Tocotrienols are members of the vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 family. An essential nutrient for the body, vitamin E is made up of four tocopherol

Tocopherol

Tocopherols are a class of chemical compounds of which many have vitamin E activity. It is a series of organic compounds consisting of various methylated phenols...

s (alpha, beta, gamma, delta) and four tocotrienols (alpha, beta, gamma, delta). The slight difference between tocotrienols and tocopherols lie in the unsaturated side chain having three double bonds in its farnesyl isoprenoid tail. Tocotrienols are natural compounds found in select vegetable oils, wheat germ, barley, saw palmetto, and certain types of nuts and grains. This variant of vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 typically only occurs at very low levels in nature.

Chemically, vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 in all of its forms functions as an antioxidant

Antioxidant

An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

. All of the tocotrienol and tocopherol isomers have this antioxidant

Antioxidant

An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

 activity due to the ability to donate a hydrogen atom (a proton plus electron) from the hydroxyl

Hydroxyl

A hydroxyl is a chemical group containing an oxygen atom covalently bonded with a hydrogen atom. In inorganic chemistry, the hydroxyl group is known as the hydroxide ion, and scientists and reference works generally use these different terms though they refer to the same chemical structure in...

 group on the chromanol ring, to a free radical in the body. This process inactivates ("quenches") the free radical by effectively donating a single unpaired electron (which comes with the hydrogen atom) to the radical. Although the many vitamer

Vitamer

A vitamer of a particular vitamin is any of a number of chemical substances, each of which shows vitamin activity. Very commonly each "vitamin" is not a single chemical, but rather multiple chemical substances called vitamers, each of which is defined by its different biological activity.For...

s of vitamin E have different distributions and metabolic fates, there is as yet no accepted evidence that any of the active forms of vitamin E are able to do any essential function in the body that each of the others is not also able to do. Specifically, symptoms caused by alpha-tocopherol deficiency can be alleviated by tocotrienols. Thus, tocotrienols may be viewed as being members of the natural vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 family not only structurally but also functionally. Thus, one model for the function of vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 in the body is that it protects cell membranes, active enzyme sites, and DNA from free radical damage.

While the majority of research on vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 has focused on alpha-tocopherol, studies into tocotrienols account for less than 1% of all research into vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

. More recently, tocotrienols have reached a new measure of scientific recognition, with nearly 30% of peer-reviewed research articles on the vitamin published within the last two years (2009–2010). The first-ever scientific compilation of tocotrienol research, Tocotrienols: Vitamin E Beyond Tocopherols, was published in 2008 by CRC and AOCS Press, while a second edition has been approved for publication in May 2012.

Tocotrienols are named by analogy to tocopherols (from Greek words meaning to bear a pregnancy (see tocopherol

Tocopherol

Tocopherols are a class of chemical compounds of which many have vitamin E activity. It is a series of organic compounds consisting of various methylated phenols...

); but with this word changed to include the chemical difference that tocotrienols are trienes

Polyene

Polyenes are poly-unsaturated organic compounds that contain one or more sequences of alternating double and single carbon-carbon bonds. These double carbon-carbon bonds interact in a process known as conjugation, which results in an overall lower energy state of the molecule.Organic compounds with...

, meaning that they share identical structure with the tocopherols except for the addition of three double bonds

Covalent bond

A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....

 to their side chain

Side chain

In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

s.

Tocotrienols extracted from natural sources are d-tocotrienols. Tocotrienols have only a single chiral center, which exists at the 2' chromanol ring carbon, at the point where the isoprenoid tail joins the ring; the other two corresponding centers in the phytyl tail of the corresponding tocopherols, do not exist due to tocotrienol's unsaturation at these sites. In theory, tocotrienol stereoisomers may thus exist in the natural d-tocotrienol form, or as the unnatural isomeric 'l-tocotrienols' which have a 2S (rather than 2R) configuration at the molecules' single chiral center. In practice, however, tocotrienols are extracted from natural sources, and synthetic l and d,l forms are not marketed as supplements.

Discovery of tocotrienols

The discovery of tocotrienols was first reported by Pennock and Whittle (USDA, Liverpool) in 1964, describing the isolation of tocotrienols from rubber. The biological significance of tocotrienols was clearly delineated in the early 1980s, when its ability to lower cholesterol was first reported by Qureshi and Elson (UWisconsin/Madison). During the 1990s, the anti-cancer properties of tocopherols and tocotrienols began to be delineated.

