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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:151-154, February 2005

Recent Advances in Nutritional Sciences

Tocotrienols: Constitutional Effects in Aging and Disease1

Sebastian Schaffer2, Walter E. Müller and Gunter P. Eckert

Institute of Pharmacology (ZAFES Member), Biocenter Niederursel, University of Frankfurt, Frankfurt am Main, Germany

2To whom correspondence should be addressed. E-mail: S.Schaffer{at}em.uni-frankfurt.de.


   ABSTRACT
TOP
 ABSTRACT
LITERATURE CITED
 
Tocotrienols, a class of vitamin E analogs, modulate several mechanisms associated with the aging process and aging-related diseases. Most studies compare the activities of tocotrienols with those of tocopherols ("classical vitamin E"). However, some biological effects were found to be unique for tocotrienols. Although the absorption mechanisms are essentially the same for all vitamin E analogs, tocotrienols are degraded to a greater extent than tocopherols. The levels of tocotrienols in the plasma of animals and humans were estimated to reach low micromolar concentrations. One hallmark in the origin of disease and aging is the overproduction of reactive oxygen species (ROS). Tocotrienols possess excellent antioxidant activity in vitro and have been suggested to suppress ROS production more efficiently than tocopherols. In addition, tocotrienols show promising nonantioxidant activities in various in vitro and in vivo models. Most notable are the interactions of tocotrienols with the mevalonate pathway leading to the lowering of cholesterol levels, the prevention of cell adhesion to endothelial cells, and the suppression of tumor cell growth. Furthermore, glutamate-induced neurotoxicity is suppressed in the presence of tocotrienols. This review summarizes the main antioxidant and nonantioxidant effects of tocotrienols and assesses their potential as health-maintaining compounds.

KEY WORDS: • tocotrienols • antioxidants • cholesterol • cancer • neurotoxicity

Natural vitamin E includes 2 groups of closely related fat-soluble compounds, the tocotrienols (TCTs)3 and tocopherols (TCPs), each with the 4 analogs, {alpha}, ß, {gamma}, and {delta} (Fig. 1). All vitamin E analogs possess a 6-membered, aromatic chromanol ring structure and a side chain. The TCPs have a phytol chain, whereas the TCTs have an unsaturated side chain with double bonds at the 3', 7', and 11' positions of the hydrocarbon tail. Based on its lipophilicity, vitamin E is considered to be the major chain-breaking antioxidant preventing the propagation of oxidative stress, especially in biological membranes (1). Recent data suggest that a common mechanism based on oxidative stress emanating from an overproduction of reactive oxygen species (ROS) contributes to the aging process and aging-related diseases in many or even all species (2). Furthermore, the combination of a Western lifestyle, a nonbalanced diet, and increasing mean life expectancy is responsible for the frequent occurrence of cardiovascular, malignant and neurodegenerative diseases. On the basis of epidemiologic and retrospective studies, supplementation with antioxidants such as TCPs is considered to be a nutrition-based strategy to prevent diseases and to support healthy aging. However, findings from controlled clinical trials failed to show a strong effect of TCP intake on Alzheimer’s and cardiovascular disease progression (3,4). Recently, TCTs have gained increasing scientific interest due to their eminent antioxidant effects and an nonantioxidant activity profile that differs somewhat from that of TCPs. TCTs are found in abundance in plant foods such as rice bran or palm oil (5). This article reviews the potential effect of TCTs on the aging process as well as the emergence and progression of aging-related diseases.



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  		FIGURE 1 Structure of tocotrienols and tocopherols.

