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# Does anyone try tocotrienols?

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they're so underresearched

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17.3 ACTION OF TOCOTRIENOL AND TOCOPHEROL IN THE MEMBRANES
T has a saturated phytyl side chain, while T3 has an unsaturated isoprenoid side chain with three double bonds at 3′, 7′, and 11′ position, respectively. Although these different side chains do not affect the chemical reactivities of T and T3 toward radicals, they exert physical effects such as fluid- ity in the membrane and mobility between the membranes (Atkinson et al. 2008). The electron para- magnetic resonance (EPR) studies using spin labels having stable nitroxide radical at the different position of stearic acid revealed that T increased membrane rigidity slightly more significantly than the corresponding T3 (Suzuki et al. 1993; Yoshida et al. 2003). As described earlier, Serbinova et al. observed higher antioxidant capacity of α-T3 than α-T and ascribed this difference to its higher recycling efficiency from chromanoxyl radicals, its more uniform distribution in membrane bilayer, and its stronger disordering of membrane lipids, which makes interaction of chromanols with lipid radicals more efficient than α-T (Serbinova et al. 1991). The effects of side chains on the rate of incorporation into the membranes were found more sig-
nificant, that is, T3 is incorporated into and transferred between the membranes more rapidly than T (Yoshida 2003). This may be ascribed to a shorter chain of T3 than T. It has been shown that the shorter the side chain length of chromanols, the faster the rate of incorporation into the membranes (Niki et al. 1988). This difference is important in the cell culture system as described in the following

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The gamma isomer is about 30× more potent in lipid-lowering capability as compared to the alpha isomer (Serbinova et al. 1991; Qureshi et al. 2002). The location of the double bonds and the structure of tocotrienols is very close to that of farnesyl (farnesylated benzopyran analogs), which is the compound preceding the formation of squa- lene in cholesterol synthesis (Parker et al. 1993). Farnesyl is also the compound converted to ubiquinone (coenzyme Q-10) via the formation of all-trans-geranylgeranyl pyrophosphate, as well as to various prenylated proteins and dolicols. Tocotrienols increase the conversion of farnesyl to farnesol, which reduces the conversion of farnesyl to squalene and then to cholesterol (Parker et al. 1993). This also increases endogenous levels of ubiquinone in mitochondria. In addition, the farnesol signals two post- transcriptional pathways suppressing 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity by increasing the controlled degradation of the reductase protein and reducing the efficiency of translation of HMG-CoA reductase mRNA (Parker et al. 1993; Correll et al. 1994; Khor et al. 1995). This prevents upregulation of the HMG-CoA enzyme in response to statin therapy and further reduces LDL cholesterol when tocotrienols are used in combination with statin therapy in humans. The 2.4× increase in degradation of the reductase enzyme reduces the T 1/2 from 3.73–1.59 h.
There is a 57%–76% decreased efficiency of translation of the reductase mRNA and a 23%–76% decrease in reductase protein mass levels. In addition, the LDL receptor protein is augmented, increasing the number of LDL receptors and LDL removal as well as stimulation of apolipoprotein B degradation clearance (Pearce et al. 1992, 1994; Parker et al. 1993). There is a dose-dependent cholesterol reduction associated with tocotrienols. As the dose of tocotrienols increases, additional conversion to alpha-tocopherol may occur, which will limit the antilipid effects (Qureshi et al. 2002). If the alpha-tocopherol concentration is >20%, it will inhibit the tocotrienol lipid-lowering effects (Qureshi et al. 1986, 1996; Hosomi and Arita 1997). Alpha-tocopherol may compete for binding with the alpha-tocopherol transfer protein (TTP), and thus interfere with the transport of tocotrienols in the circulation (Hosomi and Arita 1997). In addition, alpha-tocopherol attenuates the inhibitory effects of tocotrienols on HMG-CoA reductase and actually induces enzymatic activity (Qureshi et al. 1996, 2002). This increase in HMG-CoA reductase activity with alpha-tocopherol may be one of the reasons that moderate to high dose alpha-tocopherol—as has been used exclusively in clinical trials—has not consistently reduced cardiovascular events in human prospective clinical trials. It is estimated that about 40% of the plasma tocotrienols are carried in LDL (O’Byrne et al. 2000).

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Adachi and Ishii reported that administration of VE composed of 22% alpha-Tp, 24% alpha-T3,
37% gamma-T3, and 12% delta-T3 could extend mean lifespan and reduce the accumulation of protein carbonyl, which is an indicator of oxidative damage during aging. Conversely, alpha- Tp acetate did not affect these parameters (Adachi and Ishii, 2000). VE also protected against
Prolongevity Effects of Tocotrienols 281
ultraviolet B-induced oxidative stress when it was administered before or after irradiation, and this protective effect was later reconfirmed using mice (Shibata et al., 2010).

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The reason why desmethyl T3s (T3s with fewer methyl groups) were more effective than alpha-
T3 is possibly explained by the number of methyl groups at the chromanol group of T3 (Tan and Mueller, 2008). Delta-T3 is monomethylated at the C8 position of the chromanol, making it the least substituted, and therefore the most potent, isomer of the four T3 compounds. Gamma-T3 is dimeth- ylated at the C7 and C8 positions of the chromanol and may be the second most potent isomer. The presence of lipofuscin, the so-called age pigment that accumulates with aging, was analyzed
in nematodes at 5, 7, 10, and 15 days of age (Gerstbrein et al., 2005). Lipofuscin is thought to be gen- erated by oxidative degeneration and autophagy of cellular components. Age-dependent accumula- tion of lipofuscin in the intestinal cells of worms has been demonstrated previously (Klass, 1977). However, CyD-mediated oral supplementation with T3 did not alter lipofuscin accumulation irre- spective of the prolongevity effect. Antioxidants and lifespan extension are not always associated with a reduction in the age pigment (Braeckman et al., 2002; Kampkötter et al., 2007). Furthermore,

Edited by InquilineKea

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