TOCOTRIENOLS

Vitamin E is the collective name for a group of substances with defined biological activity (prevention of sterility, of oxidative haemolysis, of muscle dystrophy). The group consists of four Tocopherols (alpha, beta, gamma, delta) and the four corresponding Tocotrienols. Both Tocopherols and Tocotrienols are composed of a chromanol ring system and an isoprenoid side chain. Whereas the side chain of the Tocopherols is saturated, three double bonds are present in the side chain of the Tocotrienols ("farnesyl" side chain). Alpha-, beta, gamma-, and delta-Tocopherol and the respective Tocotrienols are characterized by the methyl substitution pattern of the Chromanol ring. Probably because Tocotrienols are less common than Tocopherols, less attention has been paid to them in the past. More recent research, however, has demonstrated that Tocotrienols play a specific role which goes beyond their known vitamin E activity: They were found to be hypocholesterolemic, anticancerogenic, antithrombotic, strongly antioxidative and antiinflammatory in various experimental animal models and studies with human subjects (QURESHI, 1996(I)). The key to some of the special activities of Tocotrienols is apparently their ability to down regulate the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase, HMGR) as described in many publications (QURESHI, 1991(I); PARKER, 1993; ELSON, 1995; ELSON, 1995 (II), PEARCE, 1992). The mechanism of this inhibition is posttransscriptional and is owed to the farnesyl side chain of the Tocotrienols but also to the methyl substitution pattern of the Chromanol ring (gamma-Tocotrienol was found to be most effective) (PEARCE, 1994). In addition to the inhibition of HMGR Tocotrienols seem to be able to specifically modulate the intracellular mechanism for controlled degradation of the HMGR protein (PARKER, 1993). The HMGR blocking efficiency of Tocotrienols is apparently attenuated by alpha-Tocopherol (QURESHI, 1995, 1996(III)). Since HMGR CoA reductase is the key enzyme of the mevalonate and hence the cholesterol synthesis, its suppression lowers cholesterol synthesis in the liver and reduces the blood cholesterol levels. This was confirmed in various studies (QURESHI, 1988, 1991(I), 1996(I)). The mechanism is similar to the mode of action of hypocholesterolemic pharmaceuticals as e.g. Lovastatin. A synergism between Tocotrienols and Lovastatin was indeed observed (QURESHI, 1996(II)). An anticarcinogenic effect of Tocotrienols was proven in many investigations. CARROLL (1995) found gamma-Tocotrienol a more efficient inhibitor of the growth of cultured human breast cancer cells than the synthetic drug tamoxifen. A similar result is reported by GUTHRIE (1994) and NASARETNAM (1995) who also found alpha Tocopherol to be ineffective in this respect. A strong inhibition of tumor promotion in human lymphoblastoid cells is reported by GOH (1994). KATO (1985) observed that alpha-Tocotrienol prolongs the life span of cancer infected mice. Cancerostatic effects of Tocotrienols in animal studies were published by SUNDRAM (1989), KOMIYAMA (1989), WAN ZURINAH (1991), TAN (1992) and RAHMAT (1993). The carcinostatic (as well as the hypocholesterolemic) effect of Tocotrienols may be explained by the inhibition of the HMGR. The suppression of the mevalonate synthesis depletes tumor tissues of two intermediate products, farnesyl and geranyl pyrophosphate, which are normally incorporated into growth control associated proteins (ELSON, 1995(II)). A further explanation of the anticarcinogenicity of (especially: gamma) Tocotrienol may be its influence on the activity of detoxificataion enzymes: Gamma-glutamyl transpeptidase (gamma-GT) (a phase I enzyme) was inhibited in cultured rat hepatocytes while glutathione S-transferase (GST) (phase II enzyme) activity 122 was enhanced (NGAH, 1992; ONG, 1993, 1994; ELSON, 1994). A study by SERBINOVA (1991) demonstrated that alpha-Tocotrienol possesses 40-60 times higher antioxidant activity against induced lipid peroxidation in rat liver microsomal membranes and a better (6.5 times) protection of cytochrome P-450 against oxidative damage than alpha-Tocopherol. She came to the conclusion that the higher antioxidative potential of alpha-Tocotrienol is owing to three properties: (i) its higher recycling efficiency from chromanoxyl radicals, (ii) its more uniform distribution in membrane bilayer, and (iii) its stronger disordering of membrane lipids which makes interaction of chromanols with lipid radicals more efficient. This particular antioxidative effect in membranes was confirmed by SUZUKI (1993). He found alpha-Tocotrienol to exhibit significantly greater peroxyl radical scavenging potency than alpha-Tocopherol in phosphatidylcholine liposomes, whereas both antioxidants have identical activity in hexane. The combination of antioxidant and hypocholesterolemic effect may explain the excellent antiatherosclerotic activity of Tocotrienols as observed by TEOH (1994), TOMEO (1995) and WATKINS (1993). QURESHI (1991(I), 1995, 1996(I)) reported that Tocotrienols decrease the thromboxane B2 levels in humans and animals (1991(II)). (The measurement of thromboxane B2 is an indicator of thromboxane A2 production; thromboxane A2 is a potent inducer of platelet aggregation and it is rapidly hydrolysed to its stabile form thromboxane B2) MAHADEVAPPA (1991) showed that palm Tocotrienols have anti-aggregation effect on blood platelets suggesting a role in the inhibition of the thrombosis process. Tocotrienols occur as minor components for example in grape seed oil, rice bran oil and barley oil. Palm oil is a particularly rich source of natural Tocotrienols.

