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Dietetic and Pharmaceutical Raw Materials
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.
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,
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.
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,
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
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).
