ABSTRACT
Tocotrienols (T3) are vitamin E forms with an isoprenyl side chain that are characterized by poor bioavailability and sustained metabolism, which may explain the very low tissue levels as well as the poor vitamin activity as assessed by the fetal resorption test. However, when used as supplements or tested in vitro, these forms show distinctive biological activities that are consistent with a series of health-promoting effects such as cholesterol-lowering, cytoprotection, and anticarcinogenic effects (reviewed in Aggarwal et al. [2010]). In vitro and in vivo experiments have demonstrated that these properties are dependent on speci•c signaling and metabolism (recently reviewed in Viola et al. [2012]) that clearly differentiate these vitamers from the most abundant forms of vitamin E in human tissues and body ›uids, i.e., α-and γ-tocopherol (TOH). Obviously, these differences go far beyond the well-recognized antioxidant role that these vitamers may play in cell membranes and biological ›uids
9.1 Introduction .......................................................................................................................... 117 9.2Cell Targets and Signaling of HMT3................................................................................... 118
9.2.1Antioxidant and Redox-Derived Effects................................................................... 118 9.2.2Cell Signaling and Transcriptional Response........................................................... 121
9.3Metabolism and Transformation: The Detoxi•cation Response to T3................................ 122 9.3.1 T3 Side-Chain Degradation and Chroman Metabolite Formation ........................... 122 9.3.2DME Response to T3................................................................................................ 122
9.4Metabolism or Bioactivation Process?.................................................................................. 123 9.5Anticancer Mechanism of HMT3: When More Toxic Means More Effective....................124 9.6δ-T3: The Most Potent Anticancer Form of Vitamin E in HER-2/neu-Positive Breast
Adenocarcinoma ................................................................................................................... 126 9.7Cell Uptake: A Critical Aspect of the Anticancer Activity of HMT3.................................. 127 9.8In Vitro and In Vivo Studies on Toxicity and Therapeutic Window of T3........................... 127 9.9Conclusion and Further Perspectives.................................................................................... 129 Acknowledgments.......................................................................................................................... 130 References ...................................................................................................................................... 130
(Galli and Azzi 2010) and may suggest a revision of vitamin E de•nition to consider T3 as a distinct group of micronutrient vitamins within this family of compounds.