The current commercial sources of tocotrienol are rice, palm, and annatto. The ratio of tocopherol-to-tocotrienol in rice, palm, and annatto

Annatto

Annatto, sometimes called roucou or achiote, is a derivative of the achiote trees of tropical regions of the Americas, used to produce a yellow to orange food coloring and also as a flavoring...

 is 50:50, 25:75, and 0.1:99.9, respectively. α-tocopherol makes up roughly 25–50% of palm and rice vitamin E mixtures, respectively, and has been shown to interfere with tocotrienol benefits. Annatto, on the other hand, naturally contains only δ- and γ-tocotrienols and is essentially tocopherol-free, hence not confined by α-tocopherol interference issues.

Other natural tocotrienol sources include rice bran oil, coconut oil, cocoa butter, barley, and wheat germ. Sunflower, peanut, walnut, sesame, and olive oils, however contain only tocopherols.
Vitamin E supplements typically supply 50–200 mg/day of mixed tocotrienols. In a number of clinical trials, doses of tocotrienols as low as 42 mg/day have shown to reduce blood cholesterol levels by 5–35%. Tocotrienols are safe and human studies show no adverse effects with consumption of 240 mg/day for 48 months.

Tocotrienol rich fractions from rice, palm, or annatto

Annatto

Annatto, sometimes called roucou or achiote, is a derivative of the achiote trees of tropical regions of the Americas, used to produce a yellow to orange food coloring and also as a flavoring...

, used in nutritional supplements, functional foods, and anti-aging cosmetics, are available in the market at 20%, 35%, 50%, and 70% total vitamin E content. Molecular distillation occurs at lower temperatures and reduces the problem of thermal decomposition. High vacuum also eliminates oxidation that might occur in the presence of air. For the utility and quality it is desired for the absolute tocotrienol concentration to be highest, tocopherol to be the lowest, and the process used to be solvent-free. Annatto tocotrienol has the highest tocotrienol concentrations, and is tocopherol-free.

Vitamin E, be it tocopherols or tocotrienols, is extremely sensitive towards heat.

Types

Type

R1

R2

R3 >- | alpha-Tocotrienol Alpha-Tocotrienol α-Tocotrienol is one of the chemical compounds that is considered vitamin E.See the main article tocotrienol for more information.-See also:* beta-Tocotrienol* gamma-Tocotrienol* delta-Tocotrienol-References:...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion... >- | beta-Tocotrienol

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

H Hydrogen Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion... >- | gamma-Tocotrienol

H Hydrogen Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion... >- | delta-Tocotrienol

H Hydrogen Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

H Hydrogen Hydrogen is the chemical element with atomic number 1. It is represented by the symbol H. With an average atomic weight of , hydrogen is the lightest and most abundant chemical element, constituting roughly 75% of the Universe's chemical elemental mass. Stars in the main sequence are mainly...

Me Methyl group Methyl group is a functional group derived from methane, containing one carbon atom bonded to three hydrogen atoms —CH3. The group is often abbreviated Me. Such hydrocarbon groups occur in many organic compounds. The methyl group can be found in three forms: anion, cation and radical. The anion...

Comparison of tocotrienol and tocopherol

Tocotrienols are forms of natural vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 that can protect against brain cell damage, prevent cancer and reduce cholesterol. These biological characteristics, however, are not present in tocopherols.

Since the 1980s, there have been more studies proving tocotrienols are more potent in their anti-oxidation and anti-cancer effect than the common forms of tocopherol due their chemical structure. The unsaturated side-chain in tocotrienols causes them to penetrate tissues with saturated fatty layers more efficiently, making them ideal for anti-aging oral supplements and the skincare range. Tocotrienols are better able than tocopherols at combating oxidative stress of skin that had been exposed to UV rays of the sunlight.

Vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 has long been known for its antioxidative properties against lipid peroxidation in biological membranes and alpha-tocopherol is considered to be the most active form. In vivo, tocotrienols are more powerful antioxidants, and lipid ORAC values are highest for δ-tocotrienol. Since 2000, scientists have suggested tocotrienols are better antioxidants than tocopherols at preventing cardiovascular diseases and cancer. From the pharmacological standpoint, current formulation of vitamin E

Vitamin E

Vitamin E is used to refer to a group of fat-soluble compounds that include both tocopherols and tocotrienols. There are many different forms of vitamin E, of which γ-tocopherol is the most common in the North American diet. γ-Tocopherol can be found in corn oil, soybean oil, margarine and dressings...

 supplements, composed mainly of alpha- tocopherol, seems questionable.

α-tocopherol interference

Various studies have shown that alpha-tocopherol interferes with tocotrienol benefits. This was first published by Qureshi et al. in 1996, where researchers administered varying amounts of α-tocopherol and/or tocotrienol to six groups of chickens. The group that received only a minimal amount of α-tocopherol showed the greatest reduction in lipid parameters, while the group with the highest amount of alpha-tocopherol had an increase in cholesterol production. A separate study confirmed that high levels of α-tocopherol increase cholesterol production.
α-tocopherol interference with tocotrienol absorption was described previously by Ikeda et al., who showed that α-tococopherol interfered with absorption of α-tocotrienol, but not γ-tocotrienol. More recently, Japanese researchers found that tocopherols, and α-tocopherol in particular, interfered with δ-tocotrienol’s ability to induce apoptosis in cancer cells, while blocking the absorption of δ-tocotrienol. Finally, α-tocopherol was shown to interfere with tocotrienols by increasing their catabolism.

Synthetic tocotrienols

Curiously, synthetic tocotrienol is not commonly available despite the ability to generate the compounds through chemical reactions. Depending on the route of synthesis, the product may result in a racemic mix of dl-tocotrienol which consists of a mix of d and l (left and right) forms that are lateral inversions of one another. However, pure isomers of either the d or l tocotrienol forms should also be possible using the right chemistry. In theory these would then likely confer many of the clinical benefits claimed for natural tocotrienol while being extremely pure in comparison and relatively cheap to produce.

Health effects of tocotrienols

Many research claims of tocotrienols' health benefits for human beings have been made. The toxicity levels for humans are presently unknown. The no-observed-adverse-effect level (NOAEL) for rats is estimated at 120–130 mg/kg body weight/day. As of 2004, the Food and Nutrition Board of the Institute of Medicine

Institute of Medicine

The Institute of Medicine is a not-for-profit, non-governmental American organization founded in 1970, under the congressional charter of the National Academy of Sciences...

 of the United States National Academy of Sciences

United States National Academy of Sciences

The National Academy of Sciences is a corporation in the United States whose members serve pro bono as "advisers to the nation on science, engineering, and medicine." As a national academy, new members of the organization are elected annually by current members, based on their distinguished and...

 did not define either the health benefits or the health risks, i.e. the Estimated Average Requirement, the Recommended Dietary Allowance, the Adequate Intake and the Tolerable Upper Intake Level (UL) were defined for alpha-tocopherol (except the ULs for infants) but not for tocotrienols.

Tocotrienols and stroke-induced Injuries

In the peer-reviewed Stroke journal (Oct 2005), oral supplementation of a natural full spectrum palm tocotrienol complex to spontaneously hypertensive rats led to increased tocotrienol levels in the brain. The rats, supplemented with tocotrienols, showed more protection against stroke-induced injury compared to controls (non-supplemented group). This study demonstrated that oral supplementation of the palm tocotrienol complex acts on key molecular checkpoints (c-Src and 12-Lipoxygenase) to protect against glutamate- and stroke-induced neurodegeneration and ultimately protect against stroke in vivo. The protective effects of tocotrienols are independent of their antioxidant activity because tocopherols were effective only at higher concentrates.

In 2005, a study jointly undertaken at Wayne State University and Ohio State University Medical Center showed that tocotrienol can be efficiently delivered to organs and could therefore offer the health benefits suggested by in vitro and in vivo studies. "Our results demonstrate that tocotrienols is efficiently delivered to the bloodstream despite the fact that the transfer protein has a lower affinity for tocotrienols than it has for tocopherols," said Chandan Sen of Ohio State University and senior author of the study.

