A tocotrienol-rich fraction (TRF(25)) and novel tocotrienols (d-P(21)-T3 and d-P(25)-T3) of rice bran significantly lowered serum and low density lipoprotein cholesterol levels in chickens. The present study evaluated the effects of novel tocotrienols on lipid metabolism in swine expressing hereditary hypercholesterolemia. Fifteen 4-mo-old genetically hypercholesterolemic swine were divided into five groups (n = 3). Four groups were fed a corn-soybean control diet, supplemented with 50 microg of either TRF(25), gamma-tocotrienol, d-P(21)-T3 or d-P(25)-T3 per g for 6 wk. Group 5 was fed the control diet for 6 wk and served as a control. After 6 wk, serum total cholesterol was reduced 32-38%, low density lipoprotein cholesterol was reduced 35-43%, apolipoprotein B was reduced 20-28%, platelet factor 4 was reduced 12-24%, thromboxane B(2) was reduced 11-18%, glucose was reduced 22-25% (P<0.01), triglycerides were reduced 15-19% and glucagon was reduced 11-17% (P<0.05) in the treatment groups relative to the control. Insulin was 100% greater (P<0.01) in the treatment groups than in the control group. Preliminary data (n = 1) indicated that hepatic activity of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase was lower in the treatment groups, and cholesterol 7alpha-hydroxylase activity was unaffected. Cholesterol and fatty acid levels in various tissues were lower in the treatment groups than in control. After being fed the tocotrienol-supplemented diets, two swine in each group were transferred to the control diet for 10 wk. The lower concentrations of serum lipids in these four treatment groups persisted for 10 wk. This persistent effect may have resulted from the high tocotrienol levels in blood of the treatment groups, suggesting that the conversion of tocotrienols to tocopherols may not be as rapid as was reported in chickens and humans.
Most tocopherols and tocotrienols, with the exception of alpha-tocopherol, are not retained by humans. This suggests that alpha-tocopherol is recognized uniquely; therefore, it may exert an exclusive function. alpha-Tocopherol possesses distinct properties that are independent of its prooxidant, antioxidant or radical-scavenging ability. alpha-Tocopherol specifically inhibits protein kinase C, the growth of certain cells and the transcription of the CD36 and collagenase genes. Activation events have also been seen on the protein phosphatase 2A (PP(2)A) and on the expression of other genes (alpha-tropomyosin and connective tissue growth factor). Neither ss-tocopherol nor probucol possessed the same specialty functions as alpha-tocopherol. Recently, we isolated a new ubiquitous cytosolic alpha-tocopherol binding protein (TAP). Its motifs suggest that it is a member of the hydrophobic ligand-binding protein family (CRAL-TRIO). TAP may also be involved in the regulation of cellular alpha-tocopherol concentration and alpha-tocopherol-mediated signaling.
Synthetic alpha-tocotrienol was separated into four geometrical E/Z side chain isomers by preparative HPLC (permethylated beta-cyclodextrin phase). The isolated isomers were resolved in ethylene glycol dimethyl ether, converted into the corresponding methyl ether using dimethyl sulfate, and the tocotrienol methyl ethers were extracted with n-hexane. A subsequent HPLC separation on a chiral phase (adsorbent cellulose derivated with 3,5-dimethyl phenyl carbamate) discriminates between the enantiomers of each E/Z side chain isomer, achieving the complete resolution of the eight occurring synthetic RS,E/Z-alpha-tocotrienols. The method can be shortened by omitting the preparative separation of the E/Z tocotrienol isomers prior to the chromatography on the chiral dimethyl phenyl carbamate phase. The simplified method achieved the following separation: RS,E/Z-alpha-tocotrienol separated into five peaks, RS,E/Z-beta-tocotrienol into eight, RS,E/Z-gamma-tocotrienol into six and RS,E/Z-delta-tocotrienol into eight peaks. The naturally occurring R,E-E-tocotrienol isomer could be identified within the synthetic RS,E/Z-isomers by co-chromatography with tocotrienol methyl ethers derived from natural sources, respectively.
Vitamin E, the most important lipid-soluble antioxidant, was discovered at the University of California at Berkeley in 1922 in the laboratory of Herbert M. Evans (Science 1922, 55: 650). At least eight vitamin E isoforms with biological activity have been isolated from plant sources. Since its discovery, mainly antioxidant and recently also cell signaling aspects of tocopherols and tocotrienols have been studied. Tocopherols and tocotrienols are part of an interlinking set of antioxidant cycles, which has been termed the antioxidant network. Although the antioxidant activity of tocotrienols is higher than that of tocopherols, tocotrienols have a lower bioavailability after oral ingestion. Tocotrienols penetrate rapidly through skin and efficiently combat oxidative stress induced by UV or ozone. Tocotrienols have beneficial effects in cardiovascular diseases both by inhibiting LDL oxidation and by down-regulating 3-hydroxyl-3-methylglutaryl-coenzyme A (HMG CoA) reductase, a key enzyme of the mevalonate pathway. Important novel antiproliferative and neuroprotective effects of tocotrienols, which may be independent of their antioxidant activity, have also been described.