Tocotrienols comprise one of the two groups of molecules belonging to the vitamin E family, the other group being the tocopherols. Tocotrienols and tocopherols are sometimes collectively called tocols. Just as there are four natural tocopherols, alpha-, beta-, gamma- and delta-tocopherol, there are also four natural tocotrienols, alpha-, beta-, gamma- and delta-tocotrienol. The tocotrienols differ from the tocopherols in the chemical nature of the side chain or tail. Tocopherols have a saturated phytyl side chain, whereas tocotrienols have an unsaturated isoprenoid or farnesyl side chain possessing three double bonds.
The major source of tocotrienols are plant oils, and the richest sources are palm oil, rice bran oil, palm kernel oil and coconut oil. Tocotrienols are also found in such cereal grains as oat, barley and rye. Vegetable oils, such as those from canola, cottonseed, olive, peanut, safflower, soybean and sunflower, contain little to no tocotrienols. However, those oils do contain tocopherols. Corn oil has small amounts of tocotrienols.
All of the natural tocotrienols are fat-soluble, water-insoluble oils. The tocotrienols, as well as the tocopherols, possess chain-breaking, peroxyl radical scavenging activities. In contrast to tocopherols, tocotrienols inhibit the rate- limiting enzyme of the cholesterol biosynthetic pathway beta-hydroxy-beta-methylglutaryl-coenzyme A (HMG-CoA) reductase.
Tocotrienols have antioxidant activity. They may also have hypocholesterolemic, anti-atherogenic, antithrombotic, anticarcinogenic and immunomodulatory actions.
MECHANISM OF ACTION
All the tocotrienols are lipid soluble, chain-breaking, peroxyl radical scavengers. As such, they can protect polyunsaturated fatty acids (PUFAs) within membrane phospholipids as well as PUFAs within plasma lipoproteins, such as low density lipoproteins, from lipid peroxidation. Which of the tocols have the highest antioxidant activity is still open to debate. For many years, alpha-tocopherol was thought to be the most potent antioxidant in the vitamin E family. Some studies have shown tocotrienols to be more effective inhibitors of both lipid peroxidation and protein oxidation than alpha-tocopherol.
Tocotrienols inhibit the rate-limiting enzyme of the cholesterol biosynthetic pathway, beta-hydroxy-beta-methlyglutaryl-coenzyme A (HMG-CoA) reductase. Tocopherols do not have this activity. This hypocholesterolemic effect of tocotrienols is accounted for by the tocotrienol isoprenoid side-chain’s ability to increase the concentration of cellular farnesol. Farnesol is derived from mevalonate, the product of the HMG-CoA reductase reaction. Farnesol, post-transcriptionally, suppresses HMG-CoA reductase synthesis and enhances the proteolytic catabolism of this enzyme. This mechanism is different from that of the statin hypocholesterolemic drugs (atorvastatin, cerivastatin, fluvastatin, lovastatin and pravastatin) which are competitive inhibitors of the enzyme. Gamma-tocotrienol and delta-tocotrienol are significantly more active than alpha-tocotrienol in suppressing HMG-CoA reductase activity.
The possible anti-atherogenic activity of tocotrienols can be accounted for by a few mechanisms. These include inhibition of LDL oxidation, suppression of HMG-CoA reductase activity and inhibition of platelet aggregation. Additional possible mechanisms include tocotrienol-mediated reduction of plasma apolipoprotein B-100 (apoB) levels, reduction of lipoprotein (a) [Lp (a)] plasma levels and inhibition of adhesion molecule (e.g., ICAM-1 and VCAM-1) expression and monocyte cell adherence. High plasma levels of apoB as well as Lp (a) are considered risk factors for coronary artery disease.
Tocotrienols’ possible antithrombotic effect may be due to tocotrienols’ (especially gamma-tocotrienol’s) inhibition of thromboxane B2 synthesis, as well as their suppression of plasma levels of platelet factor 4.
Tocotrienols have been found to inhibit the growth of several tumor cell lines in culture, including both estrogen receptor-negative and estrogen receptor-positive human breast cancer cells. The mechanism of this effect is unclear, but there is some speculation about it. Tocotrienols may upregulate apoptosis in these lines. Another possible mechanism may relate to tocotrienols’ post-transcriptional suppression of HMG-CoA reductase. The suppression of mevalonate synthesis depletes tumor tissues of farnesyl pyrophosphate and geranylgeranylpyrophosphate. These intermediates in the cholesterol biosynthetic pathway play important roles in growth control-associated proteins. Suppressing the production intermediates could result in suppression of prenylation of the oncogene ras protein. Post-translational farnesylation of Ras is required for the cytoplasmic localization of the active Ras p21 to the cell membrane, enabling this oncogene to stimulate growth and induce malignant transformation.
A more uniform distribution in membrane bilayer and a stronger disordering of the membrane lipids, hence facilitating the interactions of chromanol ring with lipid radicals. This facilitates the removal of labile pool of oxidized LDL from the plaque and vascular endothelium and hence, promotes reversal of arterial blockage.
