Are You Consuming the Right Vitamin E Supplement



MISCONCEPTIONS AND THE NEED TO RE-LOOK AT CLINICAL TRIALS FOR VITAMIN E

P.T. Gee

Palm Nutraceuticals Sdn. Bhd.

Introduction

Vitamin E was first discovered in 1922 as a substance essential for rat pregnancy. Humans and animals do not synthesize vitamin E and they have to acquire vitamin E from plants. Vitamin E refers to a group of compounds and very often the term is incorrectly and misleadingly used. It is therefore appropriate to have a better understanding of the nomenclature of vitamin E and the related components.

Nomenclature

In accordance with the IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) Recommendations 1981 on the nomenclature of tocopherols and related compounds, and the recent discovery of tocomonoenols, the following nomenclature is adopted:

Vitamin E should be used as the generic descriptor for all tocol, tocomonoenol and tocotrienol derivatives exhibiting qualitatively the biological activity of α-tocopherol.

Tocol is the trivial designation for 2-methyl-2-(4’,8’,12’-trimethyltridecyl)chroman-6-ol.

Tocopherol should be used as the generic descriptor for all mono-, di- and tri-methyltocols. Tocopherols have three chiral centers at carbons 2, 4’ and 8’. All natural tocopherols have the configuration of 2R,4’R,8’R according to the sequence-rule system. The semi-systematic name for α-tocopherol is (2R,4’R,8’R)-α-tocopherol and very often is simplified by the trival name RRR-α-tocopherol (previously known as d-α-tocopherol). Therefore a tocopherol can have eight stereoisomers: RRR, RRS, RSR, SRR, RSS, SRS, SSR and SSS. These isomers do not have the same vitamin E activity (100, 90, 57, 31, 73, 37, 21 and 60% vitamin E activities for the α-tocopherol isomers respectively). Synthetic α-tocopherols shall have all the eight stereoisomers in equal proportion if the synthesis is carried out without any control on stereochemistry. The mixture is called all-rac-α-tocopherol (previously known as dl-α-tocopherol).

There are four homologues for tocopherols (I). These are α-, β-, γ- and δ-tocopherol and are denoted by α-T, β-T, γ-T and δ-T respectively. They differ in the methyl substitution at the chroman ring. α-T has all the three hydrogens at carbons 5, 7 and 8 of the chroman ring respectively substituted by methyl groups (R1=R2=CH3); β-T has methyl substitution at carbons 5 and 8 (R1=CH3, R2=H); γ-T has methyl substitution at carbons 7 and 8 (R1=H, R2=CH3); and δ-T has only carbon 8 substituted with a methyl group (R1=R2=H).

Tocotrienols (II) have a similar chroman ring structure with tocopherols but differ in the side chain. Tocopherols have saturated phytyl side chain whereas tocotrienols have three double bonds in the farnesyl side chain. Just like tocopherols, tocotrienols also have the four homologues viz α-, β-, γ- and δ-tocotrienols and are denoted by α-T3, β-T3, γ-T3 and δ-T3 respectively.

Unlike tocopherol, tocotrienol has only one chiral center at carbon-2. All naturally occurring tocotrienols have R configuration at the chiral center and all-trans (E,E) configuration at the double bonds.

Two tocotrienol related compounds, desmethyl tocotrienol and didesmethyl tocotrienol (Qureshi et al 2000) were reported. The former is without any methyl substitution at carbons-5, 7 and 8 in whereas the latter is without any methyl substitution at carbons-2, 5, 7 and 8 in the structure (II).

α-Tocomonoenol, denoted by α-T1, is similar to α-tocopherol but with a double bond at the side chain. There are only two known naturally occurring isomers, one with a double bond at carbon-11’ (Matsumoto et al 1995) whereas the other with a double bond at carbon-12’ (Yamamoto et al 2001).

It is obvious that α-T is not synonymous with vitamin E but it is one of the many forms of vitamin E.

For simplicity, terms without indicating the configuration prefix shall be used. It is understood that all naturally occurring tocopherols and tocomonoenols have RRR configuration, all synthetic vitamin E have the all-rac configuration, all naturally occurring tocotrienols have R configuration and all double bonds at the tocotrienol side chain are of all-trans configuration.

