Although Vitamin E was discovered in 1922, it has only been in the last ten years that it has come to be understood not as a single compound but as a whole group of substances, including alpha, beta, gamma and delta tocopherols as well as alpha, beta, gamma and delta tocotrienols. A large number of nutritional supplements primarily contain alpha tocopherol, creating the perception that only this compound is synonymous with vitamin E. However, recent studies show that other substances with vitamin E activity are just as important for human health.
Vitamin E was initially identified as being vital for reproduction. Today, it is considered to be an essential nutrient, involved in a number of biological systems including defence mechanisms against oxidation, cardiovascular and neuro-muscular systems as well as regulation of cell growth.
Alpha or gamma tocopherol
Several large-scale studies have demonstrated the benefits of vitamin E supplementation for reducing the risk of cardiovascular disease and death from heart attack although other research has not produced such findings. These inconsistencies could be explained by the fact that only alpha tocopherol was investigated in some of these studies, rather than including gamma tocopherol or the tocotrienols.
It may also explain why vitamin E found in food is more effective at lowering the risk of death from cardiovascular disease than alpha tocopherol supplements - the diet provides a wide spectrum of compounds from the vitamin E family.
In addition, studies suggest that high doses of alpha tocopherol significantly reduce the absorption of gamma tocopherol and the effects of tocotrienols. One group of scientists observed that when volunteers (aged 30-60) were given daily supplements of 1200 IU synthetic alpha tocopherol for eight weeks, their plasma gamma tocopherol levels decreased by 30%-50% compared with their levels at the study’s outset. These findings highlight the benefits of choosing nutritional supplements that contain a good balance of the different compounds with vitamin E activity.
A particularly important role in cardiovascular disease
A Swedish study reported that patients suffering from coronary heart disease had lower gamma tocopherol levels than healthy subjects of the same age, and that their alpha:gamma ratio was higher.
In a very large cohort of menopausal women (almost 35,000), dietary 1
intake of vitamin E, but not alpha tocopherol supplementation, was associated with lower mortality from stroke or heart attack. It is also known that regular consumption of nuts, which are particularly rich in gamma tocopherol, reduces cardiovascular mortality.
Animal studies have also produced interesting data on the likely role of gamma tocopherol in cardiovascular protection.
In research on rats, supplementation with gamma tocopherol produced a greater decrease in blood clot formation than alpha-tocopherol. It should, however, be remembered that gamma tocopherol supplementation raises levels of both alpha and gamma tocopherol. Gamma tocopherol also demonstrated greater efficacy ex vivo at inhibiting lipid peroxidation, LDL oxidation and peroxide generation. It is similarly more effective at stimulating expression and activity of superoxide dismutase. .2
Alpha and gamma tocopherol both increase production of nitric oxide (which dilates the blood vessels) by boosting the activity of endothelial nitric oxide synthase. Only gamma tocopherol stimulates this essential enzyme’s protein expression.
A powerful antioxidant
Alpha tocopherol has long been recognised as an important antioxidant, but research now shows that the vitamin E family as a whole provides far greater efficacy. The various forms of vitamin E have complementary free radical-fighting effects.
Together, they combat a far wider range of free radicals than alpha tocopherol alone. While the latter can, to a certain extent, inhibit free radical formation, gamma tocopherol is able to immobilise and eliminate highly toxic free radicals such as dinitrogen tetroxide. It therefore protects cells against the mutagenic and carcinogenic effects of highly dangerous reactive molecules.
Protective anti-cancer effect
Gamma tocopherol’s efficacy at inhibiting the growth of prostate cancer cells is far greater than that of alpha tocopherol. In a study comparing the inhibitory effects on such growth of synthetic alpha tocopherol and natural gamma tocopherol, the latter was shown to be effective at concentrations 1000 times lower than those of synthetic alpha tocopherol. 3
In a prospective study, men with the highest plasma gamma tocopherol levels had one-fifth the risk of prostate cancer of those with the lowest levels. In addition, the protective effect of selenium and alpha tocopherol was observed only when gamma tocopherol levels were high. .4
Tocotrienols are a group of natural vitamin E compounds which in some (but not all) aspects, display similar biological characteristic to those of their molecular siblings, the tocopherols. Tocotrienol-rich foods include rice, oatmeal, palm oil and barley.
