Tocotrienols and the Modification
of Coronary Heart Disease Risk Factors

Randall E. Wilkinson, M.D.

Tocotrienols are a form of vitamin E with characteristics which differ from the tocopherol form. These characteristics include activity which positively affect defined factors of risk for coronary heart disease (CHD). This paper reviews those CHD risks, known results from modification of those risk factors and the biologic activity of the tocotrienols.

Approximately one-half of all Americans will die of coronary heart disease (CHD) or stroke, both secondary to the deterioration of circulation due to atherosclerosis. While not everything regarding its etiology is known, some risk factors are now clear. Among the identified risk factors:

Cholesterol

An elevated cholesterol level is a clearly defined risk factor for the development of atherosclerosis. More to the point, elevated levels of LDL cholesterol create the elevated risk.

Oxidation

Most importantly, it is the oxidized LDL cholesterol which is clearly implicated as the primary risk from cholesterol.

Platelet Agregation

Abnormal coagulation of platelets is an identified risk factor for the ultimate occlusive event: thrombus formation. Thromboxane A is a potent inducer of platelet aggregation and is a vasoconstrictor. As such, TXA and its more stable metabolite, TXB are recognized risk factors.

Risk Factor Modification

Because of the importance if these risk factors, a great deal of research has gone into the benefits to be gained from modifying them. In part, research has shown:

Cholesterol Reduction

Dietary Changes

Changes in diet have been demonstrated to effectively reduce both cholesterol levels and the incidence of atherosclerosis.

Limitations: The degree of cholesterol reduction is limited and is largely proportionate to dietary change. Due to the difficulty involved in bringing about changes in habit, the dietary effect alone, for most subjects, is inadequate.

Statin Drugs

The "statin" class of drugs have been demonstrated to effectively reduce cholesterol levels (both total and LDL). Typically reported reductions of LDL cholesterol, for example, by these medications are in the 20% to 30% range.   These drugs act by competitive inhibition of HMG CoA reductase, the rate-limiting enzyme responsible for cholesterol synthesis.

Limitations: The statin drugs are associated with significant risk of serious side effects, including liver toxicity, myopathy and other less frequent side effects. Additionally, the cost of these medications is significant; a typical cost for this class of medication is in the range of $2.00 per day.

Conclusion

Lowering LDL and total cholesterol levels is associated with a decreased risk of death from atherosclerotic heart disease.

Anti-Oxidant Protection

Alpha tocopherol

The 1996 CHAOS study demonstrated a reduction by 77% in non-fatal myocardial infarctions among 1,035 patients taking 400 and 800 IUs of alpha tocopherol daily for a median of 510 days.

Alpha tocopherol has no significant effect on total or LDL cholesterol levels. It does, however, provide effective protection against oxidation for LDL cholesterol in the body. Researchers generally attribute the increased protection against heart disease associated with alpha tocopherol to its antioxidant effects.

Limitations: While demonstrating excellent antioxidant protection, alpha tocopherol has not been demonstrated to positively influence other risk factors for atherosclerotic heart disease.

Conclusion

Increasing antioxidant Protection is an effective means of decreasing risk of atherosclerotic heart disease.

Tocotrienols

Vitamin E is a class of molecule, of which there are eight different forms. The four tocopherols (alpha-, beta-, gamma- and delta-tocopherol) share a saturated phytyl side chain. The four analogous tocotrienols (alpha-, beta-, gamma- and delta-tocotrienol), in contrast, have a triple-unsaturated side chain.

The form of vitamin E most commonly used as a dietary supplement is alpha-tocopherol. It is the dominant form of vitamin E in corn (86%) and wheat germ (72%). By contrast, rice bran, for example, is composed of 66% of tocols in the tocotrienol form.

Biological Activity

The unsaturated bonds, along with the resulting changes in structure of the molecule, give the tocotrienol forms a different biologic action than their tocopherol cousins. There is movement between the tocotrienol and tocopherol forms. Saturation of the tocotrienols' phytyl side chains' three bonds results in a shift from the tocotrienol form to its tocopherol analog.

