Present trends in vitamin E research

Abstract

Abstract.Nearly after one century of research and thousands of publications, the physiological function(s) of vitamin E remain unclear. Available evidence suggests a role in cell homeostasis that occurs through the modulation of specific signaling pathways and genes involved in proliferative, metabolic, inflammatory, and antioxidant pathways. Vitamin E presence in the human body is under close metabolic control so that only a-tocopherol and, to a lower extent, c-tocopherol are retained and delivered to tissues. Other vitamin E forms that are not retained in the body in significant amounts, exhibit responses in vitro that are different form those of a-tocopherol and may include tumor cell specific toxicity and apoptosis. These responses provide a therapeutic potential for these minor forms, either as such or metabolically modified, to produce bioactive metabolites. These cellular effects go beyond the properties of lipophilic antioxidant attributed to a-tocopherol particularly investigated for its alleged protective role in atherosclerosis or other oxidative stress conditions. Understanding signaling and gene expression effects of vitamin E could help assign a physiological role to this vitamin, which will be discussed in this review. Besides vitamin E signaling, attention will be given to tocotrienols as one of the emerging topics in vitamin E research and a critical re-examination of the most recent clinical trials will be provided together with the potential use of vitamin E in disease prevention and therapy.

Why tocotrienols work better: insights into the in vitro anti-cancer mechanism of vitamin E

“…As described in the previous section, the activity of d-T3 observed in this in vitro experimental model system, can be partially explained by a high uptake rate that rapidly brings the cell content of this vitamer to the levels required to produce its anti-cancer activity. However, experimental evidence clearly suggests the existence of a marked cell and disease-related specificity for T3 effects that suggests other and more complex mechanisms than a simple increase in the uptake rate, and this appear to be true also for the other forms of vitamin E [reviewed in (Galli and Azzi 2010)]. Intrinsic characteristics of cancer cells may sustain the therapeutic potential and specificity of action of T3.…”

“…Upstream elements in this signaling include PKC and the survival pathway ERK-MAPK that is known to influence the mitochondrial signaling in response to foreign stimuli and endobiotics such as hormones and redox-active metabolites [recently reviewed in (Luchetti et al 2010)]. PKC was the former component in the cell signaling that was identified to be controlled by vitamin E (Galli and Azzi 2010) and is the earliest kinase that responds in a concentration and time-dependent manner to vitamin E leading to signal transduction from the plasmalemma to downstream elements. Membrane translocation and activity of PKC are directly influenced by chromanols (Varga et al 2008), which may provide a mechanism to explain the close correlation between kinetics profiles of anti-proliferative signaling and uptake rate (i.e., relative concentration within the lipid bilayer) of vitamin E molecules (Betti et al 2006).…”

“…As far as toxicity and adverse reactions concern, oral vitamin E is considered to have very low toxicity in healthy humans (Hathcock et al 2005;Galli and Azzi 2010); 1,000 mg/day is the upper safe limit and 17 mg/kg bw/day, assuming a 60 kg person, is the tolerable upper intake level of a-TOH for adults as proposed by the Food and Nutrition Board, Institute of Medicine (Food and Nutrition Board 2000). Although systematic investigation has not been performed, clinical studies on oral supplements and food rich in T3 are consistent with absence of toxicity in humans.…”

“…The unsaturated chain characteristic of all the T3 forms confers well-defined physical and chemical characteristics that appear to include vitamer-specific interactions with other lipids and cell proteins (Atkinson et al 2008). The HM ring, other than bringing the hydroxyl group in position 6, i.e., the antioxidant moiety common to all the tocol derivatives, is responsible of signaling effects that differentiate these vitamers from the other vitamin E forms (Galli and Azzi 2010). The former and more characterized consequence of the combination of the hypomethylated chroman ring with the isoprenyl moiety is that of producing a well-defined response of bioavailability and transformation.…”

“…Specificity of action and health-promoting properties of T3, however, involve other and so far poorly understood players (Galli and Azzi 2010). These may include a-TTPlike and/or low affinity binding proteins and other proteinlipid and lipid-lipid interactions in cell membranes and in the cytosol (Atkinson et al 2008), as well as intracellular receptors such as ERb (Comitato et al 2009), and orphan receptors such as SXR (Zhou et al 2004) and PXR (Brigelius-Flohe 2005).…”