tocotrienol molecular “tail” is the distinguishing factor that gives tocotrienols additional health benefits than tocopherols. Please tell us more about the mechanism associated with that and cholesterol reduction, and how it differs from how statins lower blood cholesterol by decreasing cholesterol production in the liver.
Tan: Statins are competitive inhibitors of cholesterol synthesis (production in the body). This means that they work directly on the enzyme responsible for cholesterol synthesis, which is called HMG CoA reductase (HMGR), by competing directly with substrates for the HMGR. This is fantastically powerful for lowering cholesterol, if only statins were to do just this job. But to its disadvantage, statin is an “indiscriminate” cholesterol reducer. Let me illustrate. Statins not only inhibit cholesterol production, but they unfortunately also inhibit the production of some essential proteins and intermediates that are produced in the same pathway, competitively. One example is that CoQ10 production is also decreased and CoQ10 deficiency can lead to congestive heart failure, chronic myopathy, reduced energy production and chronic fatigue. Other important biochemicals that may be depleted during statin treatment are dolichol and hemes, deficiency of which can lead to global myopathy and non-iron anemia.
Tocotrienol is a non-competitive inhibitor of the HMGR, but works much further downstream in the pathway to downregulate or “dial down” cholesterol synthesis. Tocotrienol’s farnesyl tail detaches phosphate groups from farnesyl pyrophosphate (i.e., dephosphorylates), and the excess freed farnesol, an intermediate in the HMGR pathway, dials down the enzyme synthesis. In addition, tocotrienol has been shown to degrade the protein HMGR directly via a process scientists call “disquintination”. This was originally shown in the 1990s in a study done by Bristol-Myers Squibb (6). Fifteen years later, this original study was revalidated, where researchers Drs. Song and DeBose-Boyd of the University of Texas elucidate the biochemical mechanism for the hypocholesterolemic effect of tocotrienols, specifically delta- and gamma-tocotrienol, on HMGR (7). This is an unequivocal proof that tocotrienol reduces cholesterol synthesis. The 2006 study was publicly endorsed by Dr. Joseph Goldstein and Dr. Michael Brown, who received the 1985 Nobel Prize for their discovery of the LDL receptor (8).
Therefore, tocotrienol “dials down” cholesterol synthesis without consequences, and statins “shut down” cholesterol synthesis with major consequences.
Passwater: Let’s take this “dial down” by tocotrienol and “shut down” by statins further. Your connection to the geranyl geraniol (GG) as the last common step between animal and plant is extremely interesting. If one takes statin, then the GG would decrease (see Figure 2). What would be the consequence of GG depletion?
Tan: Our body manufactures a pool of basic isoprenoids (Isoprenoid Pool) for many systemic functions downstream. It is generally understood that farnesol is the last committed step for cholesterol synthesis in mammals, including humans. Therefore, GG is the first uncommitted step to cholesterol synthesis and the first committed to many syntheses, including CoQ10 and proteins (see Figure 4). Taking statins depletes the isoprenoid pool, along with farnesol (hence the cholesterol reduction) and GG (hence the undesired myopathy, anemia, chronic fatigue, etc.). These isoprenoids are competitively dropped. These are not just “side effects,” but “major effects” systemic to the body. Therefore, statins are not “specific” cholesterol reducers, but “indiscriminate” cholesterol reducers. Tocotrienols are not an HMGR competitive inhibitors and do not affect GG.
Passwater: Does tocotrienol lower CoQ10 levels?
Tan: We can confirm that tocotrienol does not lower CoQ10 levels, probably because it does not inhibit GG. In fact, in an initial clinical trial patients actually showed an increase of up to 20% in CoQ10 levels (9), thanks to the efforts of Dr. Bill Judy (an expert in CoQ10 and frequent quest in your columns) who assisted me in conducting these analyses.
Figure 4: Biochemical pathways to cholesterol, CoQ10 and protein production.
Passwater: Tocotrienols have also 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 just discussed. When cholesterol is in excess, a feedback mechanism is set up to tell the HMGR 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). In this way, tocotrienol reduces Ras (an oncogene responsible for cell growth), arrests cells in the G1 phase, and initiates cell death or apoptosis (11). Tumor HMGR showed exceedingly high sensitivity to tocotrienols (especially delta- and gamma-tocotrienol) and surprisingly, also GG.
Another mechanism has to do with direct apoptosis activation. Here, tocotrienol may stimulate death receptors such as tumor necrosis factor (TNF) and Fas, which leads to activation of caspases, including caspase-8, -9 and -3. Activation of these caspases mediates the various cytoplasmic and nuclear events associated with apoptosis (12). I would say that the jury is still out on the molecular biology of cancer-kill by tocotrienol.
More recently, researchers have discovered that tocotrienol has anti-angiogenic properties. Angiogenesis is a mechanism tumors used to grow new vessels (arteries) from nearby arteries to feed it with much-needed nutrients and fuel its 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. Mizushina showed that tocotrienol inhibits the proliferation and formation of tubes by bovine aortic endothelial cells, and delta-tocotrienol had the strongest inhibitory activity (13). 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.
