Tocotrienols In Health & Disease: A Novel Antioxidant In The Treatment Of Hypercholesterolemia & Cancer

 

by Carl Germano, M.A., R.D., CNS

In the early isolation of vitamin E from plant oils, the proposed term tocopherols was used to name the initial four compounds that shared similar structure. These compounds were designated as alpha, beta, delta and gamma tocopherol. Their structures have two primary parts, a complex ring and a long saturated side chain. Tocopherols (vitamin E) play an important role as the major lipid soluble antioxidants that protect our bodies against free radical damage. A wealth of studies exist on vitamin E's role in reducing the risk of developing heart disease and other debilitating illnesses with as little intake as 100 IU daily. In addition to the four tocopherols, another related series of compounds, tocotrienols, have been discovered which are less widely distributed in nature. Comparatively, the tocotrienol structure differs by possessing three double bonds in their side chain rather than being saturated. While tocopherols are predominantly found in corn, soybean and olive oils, tocotrienols are particularly rich in palm, rice bran and barley oils. Therefore, vitamin E is the term used for eight naturally occurring essential fat-soluble nutrients: alpha, beta, delta & gamma tocopherols plus a class of compounds related to vitamin E called alpha, beta, delta and gamma tocotrienols. Interestingly, tocotrienols have been shown to elicit powerful antioxidant, anti-cancer and cholesterol lowering properties. Some studies have confirmed that tocotrienol activity as an antioxidant, anti-cancer and cholesterol reducing substance to be much stronger than tocopherols. In view of the fact that tocotrienols were once thought to be of lesser nutritional value than the tocopherols, it is apparent that their activity and importance rank them as one of the most important class of nutritional compounds for the prevention and treatment of disease.

Cardiovascular Disease

With a strong relationship between atherosclerosis and cholesterol, much attention has been given by pharmaceutical companies to develop new cholesterol lowering agents. Unfortunately, to date, all of the available pharmaceutical cholesterol lowering drugs are without significant side effects. Ironically, the liver, which is the major organ involved in the synthesis and distribution of cholesterol, is targeted in a deleterious manner by these pharmaceuticals directed at hypercholesterolemia. Fortunately, several important nutritional agents have been used successfully to assist in lowering cholesterol such as antioxidants, garlic, niacin, hydroxycitrate, folic acid, chromium and fiber. To complete this arsenal of non-toxic beneficial nutrients, tocotrienols have demonstrated significantly important activity in regulating the synthesis of cholesterol and acting as a potent antioxidant and anti-tumor agent.

Both animal and human studies have shown that tocotrienols have positive effects on serum lipids, prostaglandins and platelet function in hypercholesterolemic subjects.

Tocotrienols exert an antioxidant and cholesterol synthesis inhibiting action and are very valuable in any nutritional protocol addressing atheroclerosis. The mechanism by which tocotrienols exert their cholesterol lowering effect involves the suppression of the enzyme, HMG-CoA reductase, responsible for its synthesis. Therefore, tocotrienols decrease the liver's capacity to manufacture cholesterol. In one double blind, crossover study, serum concentrations of total cholesterol and thromboxane (a potent inducer of platelet aggregation and vasoconstriction) decreased significantly in only those subjects given a natural, palm derived tocotrienol mix. Astonishingly, some of the participants had lowered their cholesterol by 31% in only 4 weeks when given 200mg gamma tocotrienol. The study concluded that gamma tocotrienol was the most potent cholesterol inhibitor of all the tocotrienols. In other studies, it was noted that antioxidants such as tocotrienols may protect against atherosclerosis since tissue injury from free radicals is the final pathway of damage in the diseased artery. Many studies have suggested an important inverse relationship between the development of atherosclerosis and antioxidant concentrations Assessment of tocotrienols on serum cholesterol, oxidized lipids and arterial damage revealed that tocotrienols were more effective than tocopherols in preventing increases of the "bad" LDL and total cholesterol levels in animals fed high cholesterol diets. The studies that investigated the effects of tocotrienols on levels of thromboxane in animals and humans were equally impressive. Tocotrienols were shown to cause a decrease in thromboxane levels in humans by 20 - 26% and a decrease in platelet aggregation. While both tocopherols and tocotrienols offered significant protection against damage to the arterial wall, tocotrienols had a much stronger lipid lowering effect. Therefore, a combination of alpha tocopherol and tocotrienols is the best approach to treating atherosclerosis and hypercholesterolemia since both compounds have similar yet different roles to play.