 
    Tocotrienol Bioavailability. There is still much controversy about the absorption, retention, and metabolism of TCTs (Fig. 2). Cell culture studies suggest that TCTs and TCPs are metabolized similarly, i.e., by {omega}-oxidation followed by ß-oxidation of the side chain, although TCTs were found to be degraded to a larger extent than TCPs (6). Recently, Yap et al. (7) investigated in humans the bioavailability and pharmacokinetics of {alpha}-, {gamma}-, and {delta}-TCT in different food states. The plasma levels of all 3 TCTs increased markedly with food intake. Thereafter, TCT concentrations in the plasma dropped rapidly initially followed by a more gradual decline. TCT plasma levels were reported to reach 1 µmol/L in humans and between 3 and 20 µmol/L in various animal species (8–11). TCTs were found in various tissues of rats, especially adipose tissues, skin, and heart, after oral application, suggesting that TCTs are absorbed and distributed in vivo (12,13). Moreover, oral supplementation of female rats produced a moderate accumulation of TCTs in the brains and an even significantly higher TCT concentration in the brain of rat pups (14).



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  		FIGURE 2 Overview on the absorption and metabolism of tocotrienols and their proposed effects in vitro and in vivo.

 
    Antioxidant Activity of Tocotrienols. The antioxidant potencies of TCTs and TCPs were compared in a variety of extensive in vitro experiments, although with conflicting results. TCTs showed a >60% lower half-maximal antioxidant efficiency concentration in liposomes than TCPs (15,16). This superior antioxidant activity of TCTs is thought to be related to a more uniform distribution within membranes, a disordering effect on the membrane lipids, and a higher recycling efficiency from chromoxyl radicals (17). In contrast, a recent study (18) showed only marginal, if any, differences between the antioxidant activity of TCTs and TCPs in cell-free and liposome test systems. However, given that only one concentration of TCTs and TCPs was compared, the importance of the latter study is limited. Also, when investigated under more elaborated experimental settings, TCTs protect cells to a greater extent than TCPs or vitamin C against ROS-mediated lipid peroxidation or erythrocyte hemolysis (19,20). Similarly, in Caenorhabditis elegans exposed to UV-B light, pre- and postadministration of TCTs lowered protein carbonylation and extended mean life span. In contrast, {alpha}-TCP supplementation did not have any significant effects (21). In addition, TCTs recently displayed high antioxidant activity in feeding experiments in rats and humans (10,22).

    Tocotrienols Modulate Cardiovascular Disease Risk Parameters. Cardiovascular disease (CD) remains one of the most important causes of morbidity and mortality, especially in men and women > 60 y old. The lowering of cholesterol levels was shown to reduce the risk of CD. Statins reduce cholesterol by competitively inhibiting the rate-limiting enzyme of cholesterol synthesis 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase, whereas TCTs produce this effect post-transcriptionally by increasing HMG-CoA reductase degradation as well as decreasing the efficiency of the translation of HMG-CoA reductase mRNA (23). The in vitro cholesterol-lowering effect of TCTs or TCT-rich fractions was also shown in various animal models (9,24). Data for humans, however, are less consistent. In placebo-controlled, double-blind studies, Mensink et al. (25) and Mustad et al. (11) did not find any favorable effects of different TCT combinations on serum lipoprotein profile in hypercholesterolemic patients after 4- (200 mg TCT/d) and 6-wk (160 mg TCT/d) supplementation periods. The outcome of these studies is in contrast to publications from Qureshi et al. (26,27), which reported significant cholesterol-reducing effects of TCTs and TCT-rich fractions in animals and humans. The contradictory effects of TCTs on cholesterol levels were suggested to be due to differences in dietary cholesterol and energy intake of study subjects. Furthermore, {alpha}-TCP concentrations > 20% in TCT-rich supplements might attenuate the cholesterol-lowering potential of TCTs (27), an explanation that was questioned, however, in a review by Kerckhoffs et al. (28). Recently, Qureshi et al. (29) confirmed their earlier results by reporting a dose-dependent suppression of serum cholesterol by a TCT-rich (25–200 mg/d) fraction of rice bran in hypercholesterolemic humans following the American Heart Association Step-1 diet. Similar effects were found in rats with experimental hypercholesterolemia that were fed a TCT-rich fraction for 6 mo. Reduced enzymatic activity and protein mass of HMG-CoA reductase subsequently led to a significant reduction in plasma cholesterol (30).