Finally, tocotrienol has superior antioxidant properties that may be attributed to its effect on cancer and inflammation. Tocotrienol may reduce lipid peroxidation and inhibit formation of mutagenic nitrogenous species, therefore preventing DNA mutations that increase the risk of cancer (14). For example, tocotrienol may inhibit cancer by the quenching of free radicals or increase the efficacy of antitumor actions by strengthening the immune system (15). Interestingly, a mixture of tocopherol-free delta- and gamma-tocotrienol had lipid Oxygen Radical Absorbance Capacity (ORAC) values that were about 30 times greater than vitamin E (as alpha-tocopherol), and also slightly better than those of the more highly regarded antioxidants resveratrol and EGCG (see Figure 5). This is a good measure of tocotrienol’s antioxidant properties.
Keep in mind that most ORAC readings that we are familiar with are the water-soluble or hydro-soluble ORAC (H-ORAC). We need high L-ORAC to protect lipid membranes.
Figure 5: ORAC values of some important antioxidants. The ORAC value of delta tocotrienols is higher than the other excellent antioxidants shown.
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 tocotrienols in a particular range or ratio to tocopherol lowered 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 as early as 1980 in his 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 (16) and that alpha-tocopherol by itself actually upregulates HMGR (14). Other research groups found that alpha-tocopherol decreases the absorption of tocotrienol (17), increases its breakdown (18) and upregulates human Supernatant Protein Factor (19), 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% (16), but in later experiments, Dr. Qureshi consistently 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: I usually recommend that people take their tocopherols in the morning and take their tocotrienol supplement in the evening with dinner. Remember that tocotrienol is not meant to replace tocopherol. Tocopherol was originally discovered to prevent fetal resorption (20), and later to protect red blood cells (21). However, over the years the amount of tocopherol in supplements has increased far beyond the RDA of 30 IU. 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 of the alpha-tocopherol interferences with tocotrienol benefits, and that the two should be taken apart.
Passwater: Why is it that there are so many mixed tocotrienol/tocopherol products in the market?
Tan: The earlier studies on tocotrienol were done using palm or rice tocotrienol-rich fractions (TRF), which really means a mixture of tocopherols and tocotrienols (see Figure 3). 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-lowering 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 usage.
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. These findings also have important implications for those with metabolic syndrome and diabetes. The study is included in 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.
In the same book, we are publishing a study on tocotrienol’s effect on chlamydial infections (22). 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 (23). More importantly, Chlamydia pneumoniae has been found in atherosclerotic tissue, and is believed to aggravate the progression of atherosclerosis (24). In our cell line studies, tocotrienol reduced chlamydial infection and delta-tocotrienol worked by 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. Previously, Dr. Theriault of the University of Hawaii/Manoa showed that tocotrienols reduce cellular adhesion molecule expression and monocytic cell adherence. In particular, delta-tocotrienol showed the most profound inhibitory effect on monocytic cell adherence as compared with tocopherols and other tocotrienol isomers (25, 26). This is an exceptional finding because delta-tocotrienol was 60–90-fold more potent than the other tocotrienols. The potency of tocotrienols in descending order 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 phenomenon occurs via inhibition of vascular cell adhesion molecule, VCAM-1 expression by delta-tocotrienol (27).
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 (28). 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 (29), breast (30), prostate (31) and colorectal cancers (32).
Most recently, Dr. Malafa and his group of the Moffitt Cancer Center and Research Institute of the University of Southern Florida/Tampa, for whom we provided the initial material, tested tocotrienol’s effect on pancreatic cancer, one of the most deadly of all types of cancers. About 35,000 Americans get pancreatic cancer each year, and 95% do not survive beyond 6–12 months following diagnosis. Among the famous, Luciano Pavarotti succumbed to it, actor Patrick Swayze and Dr. Randy Pausch (who wrote “The Last Lecture”) are 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 (33).
Research on the anti-angiogenic properties of tocotrienol also favors delta-tocotrienol as the most potent of the isomers (13). Since angiogenesis is important in tumor growth, diabetic retinopathy, rheumatoid arthritis, and psoriasis, the anti-angiogenic delta-tocotrienol may have significant therapeutic implications for these ailments.
Passwater: Are there cases in which alpha-tocotrienol would have benefits?
Tan: Dr. Sen of the Ohio State University/Columbus showed that alpha-tocotrienol is an important neuroprotector (34). I believe the jury is still out on whether it is the best of the tocotrienol isomer for neuroprotection. For example, 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
In general, tocotrienol and EGCG is a great combination to support healthy arteries, cells and nerves. Together, they are also a great antioxidant team (see Figure 3). 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 in 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 expression of cytochrome P-450. This decreased expression slows down tocotrienol metabolism (37). This means that the lignan given along with tocotrienol will potentiate tocotrienol and increase its blood levels.
Tocotrienol would also be a good combination with CoQ10, since both have been shown to lower systolic blood pressure and reduce hypertension (38, 39).
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 has been done by Dr. Qureshi in which tocotrienol is synergistic with lovastatin (40) and it is suggestive that you can reduce the levels of statin drugs when tocotrienol is used. Anecdotally, Dr. A.P. Chieng (of 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 could view a recent webinar I presented (www.naturalproductsinsider.com/webinars/).
Passwater: What are you working on now?
Tan: I am focusing on writing the 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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© 2008 Whole Foods Magazine and Richard A. Passwater, Ph.D.
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