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General chemical structure of tocotrienols

Tocotrienols are members of the vitamin E family.[1] An essential nutrient for the body, vitamin E is made up of four tocopherols (alpha, beta, gamma, delta) and four tocotrienols (alpha, beta, gamma, delta).[2] Chemically, vitamin E is an antioxidant.[3] One model for the function of vitamin E in the body is that it protects cell membranes, active enzyme sites, and DNA from free radical damage.

alpha-Tocopherol is the main source found in supplements and in the European diet, while gamma-tocopherol is the most common form in the American diet.

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 only occur at very low levels in nature.[4]

While the majority of research on vitamin E has focused on alpha-tocopherol, studies into tocotrienols account for less than 1% of all research into vitamin E.[5]

Symptoms caused by alpha-tocopherol deficiency can be alleviated by tocotrienols. Thus, tocotrienols may be viewed as being members of the natural vitamin E family not only structurally but also functionally. The slight difference between tocotrienols and tocopherols lie in the unsaturated side chain having three double bonds in its farnesyl isoprenoid tail.[6][7] All of the isomers have some level of antioxidant activity due to the donating hydrogen atom from the hydroxyl group on the chromanol ring that reduce free radicals in the body.

Tocotrienols are named by analogy to tocopherols (from Greek words meaning to bear a pregnancy (see tocopherol); but with this word changed to include the chemical difference that tocotrienols are trienes, meaning that they share identical structure with the tocopherols except for the addition of three double bonds to their side chains.

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, tocotrienols 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.

Contents

Discovery of tocotrienols

The discovery of tocotrienols was first reported by Pennock and Whittle in 1964, describing the isolation of tocotrienols from rubber.[8] The biological significance of tocotrienols was not clearly appreciated until the early 1980s, when its ability to lower lipids was first reported. During the 1990s, the different biological properties of tocopherols and tocotrienols began to be delineated.[9]

Tocotrienols are found in high concentrations in palm oil, naturally comprising high levels of the alpha-, gamma-, delta-tocotrienols with small quantity of beta-tocotrienol.[10] Other natural tocotrienol sources include rice bran oil, coconut oil, cocoa butter, barley and wheat germ.[11] Sunflower, peanut, walnut, sesame and olive oils, however contain only tocopherols.[12]

Vitamin E supplements typically supply 50-200 mg/day of mixed tocotrienols. Tocotrienols at doses as small as 42 mg/day have been found to reduce blood cholesterol levels by 5-35% in a number of different clinical trials.[13] Tocotrienols are safe and human studies show no adverse effects with consumption of 240 mg/day for 18-24 months.[14]

Tocotrienol rich fractions, used in functional food and anti-aging cosmetics, are available in the market at 20%, 50% and 70% total vitamin E content, with a typical ratio of tocotrienols to tocopherols at 70:30. Molecular distillation occurs at low temperatures and reduces the problem of thermal decomposition. High vacuum also eliminates oxidation that might occur in the presence of air.[15]

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

Types

Type R1 R2 R3
alpha-Tocotrienol Me Me Me
beta-Tocotrienol Me H Me
gamma-Tocotrienol Me Me H
delta-Tocotrienol Me H H

Comparison of tocotrienol and tocopherol

Tocotrienols are forms of natural vitamin E that can protect against brain cell damage,[16] prevent cancer[17] and reduce cholesterol.[18] These biological characteristics, however, are not present in tocopherols.[19]

Since the 1980s, there have been more studies proving tocotrienols are more potent in their anti-oxidation[20] and anti-cancer effect[21][22] than the common forms of tocopherol due its chemical structure. The unsaturated side-chain in tocotrienols makes them penetrate tissues with saturated fatty layers more efficiently,[23] making them ideal for anti-aging oral supplements[24] and skincare range.[25] Tocotrienols are better able than tocopherols at combating oxidative stress of skin that had been exposed to UV rays of the sunlight.[26]

Vitamin E 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. However, since 2000, scientists have suggested tocotrienols are better antioxidants than tocopherols[27][28] at preventing cardiovascular diseases[29] and cancer.[30] From the pharmacological standpoint, current formulation of vitamin E supplements, which comprised mainly of alpha- tocopherol, seems questionable.[31]

Synthetic tocotrienols

Although not currently available, tocotrienols can be synthesized through chemical reactions, labeled as 'dl-tocotrienols'. Chemically synthesized tocotrienols consist of both normal and its laterally inverted compounds, which are mirror-reflections of each other. The left version has the same structure but laterally inverted compared to the right version.[32]