The researchers recruited women with normal cholesterol levels (average age of 23.5 years old) and gave them a fat-rich strawberry smoothie containing 400 mg of vitamin E containing 77 mg alpha-tocotrienol, 96 mg delta-tocotrienol, and 3 mg gamma-tocotrienol, plus tocopherols. Since vitamin E is a fat-soluble vitamin, the researchers chose to deliver the micronutrient in a fat-loaded meal in order to improve absorption. Blood measurements in the post-prandial period showed that maximal alpha-tocotrienol levels averaged almost 3 micromoles in blood plasma, 1.7 micromoles in low density lipoproteins, and 0.5 micromoles in high density lipoproteins. "This work presented first evidence demonstrating the post-absorptive fate of tocotrienol isomers and their association with lipoprotein subfractions in humans," wrote lead author Pramod Khosla of Wayne State University.

These concentrations, say the researchers, are sufficient to support the proposed neuro-protective functions of tocotrienol. "We have determined that when administered orally, tocotrienol can reach concentrations needed to serve these… protective functions," said Sen. "It is a regular dietary ingredient in Asia, so it can safely be a part of a daily diet within prepared foods or as a supplement in the United States." Can it be therapeutically used to prevent stroke? "Results from animal studies are encouraging, but it is still too soon to tell for humans," he added.

Tocotrienols and pancreatic cancer

Pancreatic cancer represents the fourth-leading cause of cancer death in the United States, with a dismal 5-year survival rate of less than 5%. Early detection and screening for pancreatic cancer in the current state should be limited to high-risk patients, although hereditary/familial factors account for only 10% of patients with pancreatic cancer.

Tocotrienol is more effective antioxidant than tocopherol because its unsaturated side chain

Side chain

In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

 facilitates better penetration into saturated fatty layers of the brain

Brain

The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...

 and liver

Liver

The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...

. Tocotrienols can lower tumor

Tumor

A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...

 formation, DNA

DNA

Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 damage and cell

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 damage. In a 1993 study where rats were induced with a potent liver cancer agent, scientists found less liver cell damage in the group fed with palm tocotrienols.

In 2009, scientists at Department of Nutrition and Food Sciences, Texas Woman's University evaluated the impact of d-delta-tocotrienol, a potent vitamin E isomer, on human MIA PaCa-2 and PANC-1 pancreatic carcinoma cells and BxPC-3 pancreatic ductal adenocarcinoma cells. They concluded suppression of mevalonate pathway activities, be it by modulators of HMG CoA reductase (statins, tocotrienols, and farnesol), farnesyl transferase (farnesyl transferase inhibitors), and/or mevalonate pyrophosphate decarboxylase (phenylacetate) activity, have a potential in pancreatic cancer chemotherapy. Moreover, a Phase I dose-escalating study evaluating the effect of pure δ-tocotrienol towards individuals with pancreatic cancer is currently underway at the Moffitt Cancer Centre, and is the first tocotrienol study that is being clinically evaluated in humans towards cancer.

Tocotrienols and breast cancer

In the 1990s, studies showed tocotrienols are the components of vitamin E responsible for growth inhibition in human breast cancer

Breast cancer

Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...

 cells in vitro

In vitro

In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...

, through estrogen-independent mechanisms. Tocotrienols work synergistically with tamoxifen, a commonly used breast cancer medicine, in killing cancer cells.

Tocotrienols can also affect cell homeostasis

Homeostasis

Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...

, possibly independently of their antioxidant activity.
Anti-cancer effects of α- and γ-tocotrienol have been reported, although δ-tocotrienol was verified to be the most effective tocotrienol in inducing apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

 (cell death) in estrogen-responsive and estrogen-nonresponsive human breast cancer cells. Based on these results on cells in culture, investigators have hypothesised that a mixture of α- and γ-tocotrienols might reduce breast cancer risk.

Further studies on tocotrienol and breast cancer indicated that gamma-tocotrienol targets cancer cells by inhibiting Id1, a key cancer-promoting protein. Gamma-tocotrienol was shown to trigger cell apoptosis as well as anti-proliferation of cancer cells. This mechanism for δ- and γ-tocotrienol was also observed in separate prostate cancer and melanoma cell line studies.