Metabolism

Vitamin E is absorbed together with food in the intestine and enters the circulation via the lymphatic system. It is packed together with lipids into chylomicrons. The absorption is non-selective as reflected by studies on deuterium-labeled α-T and γ-T (Kayden and Traber 1993). During the subsequent lipoprotein lipase-mediated catabolism of chylomicrons, some of the chylomicron-bound vitamin E appears to be transported and transferred to peripheral tissues such as muscle, adipose and brain. The chylomicron remnants are transported and taken up by the liver. At the liver, α-tocopherol is preferentially reincorporated into nascent VLDL by α-tocopherol transfer protein (α-TTP) and re-circulated in the body. The relative affinities of various forms of natural vitamin E to α-TTP were reported (Hosomi et al 1997) as: α-T (100%) > β-T (38.1%) > α-T3 (12.4%) > γ-T (8.9%) > δ-T (1.6%).

All tocotrienols, γ-T and δ-T are degraded largely to the respective carboxyethyl-hydroxychroman (CEHC) and primarily excreted in urine (Chiku et al 1984, Swanson et al 1999, Lodge et al 2001). However, the situation is uniquely different for α-T. α-CEHC is only excreted in large amounts when a plasma level of α-T exceeds 30-40 µmol/L (Schuelke et al, 2000) or when the daily intake of α-T exceeds 150 mg (Schultz et al 1995). Unabsorbed vitamin E is eliminated through bile and faeces. The uniqueness of α-T is probably due to its higher binding affinity to α-TTP, which therefore retards its catabolism.

Although the mechanism is still unclear, oral α-T supplements decrease plasma γ-T and δ-T levels in humans (Handelman et al, 1985, Huang and Appel, 2003). After two months of α-T supplementation, serum α-T concentration increased but γ-T was reduced by 58% as compared to subjects who took the placebo! The number of subjects with detectable serum δ-T was observed to decrease from 46 to 13 (Huang and Appel, 2003). It was estimated that the period required to reach a new steady-state distribution of tocopherols would be 2 years after one year of α-T supplementation (Handelman et al 1994), suggesting that the effects of long term α-T supplementation on serum concentration of γ-T and δ-T are substantial and prolonged.

Dietary α-T also decreases α-T3 but not γ-T3 in rats (Ikeda et al 2003a, 2003b). It is interesting to note that tocotrienols are preferentially distributed to the epididymal fat, perirenal adipose tissue and the skin. The concentrations of α-T3 in these tissues were observed to be significantly higher than α-T when the rats were fed with 50mg of α-T3 or α-T respectively. This perhaps provided evidence that the tocotrienols are distributed via the lymphatic system to these tissues or there may be unknown α-TTP-independent pathway for distribution, in view that the observation cannot be explained by the α-TPP affinity mechanism. Also not explained by α-TPP affinity mechanism was that the distribution of γ-T3 in all the tissues studied was not affected by supplementation together with α-T, despite that γ-T3 is expected to have much lower affinity towards binding with α-TTP. Although data were not available, it is expected that δ-T3 level may not decrease if supplemented together with α-T.

The fact that α-T3 and γ-T3 were hardly detected in the plasma but present in significant concentration at the epididymal fat, perirenal adipose tissue and the skin, bioavailability as measured by the concentration of vitamin E in the plasma is no longer accurate.

It appears that α-T not only competes preferentially with other forms of vitamin E for α-TTP but also decreases the bioavailability of other forms of tocopherols and α-T3. Therefore, it is not surprising that α-T is the predominant form of vitamin E found in the blood plasma, irrespective of the composition of dietary vitamin E intake. In fact, it is rather difficult to detect tocotrienols and δ-T in the blood plasma, both due to their low concentrations and also short circulation duration. Tocotrienols are reported to reach their peaks in blood plasma about 4-6 hours after supplementation and completely disappeared after 24 hours (Yap et al 2001, Fairus et al 2003). The half-life of tocotrienols was estimated to be 4.5 – 8.7-fold shorter than that of α-T (Yap et al 2001). Under fasting conditions, tocotrienols have poorer bioavailability and detection in blood plasma is even more difficult. Low levels of tocotrienols are detectable in the blood plasma, LDL and HDL lipoproteins in postprandial blood samples. In the blood plasma, the relative concentration of α-T3 was significantly higher (about double) than γ-T3, although α-T3 was only marginally higher than γ-T3 in the supplementation. As expected, the concentration of δ-T3 was even much lower than that of γ-T3 (Fairus et al 2003).

Besides decreasing the bioavailability of certain forms of vitamin E, dietary α-T was also reported to attenuate the impact of γ-T3 on hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity in chicken, thereby reducing the cholesterol lowering effect of tocotrienols (Qureshi et al 1996).