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.[33] As of 2004, the Food and Nutrition Board of the Institute of Medicine of the United States National Academy of Sciences 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.[34]

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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 tocotrienols level 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.[35] The protective effects of tocotrienols are independent of their antioxidant activity because tocopherols were effective only at higher concentrates.[36]

In 2005, a study jointly undertaken at Wayne State University and Ohio State University Medical Center show that tocotrienol can be efficiently delivered to organs and could therefore offer the health benefits suggested by in vitro and in vivo studies.[37] "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 present 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.[38][39]

Tocotrienols are more effective antioxidants than tocopherols because its unsaturated side chain facilitate better penetration into saturated fatty layers of the brain[40] and liver.[41] Tocotrienols can lower tumor formation,[42] DNA damage and cell damage.[43] In a 1993 study where rats were induced with potent liver cancer agent, scientists found less liver cell damage in the group fed with palm tocotrienols.[22][44]

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.[45] Moreover, a Phase I dose-escalating study evaluating the effect of a pure Tocotrienol delta isomer extracted from palm oil towards individuals with Pancreatic cancer is currently underway at the Moffitt Cancer Centre, and is the first time tocotrienol has been clinically evaluated in humans towards cancer.[46]

Tocotrienols and breast cancer

In the 1990s, studies showed tocotrienols are the components of vitamin E responsible for growth inhibition in human breast cancer cells in vitro,[47] through estrogen-independent mechanisms.[48] Tocotrienols work synergistically with tamoxifen, a commonly used breast cancer medicine, in killing cancer cells.[49]

Tocotrienols can also affect cell homeostasis, possibly independently of their antioxidant activity.[50] 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[51] (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.[52]

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 and well as anti-proliferation of cancer cells. This mechanism was also observed in separate prostate cancer and melanoma cell line studies[53].

In 2009, a study by scientists at the College of Pharmacy, University of Louisiana at Monroe showed statins and tocotrienols provide significant health benefits in the treatment of breast cancer in women, while avoiding myotoxicity associated with high dose statin monotherapy.[54]

Tocotrienols and prostate cancer

Investigation of the antiproliferative effect of tocotrienols in PC3 and LNCaP prostate cancer 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.[55] However, recent research suggested that γ-tocotrienol was most potent in suppressing prostate cancer cell proliferation, and that 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.[56]

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.[57]

Tocotrienols and cholesterol reduction

The human body makes cholesterol from the liver, producing about 1g of cholesterol 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 deposit clog up the arteries. This will cause blood flow to the brain, heart, kidneys and other parts of the body become less efficient.

Cholesterol, though needed metabolically, is not essential in diet. We can lower cholesterol in our body by eating more fruits and vegetables. Tocotrienols can decrease the liver's capacity to manufacture cholesterol. It does so by suppressing the HMG-CoA reductase, the enzyme in the liver responsible for cholesterol synthesis.[18]

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 palm tocotrienols could ease clogged up arteries. Seven high cholesterol patients with narrowing arteries experienced reverse arterial blockage of the carotid artery after consuming palm tocotrienols, while in two the conditioned worsened.[58] This 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, γ-tocotrienol appears to act on a specific enzyme called 3-hydroxy-3-methylglutaryl-coenzyme and suppresses the production of this enzyme, resulting in less cholesterol being manufactured by liver cells.[59] While a 1995 study in chickens indicated that the presence of dietary alpha-tocopherol may interfere with tocotrienol's ability to lower cholesterol [60] although a later study found the interference was seen towards alpha-tocotrienol only.[61]

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.[62] Diabetes mellitus (DM) has been recognized as the sole independent risk factor for the development of any cardiovascular disease.[63] Cardiovascular complications include 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.[64]

Recent studies are showing that vitamin E intake significantly reduce 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, these data suggest the possibility that the development of type 2 diabetes might be modified by the intake of antioxidants in the diet.[65]

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.[66][67]

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.[33]

See also

References

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External links

  • Vitamin E factsheet - Office of Dietary Supplements, National Institutes of Health
  • MeSH Tocotrienols
  • Ronald R. Watson (Editor), Victor R. Preedy (Editor) (2008). Watson R.R., Preedy V.R.. ed. Tocotrienols - Vitamin E beyond Tocopherols. Boca Raton: CRC Press. ISBN 978-1-4200-8037-7. 

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