Effect on Cholesterol

In contrast with the tocopherols, which have no effect on cholesterol, tocotrienols have significant cholesterol-lowering effects. These effects have been demonstrated in chickens, guinea pigs, rats, pigs, Japanese quail and humans.

Approximately 75% of hypercholesterolemic individuals respond to the cholesterol-lowering effects of the tocotrienols exerted on the synthesis process.

Hypercholesterotemia in unresponsive individuals, by contrast, is likely due to errors in cholesterol transport or degradation.

TRF is a novel tocotrienol-rich fraction obtained by molecular distillation from specially processed rice bran oil which has been reported on in the literature. Qureshi's report in Nutritional Biochemistry describes the results of a double blind, placebo controlled two-phase human trial over 12 weeks. Phase one was exclusively dietary; phase two added in supplementation with TRF and placebo. The results reported include:

a.) Total and LDL cholesterol reductions of 17% and 24%, respectively, with the NCEP Step-1 Diet plus treatment. Diet alone yielded only 5% and 8% reductions, respectively.

b.) Adjusting out the 25% non-responders yields total and LDL cholesterol reductions of approximately 23% and 32%, respectively, for diet plus treatment and 16% and 21 %, respectively, for TRF effect alone.

c.) TRF mediated a decrease of 15% in Apo B levels, resulting in an increase in the Apo A-I/B ratio from 1.27 to 1.46. The 0.15 increase in this important predictor of cardiovascular disease was accounted for by the TRF.

d.) TRF mediated a decrease of 17% in Lp(a) levels.

e.) The LDL:HDL ratio was reduced by 29% (from 3.82 to 2.72) among individuals receiving TRF but only 11% among patients receiving placebo; both groups were on the NCEP Step-1 diet. These results compare favorably with reported LDL:HDL ratio reductions from statin drug usage of 31 % and 34%.

f.) No changes occurred with regard to the HDL-cholesterol or to apolipoprotein A-I.

Effect on Disease Progression

One study published in 1995 reported on the use of a gamma-tocotrienol and alpha-tocopherol enriched fraction in 50 patients with cerebrovascular disease over a period of 18 months. Carotid arteries were monitored by use of bilateral duplex ultrasonography. The authors reported apparent carotid atherosclerotic regression in seven, and progression in two, of the 25 tocotrienol patients -- while none of the control group showed regression and ten of 25 showed progression. Published duplication of these findings has not yet occurred.

Mechanism of Cholesterol Reduction

The mechanism of cholesterol reduction is a novel post-transcriptional inhibition of HMG-CoA reductase, the rate-limiting enzyme responsible for cholesterol synthesis. This is accomplished by increasing the rate of natural degradation of HMG-CoA reductase.

The tocotrienols' mode of action contrasts with the competitive inhibition of HMG-CoA reductase receptors exhibited by the statin class of drugs and the "yeast extract" over-the-counter product (Cholestin). This competitive inhibition triggers an adaptive response that yields a 200-fold increase in reductase levels within a few hours. By contrast, tocotrienols cause a 50% decrease in reductase protein in less than two hours.

Proposed Mechanism of Tocotrienols' Cholesterol-Lowering Action

HMG-CoA reductase is the rate-limiting enzyme involved in production of cholesterol.   It exerts its action at the corresponding receptor site.

Statin drugs and yeast extracts decrease cholesterol production by competitive blocking of the receptor sites.  These medications are also associated with significant adverse reactions, including liver toxicity, myopathy, etc.

Clearesterol's mechanism of action is an increased rate of the natural degradation of HMG-CoA reductase.  The resulting decrease in quantity results in a decrease of cholesterol synthesis. Adverse reactions are absent at recommended dosage.

Effect on Anti-Oxidant Protection

Tocotrienois exert significantly greater antioxidant protection than their analogous tocopherols. This effect is demonstrated in the lipid membrane -- where it is most needed by living organisms -- though not in a simple homogenous system, where the activities are found to be equal. These findings led researchers to conclude that, "the different effects of alpha-tocotrienol on the molecular properties of the membrane may explain its greater anti-oxidant potency."