Clinical Trials

Despite all the eight forms of vitamin E being discovered by 1956, research and clinical trials were mainly conducted on α-T only. Perhaps this is due to the misconception that α-T is the only important form of vitamin E and it was perceived that while humans can absorb all forms of vitamin E, the body maintains only RRR-α-T (International Institute of Medicine, 2000). α-T is very often misinterpreted as “the” vitamin E! Other forms of natural tocopherols are commercially methylated into α-T.

It was speculated that many degenerative diseases are caused by free radicals and/or reactive oxygen species. As a powerful lipid-soluble antioxidant, α-T has the potential to terminate free radical reactions and deactivate the actions of reactive oxygen species, thereby has yielded an ameliorative effect on those degenerative diseases. Epidemiological studies and experiments in vitro had yielded encouraging results for the possible role of α-T as an antioxidant in prevention/improvement of degenerative diseases.

Human intervention clinical trials were conducted on both natural and synthetic α-T, either alone or in combination with other compounds, but ignoring all the other vitamin E forms, on their hopeful improvement over a wide-spread of degenerative diseases. These include:

• Alzheimer’s Disease cooperative Study (ADCS)

• Age-Related Eye Disease Study (AREDS)

• Alpha-tocopherol, Beta-Carotene Cancer prevention Study Group (ATBC)

• Cambridge Heart Antioxidant Study (CHAOS)

• Deprenyl and Tocopherol Anti-oxidative Therapy of Parkinsonism (DATATOP)

• Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarcto Miocardio Prevenzione (GISSI-Prevenzione)

• Heart Outcomes Prevention Evaluation (HOPE)

• Linqu Study

• Linxian Study A

• Linxian Study B

• The Geriatrie/MINéraux, VITamines, et AntiOXydants Network (MIN.VIT.AOX)

• Medical Research Council/British Heart Foundation Heart Protection Study (MRC/BHF HPS)

• Primary Prevention Project (PPP)

• Polyp Prevention Study (PPS)

• Roche European American Cataract Trial (REACT)

• Secondary Prevention with Antioxidants of Cardiovascular disease in Endstage renal disease (SPACE)

• Supplementation en VItamines et MINéraux AntioXydants (SU.VI.MAX)

• Vitamin E, Cataracts, and Age-Related Maculopathy (VECAT)

• Women’s Angiographic Vitamin and Estrogen (WAVE)

• Antioxidant Supplementation in Atherosclerosis Prevention (ASAP)

• VITAmins and Lifestyle study (VITAL)

Many trials did not reveal any significant effect of α-T or conclusions were unimpressive. The term vitamin E used in the above studies is a misnomer because it actually referred to α-T in all the above-mentioned clinical trials.

John Hopkins Report

On 10 November 2004, researchers at John Hopkins reported a major drawback of supplementation with high dosages (more than 400 IU/day) of α-T (Miller et al 2005). Under circumstances that most of the subjects were over 60 years old and a majority had pre-existing medical conditions, nine out of eleven trials were found to have higher mortality in the α-T supplementation group than those who took placebo! The findings were not based on new research but rather were arrived at through statistical analysis of previous 19 major trials on α-T that were carried out on 135,967 patients mainly in North America, Europe and China between 1993 to 2004, by a technique called meta-analysis. The balance eight trials involved low dosages of α-T, where there was evidence that α-T may be beneficial. Again, it should be noted that the term vitamin E used in the report should read as α-T.

The report received many criticisms as reflected by the electronic letters published at the same website. The impact at marketplace was obvious. There was a sharp fall in the demand for α-T. Consumers are facing a dilemma whether to continue or stop α-T supplementation.

Although meta-analysis may be controversial, it is appropriate and timely to analyze the probable causes of the increased mortality or the ineffectiveness of α-T. Although the current information available are limited and scattered, analyzing the increased mortality may shed light on vitamin E supplementation. It is highly unlikely that the increased mortality was due to α-T toxicity.

The Importance of the other Tocopherols

Undoubtedly, α-T has the highest vitamin E activity; while it has the highest bioavailability, it does not necessarily have the highest biological activity. The findings of the numerous clinical trials though involving hundred thousands of subjects, did not produce sufficient information on the significance of vitamin E, simply because α-T is not “the” vitamin E!