Inhibition of Hepatic 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase (HMG CoA Reductase), the enzyme in the liver that is responsible for the production of cholesterol. The unique tocotrienol prenylated (unsaturated) side chain increases cellular farnesol, which signals the proteolytic degradation of HMG CoA
Tocotrienols are the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes – by decreasing the activity of protein kinase C.
Tocotrienols were shown to lower cardio vascular disease risk factors such as:
1. Apolipoprotein B – by upregulating the LDL receptors in the liver and proteolytic degradation of ApoB, the protein moiety of LDL.
2. Lipoprotein(a) – low level of Lp(a) is associated with decrease in atherogenesis and thrombosis.
Tocotrienols were shown to have the ability to reduce serum thromboxane B2 and platelet factor 4 (Anti-Thrombotic Effect )- by reducing phospholipase A2 activity which inhibits the release of arachidonic acid from cell membrane phospholipids and inhibiting the transcriptional activation of the enzyme cyclooxygenase in the Cyclooxygenase Pathway.
SUMMARY OF BENEFITS
* Inhibit cholesterol production in the liver, thereby lowering total blood cholesterol.
* Alpha tocotrienol suppresses hepatic HMG-CoA reductase activity that results in the lowering of LDL cholesterol levels
* Tocotrienols which are naturally occurring in palm oil have been shown to suppress lower plasma cholesterol in human.
* Combination of gamma-tocotrienol and alpha-tocopherol is found as a potential hypolipemic agent in hyperlipemic humans at atherogenic risk.
* Tocotrienols inhibit cholesterogenesis by suppressing HMG-CoA reductase.
* Reverses arterial blockage (carotid arteriosclerosis), hence reducing the risk factors for cardio-vascular diseases such as arteriosclerosis and stroke. Palm based tocotrienols is the first and natural compound to be shown by human study, to have the ability to reverse arteriosclerosis.
* Medical human research showed that patients with confirmed carotid arteriosclerosis, who consumed 240mg of palm based tocotrienols/ day for 18-36 months had a decrease in the amount of cholesterol plaque in their carotid artery while those receiving placebo did not show such an effect.
* Palm based tocotrienol protects the ApoE knockout mice against cholesterol build-up and hence prevent arteriosclerosis.
Protection Against Ischemia/Reperfusion Heart Injury
* Medical study suggests that palm based tocotrienols were more efficient than alpha-tocopherol alone in the protection of the heart against oxidative stress induced by ischemic reperfusion.
Inhibit of Platelet Aggregation
* Delta-tocotrienol was significantly more potent than the alpha and gamma-tocotrienols, in the inhibition of platelet aggregation.
* Palm based tocotrienols may serve as an antithrombotic agent by decreasing platelet aggregation significantly.
Anti-cancer and Tumour Suppresive
* Palm based tocotrienols had shown to inhibit human breast cancer cells irrespective of estrogen receptor status. Tocopherol has no effect at all on human breast cancer cells.
* Delta – tocotrienol was found to be the most effective tocotrienols in inducing apoptosis (cell death) in estrogen-responsive and estrogen-nonresponsive human breast cancer cells.
* Confer anti-cancer properties.
* Inhibit tumor growth of certain cancers.
* Alpha-tocotrienol and gamma-tocotrienol have shown to prolong the life span of cancer-infected mice.
* Gamma-tocotrienol is 3 times more potent in inhibiting growth of human breast cancer cultured cells than Tamoxifen.
Potent Natural Super – Antioxidant
* Alpha-tocotrienol has been shown to be 40 – 60 times more potent than alpha-tocopherol as an antioxidant in the prevention of lipid peroxidation.
* Delta-tocotrienol is the most potent antioxidant (highest antioxidant potency) of all commercially available tocotrienols and has been shown to be the most effective tocotrienol in inhibiting human breast cancer and liver cancer cells
* Effective antioxidant in the prevention of protein oxidation and lipid peroxidation after strenous exercise for athletes, joggers and body builders.
Anti – Aging / Cosmetics and Personal Care
* Preferentially accumulates at the strata corneum of the skin. First line of defense against free radicals generated in the skin by UV/ozone rays. Prevention of skin aging and damage by oxidative rays. Being a more potent antioxidant, the tocotrienols neutralizes free radicals at a faster rate and hence protect tocopherols.
* Protection against UV-induced skin damage and skin aging.
* Tocotrienols topically applied onto the skin was found to penetrate rapidly through the skin and the highest concentrations are found in the uppermost 5 microns.
* Tocotrienol-treated skin contained Vitamin E at concentration 7-30 fold higher than control values.
* Tocotrienol augments the efficacy of sunscreens containing compounds that reduce penetration of or absorb ultraviolet radiation.
Lower Blood Pressure
* Palm gamma-tocotrienol has ability to prevent development of increased blood pressure in Spontaneously Hypertensive Rats (SHR) after 3 months supplementation.