Serbinova, at the University of California at Berkeley, in 1991 reported that "d-alpha-tocotrienol possesses 40-60 times higher antioxidant activity against... lipid peroxidation in rat liver microsomal membranes and 6.5 times better protection of cytochrome P-450 against oxidative damage than d-alpha-tocopherol."

Another significant finding for CHD came in a study reporting significantly greater recovery rates in Langendorff perfused rat hearts subjected to 40 minutes of global ischemia. Further, it also completely suppressed LDH leakage, inhibited lipid peroxidation product formation and prevented a decrease in ATP and creatine phosphate levels -- thus indicating that tocotrienol has better protective antioxidant effects on ischemia-reperfusion injury than tocopherol.

Qureshi reported that the supplementation with the TRF blend in humans "resulted in remarkable increases in the levels of LDL-bound antioxidants, especially tocotrienols, which have substantially greater antioxidant activity than [alpha-tocopherol]."

Effect on Thromboxane

Measurement of thromboxane A is difficult because of an extremely short half-life; thromboxane B, its metabolite, is a generally accepted indicator of thromboxane A production. Tocotrienols have been reported to cause a decrease of thrornboxane B by 31%, as well as a decrease in platelet aggregation of 15% to 30%, leading researchers to conclude that "tocotrienols may serve as anti-thrombotic agents by decreasing platelet aggregation significantly.">

Qureshi's human trials, referenced above, demonstrated decreases in thromboxane B (31%) and platelet factor 4 (14%) in patients taking TRF, an effect consistent with other reports on the effects of tocotrienols.

Interaction With Tocopherols

Qureshi and colleagues have demonstrated that the presence of alpha-tocopherol attenuates the HMG-CoA reductase inhibiting activity of gamma-tocotrienol in chickens. Just what implications this finding has on the advisability of the combined supplementation of alpha-tocopherol and tocotrienol forms has yet to be fully resolved. It should, however, be noted that the TRF blend is comprised of 6% alpha-tocopherol.

Impact on Cancer

Multiple studies report a significant relationship between tocotrienols and cancer. The tocotrienol rich fraction (TRF) has been reported to inhibit the growth of a human breast cancer cell line in culture by 50%; by contrast, alpha-tocopherol had no such effect.

Another study investigating hepatocareinogenesis in rats reports that "tocotrienol supplementation attenuated the impact of the carcinogens in the rats."

Goh, et al, reported in 1994 that "the results reveal that gamma- and delta-tocotrienols derived from palm oil exhibit a strong activity against tumour promotion by inhibiting EBV EA expression in Raji cells induced by... (TPA). However, alpha- and gamma-tocopherols and dimers of gamma-tocotrienol or gamma-tocopherol lack this activity."

A review article on the chemoprevention of cancer in the Journal of Nutrition in 1994 concluded that, "our review suggests that the mevalonate pathway of tumor tissues is uniquely sensitive to the inhibitory actions of the dietary isoprenoids" such as gamma-tocotrienol.

Toxicity

Human studies utilizing 200mg daily of the TRF tocotrienol blend demonstrated no reported side effects or toxicity.

Increasing dosages of 50, 100, 500, 1,000 and 20,000 ppm supplemented in corn-soy diets were fed to 2-week-old female chickens for four weeks. No adverse side effects were observed in any organs, even at a very high dose of TRF.

As a vitamin E molecule, tocotrienols share the characteristics already well-demonstrated with regard to a toxicity profile. Animal studies have demonstrated that vitamin E is not mutagenic, carcinogenic or teratogenic. In large-scale human studies, and in double-blind human studies, oral vitamin E supplementation resulted in few side effects even at doses as high as 3200 mg/day.

Conclusion

In contrast with other approaches to the above-identified risk factors for atherosclerotic vascular disease, tocotrienols modify all three factors in a positive manner.

Human trials of of orally-administered tocotrienols demonstrate significant positive modification of all three risk factors.

The risk of liver toxicity, or other significant side effects is absent with use of tocotrienols, in contrast to the statin class of hypocholesterolemic agents, as well as the over-the-counter yeast extract, Cholestin.

Tocotrienols should be considered a significant option for any individual wishing to decrease the three known risk factors of atherosclerotic heart disease reviewed in this paper.