The radioprotective effects of antioxidants and the mechanisms by which these effects are mediated depend on the properties of both the antioxidant and the compartment (e.g., cellular or tissue targets) where the radioprotective effects are measured. There is a large volume of data on the radioprotective effects of antioxidants at the cellular level, especially at the level of nuclear DNA, where the radical scavenging by the antioxidant protects this and other sensitive cellular targets. Many antioxidants have been shown to also protect the cell by acting to increase cellular antioxidant capacity through their ability to elevate the levels of natural antioxidants (e.g., GSH) and antioxidant enzymes (e.g., GPx, GRd and MnSOD). Interestingly, exposure to chronic, low-dose-rate ionizing radiation can also lead to the induction of antioxidant enzymes. For example, exposure of mice to a 0.5 Gy at a dose rate of 1.2 mGy/h for 23 days increased the gene expression of catalase and MnSOD by a factor of 2.5.65
However, at higher doses of 1.0 and 1.3 Gy accumulated at the same dose rate, gene expression either increased by only approximately 1.4 or was not significantly different from unirradiated controls, respectively. Therefore, care is needed in low-dose-rate studies in discerning to what extent various agents, like antioxidants, have on modifying the levels of antioxidant enzymes. Even so, based on what is currently known, specific chemical and/or physical properties of antioxidants can be designed to take advantage of biochemical properties or a specific cellular target. In addition, there are a number of in vitro
and in vivo
studies that show increased radioresistance in normal tissues when antioxidants are given in combination compared with antioxidants given individually.30, 31
There are a number of hypotheses that have been suggested to explain the enhanced radioprotective effect of combined antioxidant treatments related to the regulation and response to ROS, including the regeneration of vitamin E and other antioxidants by vitamin C, induction of cellular antioxidant systems, and interaction with inflammatory mediators.
The impact of radiation on the mitochondrial DNA and thus long-term reproductive health of the mitochondria, reproduction of the cell, and on cellular redox and energy state has not been studied in detail. The long-term consequences of radiation may be very dependent on this mechanism of radiation toxicity and may be greatly alleviated by properly designed antioxidants.
Regarding what is known about the radioprotective effects of antioxidants on late radiation effects in tissues, especially for non-protein antioxidants, there is only a limited understanding of these effects at a mechanistic level. Therefore, additional studies are needed of current and new antioxidant compounds to look at these and other radioprotective effects in antioxidants in irradiated cells and tissues to support rational approaches in the design of antioxidants as radioprotectors.