Similarities and differences
The fundamental difference in chemical structure between the tocopherols and the tocotrienols lies in the arrangement of substituent atoms attached to a chromanol ring and whether the long hydrocarbon chain attached to this ring is either saturated or unsaturated. The tocopherols have a completely saturated hydrocarbon chain while the tocotrienols are characterised by a partly unsaturated hydrocarbon chain.
Each tocotrienol has an identical chromanol ring to that of the corresponding tocopherol, which explains why they too are excellent antioxidants.
A number of studies have produced evidence that the tocotrienols confer important beneficial effects not offered by other forms of vitamin E.
Cell growth and anti-cancer activity
Laboratory research suggests that tocotrienols may affect growth and/or proliferation of certain types of human cancer cells. In vitro and animal studies show that tocotrienols are much more effective at inhibiting cancer cell growth than tocopherols.
in rats demonstrated that long-term supplementation with tocotrienols extracted from palm oil reduced the impact of carcinogens. Following exposure to liver toxins, some of the rats were fed a tocotrienol-enriched diet, and others a normal diet.
The ten rats exposed to toxins and fed a normal diet went on to develop liver cancer during the nine months of the study, while only one of the six rats supplemented with tocotrienols developed cancerous nodules.
Various in vitro studies have examined tocotrienols’ ability to inhibit the growth of human breast cancer cells. Different types of breast cancer cell have been identified on the basis of whether or not they express oestrogen receptors in their cell membranes. Tocotrienols inhibit growth of breast cancer cells with and without oestrogen-receptors.
If indeed tocotrienols act on cancer cells via a non-oestrogen receptor-mediated pathway as findings suggest, then they may prove to be particularly useful in treating breast cancer cells resistant to anti-oestrogen therapeutic agents.
Confirming initial results obtained by a group of Canadian scientists, researchers at the University of Texas in Austin, led by Dr Kimberley Kline, have shown that tocotrienols slow down the growth of human breast cancer cells..7
According to this study, natural source tocotrienols and RRR-delta tocopherol induced cancer cell death, with gamma and delta tocotrienols proving the most effective. The Canadian group led by Dr Najila Guthrie of the University of Western Ontario had previously demonstrated a similar effect for tocotrienols combined with mixed tocopherols, while alpha tocopherol on its own was not shown to be effective.
Investigations into other types of cancer cell revealed tocotrienols - particularly gamma and delta tocotrienols - to be the most effective among a group of compounds tested for their ability to inhibit the growth of mouse melanoma cells..8
Tocotrienols and cholesterol
Tocotrienols confer a beneficial effect on cholesterol metabolism which tocopherols do not. Studies on a large number of cell cultures have shown that tocotrienols, particularly gamma tocotrienol, inhibit cholesterol production. They appear to act on a specific enzyme called 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA), which is involved in cholesterol production in the liver. 9
As a result of tocotrienols inhibiting production of this enzyme, less cholesterol is produced in the liver, which can lead to a reduction in plasma cholesterol levels. Researchers have investigated the effects of a tocotrienol-rich preparation on human cholesterol levels.
They reported that tocotrienols significantly reduced cholesterol in subjects with the highest levels . 10
In a double-blind crossover study of 25 patients with high levels of serum lipids, daily administration of four 50mg capsules of mixed tocotrienols with palm oil for eight weeks produced a significant reduction in levels of total and LDL cholesterol (15% and 8% respectively). No change was observed in a control group given corn oil. 11
Benefits for cardiovascular health
One of the most interesting discoveries has undoubtedly been the ability of tocotrienols to clear atherosclerotic blockages (stenosis) from the carotid artery, raising the possibility of significantly reducing the risk of a heart attack.
