Dimethyl sulfoxide prevents DNA nicking mediated by ionizing radiation or iron/hydrogen peroxide-generated hydroxyl radical.

Abstract

Eighty percent of the single-strand DNA breaks induced by y-irradiation were prevented by the hydroxyl radical (-OH) scavenger dimethyl sulfoxide (Me2SO); CH4 was generated in the process as a product of the interaction of -OH and Me2SO. In contrast, Me SO completely blocked DNA nicking by an iron/ H202 system which produces -OH but smaller amounts of CH4 from Me2SO. Because Me2SO prevented DNA breaks from the more efficient iron/H202 system but only blocked 80% of irradiation-mediated nicking, the results sugest that -OH is responsible for 80% ofthe DNA single-strand breaks and the remaining 20% is due to interactions not involving OH.vents the formation of 80% of the single-strand breaks in DNA introduced by ionizing radiation in the presence of oxygen. During both of these processes, CH4, a product of the interaction of OH and Me2SO (8,10), is generated. The results indicate that at least 80% ofsingle-strand breaks introduced in DNA by ionizing radiation are due to an indirect effect and that 80% ofbreaks are probably generated by -OH; 20% ofbreaks are due to some process other than -OH, but our results do not indicate whether this process is direct or indirect.Lethal damage to cells exposed to ionizing radiation has been attributed mostly to effects on the structure of cellular DNA. For this reason the radiochemistry of DNA and its component parts has been studied extensively in the past 3 decades (for reviews, see refs. 1 and 2). Damage to DNA from ionizing radiation might occur directly ifenergy were transferred, without intermediates, to ionize or to excite components of the DNA. Damage might also develop indirectly if irradiation of water generated toxic products which then reacted with the DNA. One recent analysis ofthese processes based on theoretical considerations concluded that both direct and indirect damage to DNA occurs and that about 45% ofthe damaged nucleotides are derived from the direct interaction (3). This is important because radioprotective agents, which are believed to act by scavenging the toxic products such as -OH and other free radicals, are likely to interfere only with the indirect processes. Experiments with many such agents have found that about 70% of the single-strand breaks introduced into DNA by ionizing radiation can be eliminated, suggesting that only 30% of the breaks result from direct action of radiation of the DNA (4, 5). In these studies the frequency ofradiation-induced strand breaks was estimated from the sedimentation rate of damaged DNA on alkaline sucrose gradients. It is known that alkali-labile lesions in irradiated DNA can be converted into interruptions in the DNA phosphodiester backbone (6, 7). Measurements in alkali therefore overestimate the number ofbreaks. We have reinvestigated this question using procedures that assess the direct formation ofsingle-strand breaks more accurately. We also have studied in detail the radioprotective effect ofthe -OH scavenger dimethyl sulfoxide (Me2SO) (8-11). Animals (12) or cells (13) irradiated in the presence ...

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