γ-T appears to be a more effective trap for lipophilic electrophiles (such as reactive nitrogen oxide species) than α-T. Both γ-T and γ-CEHC, but not α-T, inhibit cyclooxygenase activity and thus possess anti-inflammatory properties (Jiang et al 2000). Some human and animal studies indicate that plasma concentrations of γ-T are inversely associated with the incidence of cardiovascular disease and prostate cancer. A Swedish study reported that patients with coronary heart disease had lower levels of γ-T and a higher α-T : γ-T ratio than healthy age-matched subjects (Ohrvall et al 1996). It was demonstrated that γ-T inhibited prostate cancer cell growth at a concentration 1,000 times lower than synthetic α-T (Moyad et al 1999). While α-T, β-T and γ-T did not show any anti-angiogenic property, δ-tocopherol showed weak anti-angiogenic property at concentration more than 100μM (Inokucki et al 2003). These are just examples of some of the many findings indicating that γ-T is more potent in prevention of degenerative diseases (for reviews see Jiang et al 2001, Brigelius-Flohè et al 2002). As for δ-T, very little information was available, presumably due to its lower abundance. It appears from limited data that δ-T behaved similar to, but was more potent than γ-T.

The observed increased mortality in the John Hopkins report probably was a consequence of depressed γ-T and δ-T due to consuming high dosages of α-T as compared to those who consumed placebo where the γ-T and the δ-T bioavailability were not diminished. Unfortunately, in all the clinical trials, only α-T was considered. Not only γ-T and δ-T were not measured in all the trials, even α-T level was not measured in many of the clinical trials. Therefore, there is no way to validate whether the higher observed mortality rate for subjects consuming higher dosages of α-T is due to a depressed γ-T and δ-T. In order not to miss valuable information, future clinical trials should include the determination of all vitamin E forms, at least for both baseline level and level immediately after the trials.

Multiple Therapeutic Potential of Tocotrienols

Although the only structural difference between tocopherol and tocotrienol is that the former has a saturated phytyl side chain whereas the latter has a farnesyl side chain (three double bonds in the three isoprene units), tocopherol and tocotrienol are distributed differently (Ikeda et al 2003b) and are physiologically different. Tocotrienols were found to have multiple therapeutic potentials, which are not shared with α-T.

Anti-cancer and Cancer Suppression

Tocotrienols are very unique and have extremely good potentials as chemo-preventive agents in the field of cancer prevention. Tocotrienols can now address the fight against cancer via at least four mechanisms:

• Improving immunological function

• Anti-angiogenesis - tocotrienols prevent the formation of new blood vessels, thereby stopping the growth and proliferation of cancer cells

• Inducing apoptosis - tocotrienols promote programmed cancer cell death

• Anti-tumour-promoting action by T3 components against tumour-promoting agents (Goh et al, 1994)

Tocotrienol supplementation has been shown to contribute to immunoregulation, antibody production, and resistance to implanted tumors. They are ten times more effective than α-T (Ashfag et al 2000). Eisai Co. Ltd. had been granted a patent using tocotrienols as improving agent of immunological function (Kouji et al 1999).

Recently, a Japanese study (Inokuchi et al 2003) had reported that tocotrienols have anti-angiogenic property whereas α-T does not. The order of effectiveness in anti-angiogenesis was reported as δ-T3>β-T3>γ-T3>α-T3. δ-T3 was about twice as effective as β-T3, thrice as effective as γ-T3 and six times as effective as α-T3.

There are numerous reports on the role of tocotrienols in inducing apoptosis of cancer cells, notably human breast cancer cells, irrespective of the estrogen receptor status of the cancer cell lines (Guthrie et al 1997, Nesaretnam et al 1995, 1998, 2000, 2004, Sylvester and Shah 2003, Shah and Sylvester 2004, Takahashi and Loo 2004, Yu et al 1999). Generally, the order of effectiveness for inducing apoptosis is δ-T3>γ-T3>α-T3. α-T is ineffective for inducing apoptosis. The following are the advantages of tocotrienols as compared to an anti-estrogen drug, Tamoxifen or Anastrozole, for breast cancer treatment:

• Tocotrienols are non-hormonal natural products with no known adverse side effects and over-dosage. Tamoxifen has many side effects.

• Unlike Tamoxifen or Anastrozole, tocotrienols are effective irrespective of the estrogen-receptor status of the breast cancer cell lines

• Unlike Tamoxifen which can be consumed for a maximum of five years, tocotrienols have no known time limit for continued consumption.

• Tocotrienol-induced apoptosis is independent of death receptor apoptotic signaling. Drugs such as Tamoxifen or Anastrozole are ineffective due to no response from the death receptors.