In 2009, a study by scientists at the College of Pharmacy, University of Louisiana at Monroe showed that lower level statin treatment in combination with γ-tocotrienol inhibits growth of highly malignant +SA mammary epithelial cells in culture (suggesting the possibility of avoiding myotoxicity associated with high dose statin monotherapy).

Tocotrienols and prostate cancer

Investigation of the antiproliferative effect of tocotrienols in PC3 and LNCaP prostate cancer

Prostate cancer

Prostate cancer is a form of cancer that develops in the prostate, a gland in the male reproductive system. Most prostate cancers are slow growing; however, there are cases of aggressive prostate cancers. The cancer cells may metastasize from the prostate to other parts of the body, particularly...

 cells suggests that the transformation of vitamin E to CEHC is mostly a detoxification mechanism, useful to maintain the malignant properties of prostate cancer cells. However, various research studies suggest that both δ- and γ-tocotrienol potently suppressed prostate cancer cell proliferation. In one study,the antiproliferative effect of γ-tocotrienol act through multiple-signalling pathways (NF-B, EGF-R and Id family proteins). In addition, the same study demonstrated the anti-invasion and chemosensitisation effect of γ-tocotrienol against PCa cells. In another study, δ-tocotrienol was at least equally or more potent than γ-tocotrienol in prostate cancer cells, and showed that alpha-tocopherol enhanced cancer cell growth.

Tocotrienols and skin cancer

In a 2009 study at the Li Ka Shing Faculty of Medicine, The University of Hong Kong, scientists found reduction in skin cancer cells when treated with gamma-tocotrienol with chemotherapy drugs. For the first time, researchers recorded the anti-invasion and chemonsensitization effect of gamma-tocotrienol against human malignant melanoma cells. In cell line and animal studies, δ- and γ- tocotrienols have been shown to suppress the growth of melanoma.

Tocotrienols and cholesterol reduction

The human body makes cholesterol from the liver, producing about 1g of cholesterol

Cholesterol

Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

 each day or 80% of the needed total body cholesterol. The remaining 20% comes from what we eat. Excessive cholesterol is a health risk because gradual fatty deposits clog up the arteries. This will cause blood flow to the brain, heart, kidneys and other parts of the body to become less efficient.

Cholesterol

Cholesterol

Cholesterol is a complex isoprenoid. Specifically, it is a waxy steroid of fat that is produced in the liver or intestines. It is used to produce hormones and cell membranes and is transported in the blood plasma of all mammals. It is an essential structural component of mammalian cell membranes...

, though needed metabolically, is not essential in diet. Tocotrienols can decrease the liver's capacity to manufacture cholesterol. They do so by dialing down HMG-CoA reductase, the enzyme in the liver responsible for cholesterol synthesis.

In 1993, American scientists conducted a double-blind placebo controlled study of 50 volunteers at the Kenneth Jordan Heart Foundation and Elmhurst Medical Center. Their results suggested that tocotrienols (from palm and rice) could ease clogged arteries. Seven high cholesterol patients with narrowing arteries experienced reversal of arterial blockage of the carotid artery after consuming tocotrienols, while in two the condition worsened. This was compared to the control group, where none improved and ten worsened.
Tocotrienols, especially δ- and γ-tocotrienols, were shown to be effective nutritional agents in treating high cholesterol. In particular, they act on a specific enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 called 3-hydroxy-3-methylglutaryl-coenzyme A reductase and dial down the production of the enzyme, resulting in less cholesterol being manufactured by liver cells. . Both δ- and γ-tocotrienols degraded the enzyme, but only δ-tocotrienol was shown to block production fully. A 1996 study in chickens indicated that the presence of dietary alpha-tocopherol may interfere with tocotrienol's ability to lower cholesterol
Investigation on FeAOX-6, which combines antioxidant structural features of both tocopherols and carotenoids into a single molecule, on macrophage functions involved in foam cell formation showed that both FeAOX-6 or alpha-tocotrienol induce a strong dose-dependent reduction of cholesterol and reduce cholesterol accumulation in human macrophages. The extent of the reduction found with alpha-tocotrienol was greater than that induced by FeAOX-6 and did not correlate with their respective antioxidant capacities.

