Vitamin E Analogs as Radiation Response Modifiers

Abstract

The potentially life-threatening effects of total body ionizing radiation exposure have been known for more than a century. Despite considerable advances in our understanding of the effects of radiation over the past six decades, efforts to identify effective radiation countermeasures for use in case of a radiological/nuclear emergency have been largely unsuccessful. Vitamin E is known to have antioxidant properties capable of scavenging free radicals, which have critical roles in radiation injuries. Tocopherols and tocotrienols, vitamin E analogs together known as tocols, have shown promise as radioprotectors. Although the pivotal mechanisms of action of tocols have long been thought to be their antioxidant properties and free radical scavenging activities, other alternative mechanisms have been proposed to drive their activity as radioprotectors. Here we provide a brief overview of the effects of ionizing radiation, the mechanistic mediators of radiation-induced damage, and the need for radiation countermeasures. We further outline the role for, efficacy of, and mechanisms of action of tocols as radioprotectors, and we compare and contrast their efficacy and mode of action with that of another well-studied chemical radioprotector, amifostine.

Figure 1

Chemical structures of tocols and their derivatives.

Figure 2

Comparison of tocols and their derivatives with amifostine: (a) comparison of optimum dose, (b) significant protection at highest radiation dose, (c) effective time window for protection and mitigation, and (d) dose-reduction factor for protection and mitigation. Alpha-tocopherol (AT), delta-tocotrienol (DT3), gamma-tocotrienol (GT3), gamma-tocopherol-N,N-dimethylglycine ester (GTDMG), alpha-tocopherol-monoglucoside (TMG), alpha-tocopherol succinate (TS), and amifostine (WR).