Elsevier

Molecular Aspects of Medicine

Volume 28, Issues 5–6, October–December 2007, Pages 692-728
Molecular Aspects of Medicine

Review
Tocotrienols in health and disease: The other half of the natural vitamin E family

https://doi.org/10.1016/j.mam.2007.03.001Get rights and content

Abstract

Tocochromanols encompass a group of compounds with vitamin E activity essential for human nutrition. Structurally, natural vitamin E includes eight chemically distinct molecules: α-, β-, γ- and δ-tocopherol; and α-, β-, γ- and δ-tocotrienol. Symptoms caused by α-tocopherol deficiency can be alleviated by tocotrienols. Thus, tocotrienols may be viewed as being members of the natural vitamin E family not only structurally but also functionally. Palm oil and rice bran oil represent two major nutritional sources of natural tocotrienol. Taken orally, tocotrienols are bioavailable to all vital organs. The tocotrienol forms of natural vitamin E possesses powerful hypocholesterolemic, anti-cancer and neuroprotective properties that are often not exhibited by tocopherols. Oral tocotrienol protects against stroke-associated brain damage in vivo. Disappointments with outcomes-based clinical studies testing the efficacy of α-tocopherol need to be handled with caution and prudence recognizing the untapped opportunities offered by the other forms of natural vitamin E. Although tocotrienols represent half of the natural vitamin E family, work on tocotrienols account for roughly 1% of the total literature on vitamin E. The current state of knowledge warrants strategic investment into investigating the lesser known forms of vitamin E.

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.

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