Lately, tocotrienols, tocopherols and their metabolites were evaluated for the anti-proliferative effect in prostate cancer cells (Conte et al., 2004). The order of effectiveness was reported as γ-T3>γ-T>α-T3>α-T. Other vitamin E members were not evaluated. Reports are available for the potential roles of tocotrienols in other types of cancer such as skin, liver and colorectal cancers but more research and development works are needed to explore further the application of tocotrienols in these areas.

Cardiovascular Diseases Prevention

Tocotrienols were reported to have many functions that can prevent or bring about an improvement in cardiovascular diseases. These include their roles in:

• Anti-inflammation - Recent research has shown that inflammation plays a key role in cardiovascular disease and other manifestations of atherosclerosis

• Natriuresis – maintaining of extracellular fluid volume by excreting sodium

• Prevention of hypertension

• Lowering cholesterol levels

• Anti-platelet aggregation and anti-thrombosis

• Reversing atherosclerosis

It is well-accepted that hypertension and high cholesterol levels in blood plasma are indicators for cardiovascular diseases. Elevated blood pressure and high cholesterol levels, especially the LDL-cholesterol, can lead to arteriosclerosis. The narrowed atherosclerotic lumen caused by the raised plaque can be easily blocked by a thrombus, causing heart attack or stroke depending whether the blockage is at coronary or carotid arteries.

It was reported that γ-CEHC, the main metabolite of γ-T3 and γ-T has anti-inflammatory (Jiang et al 2000) and natriuretic hormone function (Murray et al 1997). α-CEHC does not have these functions whereas δ-CEHC was not tested. Recently, it was reported that γ-T3 itself is a natriuretic hormone precursor (Saito et al 2003). γ-T3 was also reported to prevent development of increased blood pressure in rats (Newaz and Nawal 1999).

Many researchers have reported that tocotrienols have cholesterol lowering effect by post-transcriptional suppression of HMG-CoA reductase (Pearce et al 1992, Parker et al 1993, Qureshi et al 1995, Chao et al 2002). However, other researchers did not observe the cholesterol lowering effect in their studies.

Tocotrienols are reported to have anti-platelet aggregation properties (Mahadevappa et al 1991). It is the blockage at the narrowed lumen of an artery by a thrombus that is causing sudden immobility and mortality of patients, often without prior symptom. Tocotrienols reduced the apolipoprotein B, thromboxane B2 and platelet factor levels, just like other anti-platelet aggregation and anti-thrombotic drugs such as aspirin, but without any known side effects.

The most striking potential of tocotrienols in the treatment of cardiovascular diseases probably lies in the ability in partially reversing atherosclerosis. In clinical trials after three years, 32% of the tocotrienol group had regression of their carotid stenosis, with 4% showing marked regression. This compares to 48% of the control group receiving the placebo having progression of their stenosis, with 16% having marked progression. In the three-year period, only 8% of the tocotrienol group had progression of their stenosis (Kooyenga et al 1997a, 1997b).

In summary, it is remarkable that tocotrienols have such a wide range of properties potentially useful for the chemo-prevention of cardiovascular diseases.

Neuro-Protection

α-T3 was found to have neuro-protection against glutamate-induced neuronal cell death. It is remarkable that α-T3 is effective, even at nanomolar levels! (Sen et al 2000, Khanna et al 2003). Again, α-T was found to be ineffective. Unlike the situations in anti-cancer and cardiovascular diseases prevention, α-T3 was found to be the most potent vitamin E. This was further confirmed by a Japanese study in neuroprotection on cultured striatal neurons (Osakada et al 2004). These observations indicate the tremendous potential of α-T3 in avoiding mortality as well as aftermath immobility of stroke in cases like vascular dementia.

The Need to Re-look at Clinical Trial Design

It is timely to re-look at the clinical design in order to obtain more meaningful results. It is obvious that α-T is not the most suitable vitamin E for the study of biological activities in many of the clinical trials.

Perhaps future trials should be more specific on which vitamin E and which stereoisomer to be used. Findings to-date indicate that α-T is lacking therapeutic potential for chemoprevention of various diseases. It is appropriate to focus on natural tocotrienols as these lesser known forms of vitamin E have demonstrated remarkable potential in chemoprevention. Current understanding indicates that the biological activities of tocotrienols are specific. α-T3 is the most potent vitamin E for neuro-protection whereas δ-T3 and γ-T3 are more potent in the prevention of certain cancers and cardiovascular diseases.