Adhesion molecules are also involved in atherogenesis by mediating cell adhesion to endothelial cells. Theriault et al. (31) reported that {alpha}-TCT markedly inhibited not only the surface expression of cell adhesion molecules [vascular cellular adhesion molecule-1 (VCAM-1), intercellular cell adhesion molecule-1, E-selectin] in human umbilical vein endothelial cells (HUVEC) but also monocytic cell adhesion of THP-1 cells. Both effects were more pronounced for {alpha}-TCT than for {alpha}-TCP. An in vitro study by Noguchi et al. (32) found that {alpha}-TCT affected VCAM-1 expression similarly at 90% lower concentrations than that of {alpha}-TCP (e.g., 2.5 vs. 25 µmol/L, respectively). The same difference in efficiency was observed in THP-1 adhesion to HUVEC. The superior inhibitory effect of {alpha}-TCT has been linked to its 10-fold higher intracellular accumulation. Moreover, in a direct comparison of various TCT analogs, {delta}-TCT displayed the highest efficiency toward the prevention of adhesion molecule expression and monocytic cell adhesion. Changes in protein prenylation, via interference with the HMG-CoA reductase-controlled mevalonate pathway, might be responsible for the observed effects of TCTs (33).

In hypertension, another important risk factor for the development of CD, endothelium-dependent vascular relaxation is impaired. Reduction of eNOS activity and increased removal of NO in blood vessels were postulated to mediate the observed impairment of vascular relaxation. In spontaneously hypertensive rats, Newaz et al. (22) observed a significant reduction of systolic blood pressure after a 3-mo intervention with {gamma}-TCT (15 mg/kg diet). Additionally, {gamma}-TCT treatment improved eNOS activity, leading to a significant negative correlation with systolic blood pressure.

    Antiproliferative Activity of Tocotrienols. Cancer, still one of the leading causes of death, is tightly linked to the aging-process. Earlier studies showed that high dietary intake of vitamin E contributes to the suppression of tumorigenesis. Subsequently, in vitro experiments were performed to determine the antiproliferative efficiency of various vitamin E analogs and to elucidate mechanisms facilitating cell-growth inhibition. Long-term incubation with several TCTs or TCT-rich fractions in the low micromolar range inhibited growth of preneoplastic, neoplastic, and highly malignant mouse mammary epithelial cells by 50%. In contrast, treatment with 0–120 µmol/L {alpha}- and {gamma}-TCP had no effect on cell proliferation. Furthermore, TCTs were preferentially accumulated by these cells and led to higher rates of DNA fragmentation (34). A study by Sylvester et al. (35) indicated that the effects of TCTs on cell proliferation are due to an inhibitory activity in early post-epidermal growth factor (EGF) receptor events involved in cAMP production downstream from EGF-dependent mitogenic signaling, rather than a reduction in EGF-receptor mitogenic responsiveness. The authors suggested that TCTs specifically inhibit cAMP-dependent protein kinase mitogenic signaling, in particular the phosphoinositide 3-kinase/Akt pathway. Recently, Takahashi and Loo (36) showed in human breast cancer cells that incubation with {gamma}-TCT induced a significant reduction in mitochondrial membrane potential, an early step during the initiation of apoptosis. Moreover, cytochrome c was released from the mitochondria into the cytosol after {gamma}-TCT treatment. Cytochrome c contributes to the formation of the apoptosome, a complex associated with the activation of the caspase-controlled cell death pathway. Despite the observed cytochrome c release, no changes in the Bax:Bcl-2 ratio or caspase-3 activity occurred. Hence, the apoptotic effect of {gamma}-TCT contrasts with that of some other phytochemicals. A further insight in TCT-mediated anti-proliferative activity is provided in a recent review by Mo and Elson (37) who focused on HMG-CoA reductase activity, which is elevated and deregulated in tumor cells. The HMG-CoA reductase-controlled mevalonate pathway is responsible for the supply of downstream metabolites essential for the function of growth factor receptors. Despite a resistance to sterol feedback regulation, tumor cell HMG-CoA reductase remains sensitive to isoprenoid-mediated downregulation. Farnesol acts as a mevalonate-derived mediator of HMG-CoA reductase degradation. Hence, the fact that TCTs are farnesol homologs might explain their potential in preventing cell proliferation by modulating HMG-CoA reductase degradation and translation of its mRNA.