References

CARROll,K.K. et al., 1995: Inhibition of Proliferation of Human Breast Cancer by Palm Oil Tocotrienols. Presented at the 7th Asian Congress of Nutrition. Beijing, China. October 7-11th 1995

ELSON, C.E., 1995: Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease. J. Nutr. 1995 Jun; 125(6 Suppl): 1666S-1672S

ELSON, C.E. et al., 1994: The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J. Nutr. 1994 May; 124(5): 607-14

GOH, S.H. et al., 1994: Inhibition of tumour promotion by various palm-oil tocotrienols. Int. J. Cancer. 1994 May 15; 57(4): 529-31 GUTHRIE,N. et al., 1994: Inhibition of Proliferation of MDA-MB-435 Human Breast Cancer Cells by Individual Tocotrienols from Palm Oil. Proc. Am. Assoc. Cancer Res. 35 : 629. Abstract 3749. Also Presented at the Seventh Asian Congress of Nutrition, Beijing, China, October 7-11,1995.

KATO,A. et al., 1985: Physiological Effect of Tocotrienol. J. Japan Oil Chem. Soc. (Yukagaku),34 : 375-376.

KOMIYAMA,K., et al., 1989: Studies on the Biological Activity of Tocotrienols. Chem.Pharm.Bull.Tokyo. 1989 May; 37(5): 1369-1371. MAHADEVAPPA, V.G. et al., 1991: Effect of Tocotrienol Derivatives on Collagen- and ADP-Induced Human Platelet Aggregation. Proc of 1989 Int. Palm Oil Conf.- Nutrition and Health Aspects of Palm Oil,Published by PORIM 36-38.

NESARETNAM, K, et al, 1995: Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Lipids. 1995 Dec; 30(12): 1139-43

NGAH, W.Z., et al., 1992: Effect of tocotrienols on hepatocarcinogenesis induced by 2-acetylaminofluorene in rats. Am. J. Clin. Nutr. 1991 Apr; 53(4 Suppl): 1076S-1081S

ONG, F.B. et al., 1993: Glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured rat hepatocytes treated with tocotrienol and tocopherol. Comp. Biochem. Physiol. C. 1993 Sep; 106(1): 237-40. ONG, F.B. et al., 1994: Vitamin E, glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured hepatocytes of rats treated with carcinogens. Int. J. Biochem. 1994 Mar; 26(3): 397-402 PARKER,R.A. et al. 1993: Tocotrienols Regulate Cholesterol Production in Mammalian Cells by Post-Transcriptional Supression of 3-Hydroxy-3-Methylglutaryl-Coenzym A Reductase. J.Biol.Chem. 1993 May 25; 268(15): 11230-8