Unlike α-T which can be monitored by its concentration in the blood plasma, the concentrations of all other forms of vitamin E in the plasma change rapidly with time after supplementation. This causes limitations to the monitoring of levels of other vitamin E components in blood plasma. Alternatively, the levels of other forms of vitamin E at a specific targeted tissue, such as adipose tissue, can be monitored and at that location, the influence of duration after supplementation is expected to be less obvious.

Blood plasma vitamin E is not an accurate indicator for bioavailability, as vitamin E may be delivered to the various tissues by the lymphatic system before the remnant chylomicrons are transported by the blood circulation system.

Bioavailability via oral supplementation can be affected by the presence of food, lipids and other components such as sterols. It was also well-accepted that vitamin E needs fat for its absorption (Jeanes et al, 2004) and high dosages of esterified and free plant sterols reduced the bioavailability of α-T by about 20% (Richelle et al 2004). It is probable that α-T is a confounding material for biological activity studies (not related to fertility) and together with other possible confounding materials, should be analyzed with due considerations.

Different responses from individuals taking oral supplementation also need to be considered (Roxborough et al 2000). Baseline monitoring of α-T and/or other vitamin E of interest should be first carried out.

Additional and more accurate correlation data may be obtained if the different stages of diseases can be separated for statistical analysis e.g. atherosclerosis can be defined into eight stages (I to VIII) based on histologic classification of lesions.

Genetically defective subjects should be studied separately. It is reported that about 20% of the subjects do not respond to α-T supplementation as indicated by its level in the plasma. This factor was not considered in all previous trials and its implications are therefore unknown.

Dietary Tocotrienols and Supplementation

Only two vegetable oils viz. palm oil and rice bran oil are commercially available cooking oils with significant amount (about 0.1%) of tocotrienols. Almost half of the vitamin E in rice bran oil is tocotrienols whereas about 80% of vitamin E in palm oil is tocotrienols. In addition, more than 10% of vitamin E in palm oil is δ-T3 whereas the amount of δ-T3 in rice bran oil is insignificant.

Palm oil is undoubtedly the most reliable source for tocotrienols. There is a good reason to believe that the John Hopkins meta-analysis result would not be the same if the subjects were palm oil or rice bran oil consumers (α-T does not decrease the bioavailability of γ-T3 and δ-T3).

There is no evidence for claims that supplementation with a full spectrum of vitamin E is better. It is evident that dietary supplementation may not be necessary for α-T as it is abundant in the diet and efficiently accumulated through the actions of α-TTP. In fact, supplementation of high dosages of α-T is suspected to increase the risk of all-cause mortality in some clinical trials.

Based on the current understanding on vitamin E, the above-mentioned evidences indicate that a combination of α-T3, γ-T3 and δ-T3 is essential and may be necessary for maintenance of good health.

What choices do we have?

Although α-T has the highest vitamin E activity but until there is further evidence to provide alternative explanations to the meta-analysis, one should avoid consuming in dosages greater than 150 IU per day.

As a safety measure, it would be wise for the α-T consumers to substitute their supplementation with other members of vitamin E, preferably with the more efficient tocotrienols for the above-stated reasons. In this way, the dilemma of the vitamin E consumers can be overcome and yet avoiding the possible increased risk of higher mortality due to consuming high dosages of α-T.

The presence of α-TPP but not other-TPP is probably a result of human evolution where reproduction was a critical function. This cannot be changed. What needs to be changed now is that modern pattern of food consumption and lifestyles have demanded the use of vitamin E beyond a limited function based on reproduction, but more specifically in the need for prevention and combating chronic diseases.

Conclusion

There is a need to distinguish between just α-T and vitamin E as a whole. The former is merely a member of the latter. α-T should not be confused with the rest of vitamin E members where they are not reported to suppress the bioavailability of other nutrients.

Meta-analysis of data obtained in 19 clinical trials provided the first evidence that consumption of high dosages of α-T may increase the risk of increased mortality. The John Hopkins report however, unfortunately reported that supplementation with high dosages of vitamin E (more specifically as α-T) may increase the mortality as the term vitamin E may be wrongly perceived as it is a misnomer and actually referred to α-T. It has to re-emphasize that α-T is not synonymous with the vitamin E family of natural products.

Current understanding indicates that mega-doses of vitamin E are not helpful as α-TTP has limited capacity and the duration of other forms of vitamin E in the circulation is rather short, less than 24 hours after consumption.