    Tocotrienols Are Neuroprotective In Vitro. Oxidative stress-induced programmed cell death, oxytosis, is one hallmark of neurodegenerative diseases. Elevated concentrations of extracellular glutamate inhibit the uptake of cystine and thus induce oxidative stress. Studies in HT4 hippocampal neuronal cells showed that activation of c-Src kinase and phosphorylation of extracellular signal-regulated kinase, both central events in glutamate-induced cell death, are blocked by nanomolar concentrations of {alpha}-TCT (38). For {alpha}-TCP, however, no such effects were found. Khanna et al. (39) further explored the underlying mechanisms of TCT-mediated neuroprotection. Lowering the levels of intracellular GSH triggers the activation of 12-lipoxygenase (12-LOX), which facilitates cell death by the production of peroxides and calcium influx. Primary cortical neurons were resistant to glutamate-induced cell death in the presence of physiologically relevant concentrations of {alpha}-TCT. Additional experiments indicated that {alpha}-TCT controls 12-LOX activity by hindering the access of arachidonic acid to the catalytic site of 12-LOX (39). Comparative studies with TCPs, however, are missing. Both studies suggest that {alpha}-TCT prevents glutamate-induced neurotoxicity by modulating the activity of important proteins involved in cell death signal transduction.

    Concluding Remarks. The antioxidant potential of TCTs has been the main focus of scientific interest in recent years. In vitro experiments repeatedly showed higher radical scavenging efficiency for TCTs compared with TCPs. However, this observation is challenged by data from recent studies. Furthermore, only a limited number of studies investigated the antioxidant effects of TCTs in vivo. Although promising, these data do not yet provide a sufficient basis for a dietary recommendation of TCTs as antioxidants with superior radical scavenging power. More and better-designed in vivo studies in animals and especially humans are warranted not only to address the question of the ROS-scavenging potential of TCTs compared with other antioxidants, but also to estimate possible synergistic or opposing interactions of TCTs with other elements of the antioxidant network. The nonantioxidant effects of TCTs address several health aspects associated with the aging process as well as aging-related disease. Here, the interference of TCTs with the mevalonate pathway is of particular interest because its inhibition subsequently leads to alleviated levels of peripheral cholesterol, inhibition of cell adhesion to endothelial cells, and suppression of tumor cell growth. The in vivo cholesterol-lowering effects of TCTs, however, remain inconclusive; we suggest that studies considering important parameters such as defined compositions of TCT supplements, patient selection, and accompanying dietary regimen will provide insight into the nature of the cholesterol-lowering potential of TCTs. Similarly, the observed antiproliferative and neuroprotective activity of TCTs in vitro must be confirmed in vivo.


   FOOTNOTES
 
1 Manuscript received 27 September 2004. Back

3 Abbreviations used: {alpha}-TTP, {alpha}-tocopherol transfer protein; CD, cardiovascular disease; EGF, epidermal growth factor; eNOS, endothelial nitric oxide synthase; GSH, glutathione; HMG-CoA, 3-hydroxy-3-methylglutaryl CoA; HUVEC, human umbilical vein endothelial cells; 12-LOX, 12-lipoxygenase; ROS, reactive oxygen species; TCP, tocopherol; TCT, tocotrienol; VCAM-1, vascular cellular adhesion molecule-1. Back


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