Radiation Damage

Biologic effects of radiation have been reviewed in detail by a number of authors, including von Sonntag (7), Pizzarello and Wit-cofski (8), Casarett (9), Okada (10), and Dertinger and Jung (11). Ionizing radiation can have three types of biological effect: perturbation of cellular regulation, mutation, or cell death. Most of the research on radiopro-tection has focused on cell death and consequences at the level of tissue injury and death of the organism. In mammals, death can result from damage to the blood-forming organs, gastrointestinal system, or central nervous system, depending on radiation dose. Hematopoietic death from bleeding, infection, or anemia is the endpoint that was used in most of the early studies on radioprotection, and follows 7-30 days after exposure to a potentially lethal single dose (—400 rads) in mice. These whole-body effects of relatively high doses of ionizing radiation are most easily explained in terms of depletion of stem cells by cell killing that in turn is most directly explained by DNA damage that occurs at the time of irradiation. However, the mechanisms of some other radi-iation effects, such as carcinogenesis, teratoid genesis, and delayed vascular injury, could include altered cellular regulation and secondary DNA damage. The full spectrum of biologically relevant mechanisms of radiation injury has not been fully elucidated. Many mechanisms of molecular damage that have been elucidated may not be relevant to biological damage. It is therefore difficult to classify radioprotectors according to mechanism. They are organized in this discussion mostly according to chemical features, although it should be kept in mind that structurally similar compounds could be acting by completely different mechanisms, and even a single compound may protect by different mechanisms depending on the model system used for the study.

Absorption of radiation energy by biological molecules has been considered to be either direct or indirect (12-14), although they both can result in the same kind of damage to a target molecule. Direct action involves absorption of radiation energy by a target molecule, such as DNA. The absorbed energy is sufficient to cause the ejection of an electron from an atom of the target molecule (hence the term ionizing radiation), leaving the target molecule with an unpaired electron: that is, converting it into a free radical. Indirect action involves the absorption of radiation energy by a molecule (such as H20) other than the target molecule, and subsequent transfer of the energy to the target molecules by reaction of radiolytically produced nontarget free radical with the target molecule. In either case, the result is a target molecule free radical. Subsequent reactions of the target molecule free radical can result in permanent chemical alteration, leading to a biological consequence. Reaction of the target molecule free radical with a hydrogen donor, such as a thiol, can restore the lost electron, thus restoring the target molecule (13). Repair usually refers to an enzymatic process, whereas the term restoration is the preferred usage to describe this type of chemical radioprotection.

Another mechanism of radioprotection is to scavenge the nontarget free radicals produced by radiation before they can react with the target molecule. The most important diffusible free radical involved in the indirect effect is the hydroxyl radical, formed by radioly-sis of water. Hydroxyl-radical scavenging can be the most effective mechanism of radiopro-tection of target molecules in dilute solution. However, radioprotection of mammalian cells by hydroxyl-radical scavenging is difficult to achieve because these highly reactive mole cules will react with cellular constituents very rapidly at the high solute concentrations that exist in cells, and a very high concentration of hydroxyl-radical scavenger is required to intercept the hydroxyl radicals before this happens (7).

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