It is postulated that the increased mortality was due to the action of high dosages of α-T in decreasing the bioavailability of γ-T and δ-T in the subjects as compared to the normal levels of γ-T and δ-T for those consuming the placebo. This suggests that supplementation with α-T may be undesirable because of a higher mortality risk exposure. α-T supplementation may also be unnecessary for healthy humans as dietary intake is adequate and good bioavailability is to be expected through the efficient actions of α-TTP.

It is evident that current research focusing on α-T is heading in the wrong direction. Although α-T has the highest potency in vitamin E activity, limited data has revealed that it has little therapeutic value as compared to other forms of vitamin E. However, the more potent forms of vitamin E, especially the tocotrienols, are relatively scarce in the western diet and have poor bioavailability. Supplementation may be suggested.

Well-designed research should be carried out, especially on the promising observations on multiple therapeutic potential of tocotrienols for chemo-prevention of degenerative diseases. The benefits of tocotrienols not only exceed those of the saturated vitamin E members and antioxidant action but may extend beyond these as shown in cases such as neuro-protection and protection against cancer (anti-angiogenesis, immunomodulation, etc).

Acknowledgement

The author thanks Palm Nutraceuticals Sdn. Bhd. for permission to publish this article.

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17. Jeanes YM, Hall WL, Ellard S, Lee E and Lodge JK (2004). The absorption of vitamin E is influenced by the amount of fat in a meal and the food matrix. British J Nutr 92: 575-579.

18. Jiang Q, Elson-Schwab I, Courtemanche C and Ames BN (2000). γ-Tocopherol and its major metabolite, in contrast to α-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Proc Natl Acad Sci USA 97: 11494-11499.

19. Jiang Q, Christen S, Shigenaga MK and Ames BN (2000). γ-Tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr 74: 714-722.

20. Lodge JK, Ridlington J, Leonard S, Vaule H and Traber MG (2001). α- and γ-Tocotrienols are metabolized to carboxyethyl-hydroxychroman derivatives and excreted in human urine. Lipids 36: 43-48.

21. Kayden HJ and Traber MG (1993). Absorption, lipoprotein transport, and regulation of plasma concentrations of vitamin E in humans. J Lipid Res 34: 343-358.

22. Khanna S, Roy S, Ryu H, Bahadduri P, Swaan PW, Ratan RR, and Sen CK (2003).

Molecular basis of vitamin E action: Tocotrienol modulates 12-lipoxygenase, a key mediator of glutamate-induced neurodegeneration. J Biol Chem 278: 43508-43515.

23. Kooyenga DK, Geller M, Watkins TR, Gapor A, Diakoumakis E and Bierenbaum, ML (1997a). Palm oil antioxidant effects in patients with hyperlipidaemia and carotid stenosis – 2 year experience. Asia Pacific J Clin Nutr 6: 72-75.

24. Kooyenga DK, Geller M, Watkins TR and Bierenbaum ML (1997b). Antioxidant-induced regression of carotid stenosis over three-years. Proc. of the 16th Int. Congress of Nutr, Montreal.

25. Kouji Y, Shigeiro Y and Toshitaka A (1999), Improving Agent of Immunological Function, Japanese Patent JP11049767.

26. Mahadevappa VG & Holub BJ (1991). Effect of tocotrienol derivatives on collegen- and ADP-induced human platelet aggregation. In Proc of 1989 Int Palm Oil Congress – Nutr and Health Aspects of Palm Oil, Pp. 36-38.

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28. Miller III ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ and Guallar E (2005). Meta-analysis: High-dosage vitamin E supplementation may iIncrease all-cause mortality. Ann Int Med, 142: 37-46 (Originally published online on 10 November 2004).

29. Miyazawa T, Inokuchi H, Hirokane H, Tsuzuki T, Nakagawa K, and Igarashi M (2004). Anti-angiogenic potential of tocotrienol in vitro. Biochem (Moscow) 69: 67-69.

30. Moyad MA, Brumfield SK and Pienta KJ (1999). Vitamin E, alpha- and gamma-tocopherol, and prostate cancer. Semin Urol Oncol 17: 85-90.

31. Murray ED Jr, Wechter WJ, Kantoci D, Wang WH, Pham T, Quiggle DD, Gibson KM, Leipold D and Anner BM (1997). Endogenous natriuretic factors 7: Biospecificity of a natriuretic γ-tocopherol metabolite LLU-α. J Pharmacol Exp Ther 282: 657-662.

32. Nesaretnam K, Guthrie N, Chambers AF and Caroll KK (1995). Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Lipids 30: 1139-1143.