The strongest evidence of this comes from a clinical 12
study that tested the effect of tocotrienols on carotid atherosclerosis. In this 18-month long study, 50 patients with stenosis of the carotid artery were randomly assigned to receive either 160mg of palm tocotrienols (alpha and gamma forms) with 64mg of palm oil alpha tocopherol, or a placebo of palm oil only.
After six months, the doses given to the supplement group were increased to 240mg of tocotrienols and 96mg of alpha tocopherol.
At the end of the study, ultrasound examination of the arteries showed no improvement in condition in any of the control group patients and in ten of them, the stenosis had actually got worse. In the tocotrienol-supplemented group, however, the atherosclerosis had decreased, blood flow to the brain had improved in seven of the 25 patients, and the stenosis had worsened in only two patients.
monitoring 50 patients with stenosis of the carotid artery over five years has just confirmed these findings. Patients were aged between 49 and 83, and the carotid artery had narrowed by more than 49% in almost half of them.
One group was given around 650mg of tocotrienols and alpha tocopherol, and the other a placebo. All the patients were examined initially after six months, and every year thereafter.
Ultrasound was used to measure how much the carotid artery had narrowed after four years of treatment. In the placebo group, the stenosis had deteriorated in 15 patients, remained stable in eight and had slightly improved in two. In the supplemented group, it had slightly deteriorated in three patients, had remained the same in 12 and had improved in 10.
Recent experimental research confirms a link between a reduction in oxidative damage and a longer lifespan. Palm tocotrienols were selected for a study on the ageing process conducted by the Life Sciences Research Centre in Japan. The research was carried out on nematodes (Caenorhabditis elegans), an organism model widely used in anti-ageing research. The study showed that tocotrienols, though not alpha tocopherol, increased the average lifespan of this organism.
1 Dietary antioxidants vitamins and death from coronary heart disease in postmenopausal women. Kushi LH et al., New Engl J Medicine, 1996 ; 334 : 1156-62.
2 Differential effects of alpha and gamma tocopherol on low-density lipoprotein oxidation, superoxide dismutase activity and nitric oxide synthase activity and protein expression in rats. Ksaldeen T et
al. J Am Coll Cardiol 1999; 34:1208-15.
3 Vitamin E, alpha and gamma tocopherol and prostate cancer. Moyad MA et al. Semin Urol Oncol 1999 May ; 17(é) :85-90.
4 Association between alpha tocopherol, gamma tocopherol, selenium and subsequent prostate
cancer. Helzlsouer KJ. J Natl Cancer Institute 2000; 92: 2018-23.
5 Long-term administration of tocotrienols and tumour-marker enzyme activities during
hepatocarcinogenesis in rats. Rahmat A. et al. Nutrition, 1993 May-June ;9 (3) :229-32.
6 Yu W. et al., " Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols.3 Nutr Canc 1999 ;33: 26-32.
7 Nesaretnam K. et al., Tocotrienols inhibit the growth of human breast cells irrespective of estrogens receptor status.3 Lipids 1998;33: 461-469.
8 He L ; et al., "isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. ",
9 Khor HT., et al., “Tocotrienols inhibit liver HMG-CoA reductase activity in the guinea pig.”
Nutr Res 1995; 15:537-544.
10 Qureshi AA et al., " response of hypercholesterolemic subjects to administration of tocotrienols, 1995, Lipids, 30 : 1171.
11 Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols. Qureshi AA et al. Am J Clin Nutr 1991 Ap ;53(4suppl) :1021S-1026S.
12 Antioxidant effect of tocotrienols in patients with hyperlipidemia and carotid stenosis.
Tomeo AC et al., Lipids 1995 Dec 30(12) :1179-83.
13 Tocotrienols : biological and health effects. In antioxidant status, diet, Watkins TR et al. Nutrition and Health. Papas AM editor, CRC Press, Boca Raton, 1998; 479-496