ReviewTocotrienols in health and disease: The other half of the natural vitamin E family
Introduction
The natural vitamin E family includes eight chemically distinct molecules: α-, β-, γ- and δ-tocopherol; and α-, β-, γ- and δ-tocotrienol. Tocochromanols contain a polar chromanol head group with a long isoprenoid side chain. Depending on the nature of the isoprenoid chain, tocopherols (containing a phytyl chain) or tocotrienols (geranylgeranyl chain) can be distinguished (Dormann, 2007). A striking asymmetry in our understanding of the eight-member natural vitamin E tocol family has deprived us of the full complement of benefits offered by the natural vitamin E molecules. Approximately only 1% of the entire literature on vitamin E addresses tocotrienols. A review of the NIH CRISP database shows that funding for tocotrienol research represents less than 1% of all vitamin E research during the last 30+ years. Within the tocopherol literature, the non-α forms remain poorly studied (Dietrich et al., 2006, Hensley et al., 2004, O’Byrne et al., 2000). This represents a major void in vitamin E research. Significance of the void is substantially enhanced by the observation that the biological functions of the different homologues of natural vitamin E are not identical. During the last 5 years, tocotrienol research has gained substantial momentum. More than two-thirds (210/301) of the entire PubMed literature on tocotrienols has been published on or after 2000. This represents a major swing in the overall direction of vitamin E research. The objective of this review is to highlight the potential significance of the tocotrienol half of the vitamin E family in human health and disease in light of current developments. This work focuses on three of the most described biomedical properties of tocotrienols: hypocholesterolemic, anti-cancer and neuroprotective.
Section snippets
Vitamin E biosynthesis: tocopherols and tocotrienols
The condensation of homogentisate, derived from the shikimate pathway, and phytyl pyrophosphate (phytyl-PP), derived from the non-mevalonate pathway, through the action of the homogentisate prenyltransferase (HPT) represent the key committed step of tocopherol biosynthesis (Venkatesh et al., 2006). The product of the above-mentioned reaction is 2-methyl-6-phytylplastoquinone, the first true tocopherol intermediate and common precursor of all tocopherols. Subsequent ring cyclization and
Natural sources of tocotrienols
The identification of α-tocotrienol as a cholesterogenesis-inhibitory factor derived from barley (Hordeum vulgare L.) represents a landmark early discovery highlighting the unique significance of tocotrienols in health and disease (Qureshi et al., 1986). Palm oil represents one of the most abundant natural sources of tocotrienols (Elson, 1992). The distribution of vitamin E in palm oil is 30% tocopherols and 70% tocotrienols (Sundram et al., 2003). The oil palm (E. guineensis) is native to many
Bioavailability of tocotrienols taken orally
During the last two decades, efforts to understand how dietary vitamin E is transported to the tissues have focused on α-tocopherol transport (Blatt et al., 2001, Kaempf-Rotzoll et al., 2003, Traber and Arai, 1999, Traber et al., 2004). α-Tocopherol transfer protein (TTP) has been identified to mediate α-tocopherol secretion into the plasma while other tocopherol-binding proteins seem to play a less important role (Kaempf-Rotzoll et al., 2003). Tocotrienols have been known for decades but why
Functional uniqueness of Vitamin E family members
All eight tocols in the natural vitamin E family share close structural homology and hence possess comparable antioxidant efficacy. Yet, current studies of the biological functions of vitamin E continue to indicate that members of the vitamin E family possess unique biological functions often not shared by other family members. One of the earliest observations suggesting that α-tocopherol may have functions independent of its antioxidant property came from the observation that α-tocopherol
Hypocholesterolemic effects of tocotrienol
Purification of an oily, non-polar fraction of high protein barley flour by high pressure liquid chromatography yielded 10 major components. Two of these components were identified as potent inhibitors of cholesterogenesis both in vivo as well as in vitro. Addition of the purified inhibitor I (2.5–20 ppm) to chick diets significantly decreased hepatic cholesterogenesis and serum total and low-density-lipoprotein cholesterol and concomitantly increased lipogenic activity. The high resolution mass
Anti-cancer effects of tocotrienol
Pure and mixed isoprenoids are known to possess potent anti-cancer activity (Mo and Elson, 1999). Tocotrienols are isoprenoids but tocopherols are not. Unlike in the case of neuroprotection where α-tocotrienol has emerged to be the most potent isoform (Khanna et al., 2005b, Khanna et al., 2006, Sen et al., 2004, Sen et al., 2006), there seems to somewhat of a consensus that γ- and δ-tocotrienols are the most potent anti-cancer isoform of all natural existing tocotrienols. One of the first
Neuroprotective effects of tocotrienol
On a concentration basis, the neuroprotective effects of nM tocotrienol represent the most potent biological function of all natural forms of vitamin E. Glutamate toxicity is a major contributor to neurodegeneration. It includes excitotoxicity and an oxidative stress component also known as oxytosis (Schubert and Piasecki, 2001, Tan et al., 2001). Murine HT hippocampal neuronal cells, lacking intrinsic excitotoxicity-pathway, have been used as a standard model to characterize the
Conclusion
Members of the natural vitamin E family possess overlapping as well as unique functional properties. Our knowledge about the non-α-tocopherol isoforms of natural vitamin E is scanty. Among the natural vitamin E molecules, d-α-tocopherol (RRR-α-tocopherol) has the highest bioavailability and is the standard against which all the others are compared. However, it is only one out of eight natural forms of vitamin E. Interestingly, symptoms caused by α-tocopherol deficiency can be alleviated by
Acknowledgements
Tocotrienol research in the laboratory is supported by NIH RO1NS42617. Tocotrienol used in the laboratory was natural palm-oil derived (either purified or Tocomin® SupraBio™) and provided as gift from Carotech Inc., NJ. Studies on human tissue distribution of orally fed tocotrienol are supported by the Malaysian Palm Oil Board.
References (171)
- et al.
Gamma-tocotrienol inhibits nuclear factor-kappaB signaling pathway through inhibition of receptor-interacting protein and TAK1 leading to suppression of antiapoptotic gene products and potentiation of apoptosis
J. Biol. Chem.
(2007) - et al.
The novel formulation design of self-emulsifying drug delivery systems (SEDDS) type O/W microemulsion III: the permeation mechanism of a poorly water soluble drug entrapped O/W microemulsion in rat isolated intestinal membrane by the Ussing chamber method
Drug Metab. Pharmacokinet.
(2006) - et al.
Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death
Brain Res. – Brain Res. Rev.
(1997) Effects of ischemia and electroconvulsive shock on free fatty acid pool in the brain
Biochim. Biophys. Acta
(1970)- et al.
Increased levels of brain free fatty acids after electroconvulsive shock
Life Sci.
(1970) - et al.
Vitamin E kinetics and the function of tocopherol regulatory proteins
Nutrition
(2001) - et al.
Shape and specificity in mammalian 15-lipoxygenase active site. The functional interplay of sequence determinants for the reaction specificity
J. Biol. Chem.
(1999) - et al.
Inhibition of cell proliferation by alpha-tocopherol. Role of protein kinase C
J. Biol. Chem.
(1991) - et al.
Formation and electrophysiological actions of the arachidonic acid metabolites, hepoxilins, at nanomolar concentrations in rat hippocampal slices
Neuroscience
(1994) - et al.
rice bran oil diet increases LDL-receptor and HMG-CoA reductase mRNA expressions and insulin sensitivity in rats with streptozotocin/nicotinamide-induced type 2 diabetes
J. Nutr.
(2006)