33. Nesaretnam K, Stephen R and Darbre PD (1998). Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Ibid 33: 461-469.

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36. Newaz MA and Nawal NNA (1999). Effect of γ-tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR). Clin Exp Hypertens 21: 1297-1313.

37. Ohrvall M, Sundlof G and Vessby B (1996). Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease patients. J Intern Med 239: 111-117.

38. Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S and Akaike A (2004). α-Tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons. Neuropharmacology 47: 904-915.

39. Parker RA, Pearce BC, Clark RW, Gordon DA and Wright JJ (1993). Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. J Biol Chem 268: 11230-11238.

40. Pearce BC, Parker RA, Deason ME, Qureshi AA and Wright JJ (1992). Hypercholesterolemic activity of synthetic and natural tocotrienols. J Med Chem 35: 526-541 and 3595-3606.

41. Qureshi AA, Bradlow BA, Brace L, Manganello J, Peterson DM, Pearce BC, Wright JJK, Gapor A and Elson CE (1995). Response of hypercholesterolemic subjects to administration of tocotrienols. Lipids 30: 1171-1177.

42. Qureshi AA, Pearce BC, Nor RM, Gapor A, Peterson DM and Elson CE (1996). Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chicken. J Nutr 126: 389-394.

43. Qureshi AA, Mo H, Packer L and Peterson DM (2000). Isolation and identification of novel tocotrienols from rice bran with hypocholesterolemic, antioxidant, and antitumor properties. J Agric Food Chem 48: 3130-3140.

44. Richelle M, Enslen M, Hager C, Groux M, Tavazzi I, Godin JP, Berger A, Métairon S, Quaile S, Piguet-Welsch C, Sagalowicz L, Green H and Fay LB (2004). Both free and esterfied plant sterols reduce cholesterol absorption and the bioavailability of β-carotene and α-tocopherol in normocholesterolemic humans. Am Soc Clin Nutr 80: 171-177.

45. Roxborough HE, Burton GW and Kelly FJ (2000). Inter- and intra- variation in plasma and red blood cell vitamin E after supplementation. Free Radic Res 33: 437-446.

46. Saito E, Kiyose C, Yoshimura H, Ueda T, Kondo K and Igarashi O (2003). (-Tocotrienol, a vitamin E homolog, is a natriuretic hormone precursor. J Lipid Res 44: 1530-1535.

47. Schultz M, Leist M, Petrzika M and Brigelius-Flohé R (1995). Novel urinary metabolite of alpha-tocopherol, 2,5,7,8-tetramethyl-2(2’-carboxyethyl)-6-hydroxychroman, as indicator of an adequate vitamin E supply? Am J Clin Nutr 62 (Suppl): 1527S-1534S.

48. Sen CK, Khanna S, Roy S and Parker L (2000). Molecular basis of vitamin E action. Tocotrienol potentially inhibits glutamate-induced pp60c-Src kinase activation and death of HT4 neuronal cells. J Biol Chem 17: 13049-13055.

49. Shah S and Sylvester PW (2004). Tocotrienol-induced caspase-8 activation is unrelated to death receptor apoptotic signaling in neoplastic mammary epithelial cells. Exp Biol Med 229:745-755.

50. Swanson JE, Ben RB, Burton GW and Parker RS (1999). Urinary excretion of 2,7,8-trimethyl-2-(β-carboxyethyl)-6-hydroxychroman is a major route of elimination of γ-tocopherol in humans. J Lipid Res 40: 665-671.

51. Sylvester PW and Shah S (2003). Intracellular mechanisms mediating tocotrienol-induced apoptosis in neoplastic mammary epithelial cells. In Proc Food Technol and Nutr Conf PIPOC 2003 24-28 August 2003 Putrajaya Pp 247-260.

52. Takahashi K, Loo G (2004). Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells. Biochem Pharmacol 67: 315-324.

53. Yamamoto Y, Maita N, Fujisawa A, Takashima J, Ishii Y, Dunlap WC (2001). A new vitamin E (alpha-tocomonoenol) from eggs of the Pacific salmon Oncorhynchus keta. J Nat Prod 1999 62: 1685-1687.

54. Yap SP, Yuen KH and Wong JW (2001). Pharmacokinetics and bioavailability of α-, γ- and δ-tocotrienols under different food status. J Pharm Pharmacol 53: 67-71.

55. Yu W, Simmons-Menchaca M, Gapor A, Sanders BG and Kline K (1999). Induction of apoptosis in human breast cancer cells by tocopherols and tocotrienols. Nutr Cancer 33: 26-32.

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