Those on warfarin should be cautious in using doses of tocotrienols greater than 100 milligrams daily and, if they do so, they should have their INRs carefully monitored and their warfarin dose appropriately adjusted if indicated. Likewise, those with vitamin K deficiencies, such as those with liver failure, should be cautious in using doses of tocotrienols greater than 100 milligrams daily. Tocotrienols should also be used with caution in those with lesions with a propensity to bleed (e.g., bleeding peptic ulcers), those with a history of hemorrhagic stroke and those with inherited bleeding disorders (e.g., hemophilia).
High dose tocotrienol supplementation (greater than 100 milligrams daily) should be stopped about one month before surgical procedures and may be resumed following recovery from the procedure.
Those taking iron supplements should not take tocotrienols and iron at the same time.
Tocotrienol supplements have only recently been introduced in the nutritional supplement marketplace. No adverse reactions have been reported.
Tocotrienol overdosage has not been reported in the literature.
DOSAGE AND ADMINISTRATION
Presently marketed forms of tocotrienols contain mixed tocotrienols in their unesterified forms. These products typically contain d-alpha-tocotrienol, d-gamma-tocotrienol and d-delta-tocotrienol. Gamma-tocotrienol is usually the major tocotrienol in these preparations, which are marketed in the form of softgel capsules (tocotrienol is an oil).
Doses of 200 to 300 milligrams daily, with food, have been used in clinical trials studying possible cholesterol-lowering activity of tocotrienol.
The unesterified forms of tocotrienols, as well as tocopherols, are susceptible to oxidation and should therefore be stored intightly closed, opaque containers in a cool, dry place. Tocotrienols should not be taken concomitantly with iron supplements.
Dosages of palm tocotrienols in human studies were for a specific therapeutic condition – hypercholesterolemia, carotid stenosis and breast cancer at high dosages of tocotrienols. Individual who are interested in enhancing their antioxidant status as part of a long term nutritional plan should consider a moderate use levels. For these people who want to maintain a healthy level of cholesterol, a healthy heart and cardio vascular condition and breast health, the consensus among tocotrienol research scientists was a dosage of 30-50mg/day.
Commercial dietary supplements currently offer daily supplementation of tocotrienols from 20-60mg for healthy adults. Dr Asaf Qureshi (University of Wisconsin – the first research scientist to show that tocotrienols found in barley have the ability to lower total serum cholesterol), in his article titled ?The Mutitherapeutic Properties of Palm Oil and its Novel Vitamin E? quoted that daily intake of 34-42.5mg of pure tocotrienols obtained from palm oil will provide enough tocotrienols for all the health benefits associated with them.
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Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis.
Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML.
Kenneth L. Jordan Research Group, Montclair, New Jersey 07042, USA.
Antioxidants may have a role in the prevention of atherosclerosis. In the present trial, we investigated the antioxidant properties of Palm Vitee, a gamma-tocotrienol-, and alpha-tocopherol enriched fraction of palm oil, in patients with carotid atherosclerosis. Serum lipids, fatty acid peroxides, platelet aggregation and carotid artery stenosis were measured over an 18-month period in fifty patients with cerebrovascular disease. Change in stenosis was measured with duplex ultrasonography. Ultrasound scans were done at six months, twelve months, and yearly thereafter. Bilateral duplex ultrasonography revealed apparent carotid atherosclerotic regression in seven and progression in two of the 25 tocotrienol patients, while none of the control group exhibited regression and ten of 25 showed progression (P < 0.002). Serum thiobarbituric acid reactive substances, an ex vivo indicator of maximal platelet peroxidation, decreased in the treatment group from 1.08 +/- 0.70 to 0.80 +/- 0.55 microM/L (P < 0.05) after 12 mon, and in the placebo group, they increased nonsignificantly from 0.99 +/- 0.80 to 1.26 +/- 0.54 microM/L. Both tocotrienol and placebo groups displayed significantly attenuated collagen-induced platelet aggregation responses (P < 0.05) as compared with entry values. Serum total cholesterol, low density lipoprotein cholesterol, and triglyceride values remained unchanged in both groups, as did the plasma high density lipoprotein cholesterol values. These findings suggest that antioxidants, such as tocotrienols, may influence the course of carotid atherosclerosis.
Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols.
Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, Ong A, Peterson DM, et al.
Advanced Medical Research, Madison, WI 53719.
A double-blind, crossover, 8-wk study was conducted to compare effects of the tocotrienol-enriched fraction of palm oil (200 mg palmvitee capsules/day) with those of 300 mg corn oil/d on serum lipids of hypercholesterolemic human subjects (serum cholesterol 6.21-8.02 mmol/L). Concentrations of serum total cholesterol (-15%), LDL cholesterol (-8%), Apo B (-10%), thromboxane (-25%), platelet factor 4 (-16%), and glucose (-12%) decreased significantly only in the 15 subjects given palmvitee during the initial 4 wk. The crossover confirmed these actions of palmvitee. There was a carry over effect of palmvitee. Serum cholesterol concentrations of seven hypercholesterolemic subjects (greater than 7.84 mmol/L) decreased 31% during a 4-wk period in which they were given 200 mg gamma-tocotrienol/d. This indicates that gamma-tocotrienol may be one of the most potent cholesterol inhibitors. The results of this pilot study are very encouraging.