PEARCE, B.C. et al., 1992: Hypocholesterolemic activity of synthetic and natural tocotrienols. J. Med. Chem. 1992 Oct 2; 35(20): 3595-606 PEARCE, B.C. et al., 1994: Inhibitors of cholesterol biosynthesis. 2. Hypocholesterolemic and antioxidant activities of benzopyran and tetrahydronaphthalene analogues of the tocotrienols. J-Med-Chem. 1994 Feb 18; 37(4): 526-41

QURESHI, A. A. et al., 1988: Suppression of Cholesterol Biosythesis and Hypocholesterolemic Effects of Tocotrienols from Palm Oil in the Chicken Model. Paper presented at The National Oil Palm/Palm Oil Conference: Current Development, 11-15 October, 1988, Shangri-La Hotel. Kuala Lumpur.

QURESHI, A. A. et al., 1991(I): Lowering of Serum Cholesterol in Hypercholesterolemic Humans by Tocotrienols (Palmvitee). Am. J. Clin. Nutr. 53: 1021S-1026S (1991)

QURESHI, A.A. et al., 1991(II): Dietary tocotrienols reduce concentrations of plasma cholesterol, apolipoprotein B, thromboxane B2, and platelet factor 4 in pigs with inherited hyperlipidemias. Am. J. Clin. Nutr. 1991 Apr; 53(4 Suppl): 1042S-1046S

QURESHI, A. A. et al., 1995: Response of hypercholesterolemic subjects to administration of tocotrienols. Lipids. 1995 Dec; 30(12): 1171-7

QURESHI, A. A., 1996(I): The Multitherapeutic Properties of Palm Oil and its Novel Vtamin E (Tocotrienols). Paper presented at the PORIM International Palm Oil Conference, September 23-28,1996. Hotel Istana, Kuala Lumpur.

QURESHI,A. A. et al., 1996(II): Synergistic Action of Lovastatin and Tocotrienols(Palmvitee) in the Control of LDL-Cholesterol in Hypercholesterolemic Subjects. Abs. PIPOC 96 Nutrition Module 23-24 September 1996 at Kuala Lumpur, Malaysia.

QURESHI, A. A. et al., 1996(III): Dietary alpha-tocopherol attenuates the impact of gamma-tocotrienol on hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in chickens. J. Nutr. 1996 Feb; 126(2): 389-94

RAHMAT, A, et al., 1993: Long-term administration of tocotrienols and tumor-marker enzyme activities during hepatocarcinogenesis in rats. Nutrition. 1993 May-Jun; 9(3): 229-32

SERBINOVA,E. et al., 1991: Free Radical Recycling and Intramembrane Mobility in the Antioxidant Properties of Alpha-Tocopherol and Alpha-Tocotrienol. Free Radic. Biol. Med. 1991; 10(5): 263-275.

SUNDRAM, K. et al., 1989: Effect of dietary palm oils on mammary carcinogenesis in female rats induced by 7,12-dimethylbenz(a)anthracene. Cancer-Res. 1989 Mar 15; 49(6): 1447-51

SUZUKI, Y.J, et al., 1993: Structural and dynamic membrane properties of alpha-tocopherol and alpha-tocotrienol: implication to the molecular mechanism of their antioxidant potency. Biochemistry. 1993 Oct 12; 32(40): 10692-9

TAN, B., 1992: Antitumour Effects of Palm Carotenoids and Tocotrienols in HRS/J Hairless Female Mice. Nutrition Research 12 (1) S163-S173.

TEOH, M.K. et al., 1994: Protection by tocotrienols against hypercholesterolaemia and atheroma [see comments]. Med. J. Malaysia. 1994 Sep; 49(3): 255-62

TOMEO,A.C. et al., 1995: Antioxidant Effects of Tocotrienols in Patients with Hyperlipidemia and Carotid Stenosis. Lipids. 1995 Dec; 30(12) 1179-83

WAN ZURINAH,W.N. et al., 1991: Effect of Tocotrienols on Hepacarcinogenesis Induced by 2-Acetylaminofluorene in Rats. Am.J.Clin.Nutr. 53: 1076S-1081S.

WATKINS, T. et al., 1993: gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Lipids. 1993 Dec; 28(12).

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