Antioxidant Activity & Cancer

While tocotrienols have only marginal vitamin E activity, their antioxidant effects are considerably better. This is particularly important since the tocotrienol unsaturated side chain allows for more efficient penetration into tissues that have saturated fatty layers such as the brain and liver. Experimental research examining the antioxidant, free radical scavenging effects of vitamin E (alpha tocopherol) and tocotrienols revealed that tocotrienols appear superior due to their better distribution in the fatty layers of the cell membrane. Aside from the basic free radical scavenging effect, antioxidant function is also associated with lowering DNA damage, tumor formation and other parameters of cell damage. Interestingly, the effects of long term administration of tocotrienols on liver cancer was studied in animals. Supplementation of tocotrienols in rats induced with a potent liver cancer agent demonstrated that the tocotrienols prolonged the impact of the cancer agent. Cell damage to the liver was significant in the untreated group versus the tocotrienol treated group. Other animal studies, focusing on mammary cancer, revealed that animals fed corn oil or soy bean oil based diets had significantly more tumors than those fed a tocotrienol rich palm oil diet when exposed to carcinogens. The results clearly noted that the tocotrienol rich palm oil did not promote chemically induced mammary cancer.

The past few years have brought a great deal of attention to the importance of newer antioxidants such as lipoic acid, carotenoids, polyphenols and tocotrienols. These new nutrients have demonstrated greater antioxidant and anti-cancer activity than what has been offered previously in nutritional protocols. With respect to tocotrienols, much of the early research work focused on the major components of vitamin E called tocopherols. However, present research has now provided insight and significance to the other vitamin E fractions called tocotrienols. As noted, gamma and delta tocotrienols were shown to be effective nutritional agents in the arsenal used to treat high cholesterol. While all of the tocotrienols were considered important antioxidants, it may turn out that they are the most potent of all of the lipid soluble antioxidants available. From decreasing platelet aggregation (clumping of blood) to anti-inflammatory action to anti-cancer activity, tocotrienols are considered one of the most interesting group of nutritional compounds that will play significant roles in clinical investigation and in the treatment of disease.

References

1) Serbinova, EA, et al, "Alpha Tocotrienol Is A More Powerful membrane Antioxidant Than Alpha Tocopherol", Oxid Damage Repair, 1991;77-81.

2) Perace, BC, et al, "Hypocholesterolemic Activity Of Synthetic And Natural Tocotrienols", J Med Chem, 1992;35:3595-606

3) Serbinova, EA, et al, 'Free Radical Recycling And Intermembrane Mobility In The Antioxidant Properties Of Alpha Tocopherol And Alpha Tocotrienol", Free Biology and Medicine, 1991

4) Komiyama, K., et al, "Studies On The Biological Activity Of Tocotrienols", Chem Pharm Bull, 1989; 37(5):1369-71

5) Parker, RA, et al, 'Tocotrienols Decrease Cholesterol Synthesis In HepG2 Cells By A Novel Suppression Of HMG-CoA Reductase", FASEB J, 1991

6) Quershi, AA, et al, "Lowering Of Serum Cholesterol In Hypercholesterolemic Humans By Tocotrienols". J Am Clin Nutr, 1991 Apr;53(4 Suppl):1021s-1026s

7) Quershi, AA, et al, "Dietary Tocotrienols Reduce Levels Of Plasma Cholesterol, Apolipoprotein B, Thromboxane B2 And Platelet Factor 4 In Pigs With Inherited Hyperlipidemias", J Am Clin Nutr, 1991 Apr;53(4 Suppl):1042s-1046s

8) Teoh, MK, et al, "Protection By Tocotrienols Against Hypercholesterolemia And Atheroma", Med J Malaysia, 1995; Mar;50(1):117

9) Rahmat, A, et al, "Long Term Administration Of Tocotrienols And Tumor Marker Enzyme Activities During Hepatocarcinogenesis In Rats", Nutrition, 1993 May-Jun; 9(3):229-32

10) Koba, K, et al, "Effects Of Alpha Tocopherol And Tocotrienols On Blood Pressure And Linoleic Acid Metabolism In The Spontaneously Hypertensive Rat", Biosci Biotechnol Biochem 1992 Sep;56(9):1420-3