Tocotrienols and diabetes

According to the World Health Organization (WHO), 170 million people were affected by diabetes in the year 2002, and this number is likely to increase to 366 million by the year 2030. Diabetes mellitus (DM) has been recognized as the sole independent risk factor for the development of any cardiovascular disease. Cardiovascular complications such as stroke and heart attack are increasingly causing death in diabetic patients. Alarmingly, literature statistics indicate that atherosclerosis accounts for about 8 to 10% of all diabetic deaths.

Recent studies are showing that vitamin E intake significantly reduced risk of type 2 diabetes. The relative risk (RR) of type 2 diabetes between the extreme quartiles of the intake was 0.69 (95% CI 0.51-0.94, P for trend=0.003). Intakes of alpha-tocopherol, gamma-tocopherol, delta-tocopherol, and beta-tocotrienol were inversely related to a risk of type 2 diabetes. While correlation does not imply causation

Correlation does not imply causation

"Correlation does not imply causation" is a phrase used in science and statistics to emphasize that correlation between two variables does not automatically imply that one causes the other "Correlation does not imply causation" (related to "ignoring a common cause" and questionable cause) is a...

, these data suggest the possibility that the development of type 2 diabetes might be modified by the intake of antioxidants in the diet.

In 2009, animal trials carried out in India and Malaysia revealed palm tocotrienols improved blood glucose, dyslipidemia and oxidative stress in diabetic rats. It is able to prevent the progression of vascular wall changes occurring in DM.

Tocotrienols and radiation countermeasures

When radiation strikes, be it from warfare (which is always a threat), disaster (as in Japan’s recent earthquake and tsunami), or therapy (as in cancer), the bone marrow is the first to be compromised. Those lethally affected die immediately, whereas those who are critically affected may survive the first 30 days, and survival is predominantly dependent on the bone marrow regenerating itself. Severe side effects include acute radiation syndrome (ARS) and bone marrow failure syndrome (BMFS). If the bone marrow regenerates fast enough, new blood from the marrow will replenish arteries and veins, replacing old blood that was extremely compromised. This is true for radiation in warfare, disaster or cancer.

In the past six years, the Armed Forces Radiobiology Research Institute (AFRRI) has performed extensive research on tocotrienol —a form of vitamin E — as radiation countermeasure agent. Tocotrienols occur naturally as four distinct molecules designated α-, β-, γ- and δ-tocotrienol. Of these, δ- and γ-tocotrienol are the most effective radioactive countermeasure agents. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are the primary source of radiation-induced damage, and – as potent antioxidants – tocotrienols are effective radioprotectors, supporting the hypothesis that “strong antioxidants make strong radioprotectors”. However, amelioration of radiation lethality goes beyond tocotrienol’s antioxidant properties. δ- and γ-tocotrienol display an unambiguous stimulatory effect on hematopoietic (blood-forming) tissue, with delta-tocotrienol performing better than gamma-tocotrienol.
Following total body irradiation of mice, both δ- and γ-tocotrienol regenerated blood-borne cells by increasing the total white blood cell count; only δ-tocotrienol regenerated lymphocytes. Tocotrienols almost fully restored bone marrow cellularity to normal levels following radiation, while overall cellularity in untreated controls remained depleted. In both cases, prophylactic treatment 24 hours pre-radiation was more effective than post-radiation treatment. These results suggest that tocotrienols, especially of the δ- and γ-isoforms, could be used as powerful radioprotectors in first responders to nuclear fallout areas, radiation workers, and cancer radiotherapy patients. Annatto tocotrienol is are the only source containing exclusively δ-tocotrienol (90%) and γ-tocotrienol (10%) that may be useful for radiation countermeasures, tocotrienols from rice bran contain all four: alpha, beta, gamma and delta.

No-observed-adverse-effect level

A 13-week study by H. Nakamura and colleagues at the National Institute of Health Sciences (Japan) of tocotrienols' toxicity in rats found significant changes in several blood components, increases in liver weights and (in females) reductions in ovary and uterus weights, depending on the dosages. The authors estimated the no-observed-adverse-effect level (NOAEL) to be 120 mg per kg of body weight per day for males and 130 mg per kg of body weight per day for females. Since effects on the blood components were observed in all cases with non-placebos, a no-observed-effect level (NOEL) could not be determined.

External links

• Vitamin E factsheet — Office of Dietary Supplements, National Institutes of Health