DNA strand breaks in human leukocytes induced by superoxide anion, hydrogen peroxide and tumor promoters are repaired slowly compared to breaks induced by ionizing radiation.
The repair kinetics and sensitivity to inhibitors of DNA strand breaks caused by superoxide anion, hydrogen peroxide, benzoyl peroxide and anthralin have been studied and compared with strand breaks caused by well-studied agents such as ionizing radiation and bleomycin. The latter two agents are generally believed to produce breaks indirectly by producing hydroxyl radicals, a very potent oxidizing species, which attack the phosphodiester backbone of DNA. As expected from earlier results, breaks induced by radiation and bleomycin rapidly disappear during post-treatment incubation as a consequence of the action of cellular DNA repair enzymes. Thus, strand breaks produced by hydroxyl radicals appear to be readily repaired in human leukocytes. By contrast, breaks caused by extracellular superoxide anion appeared not to be readily repaired, implying that some mechanism other than the generation of hydroxyl radicals in the vicinity of the DNA was involved. Inhibitors such as 3-aminobenzamide, cytosine arabinoside and adenine arabinoside affected the apparent rate of repair of radiation and methylmethane sulfonate-induced breaks but there was no indication that they affected superoxide anion-induced breaks. They partially inhibited repair of hydrogen peroxide-induced breaks. Breaks caused by benzoyl peroxide and anthralin were also apparently not repaired. We conclude that hydroxyl radicals are not likely the ultimate DNA strand-breaking species in cells exposed to extracellular superoxide anion and that the observed slow repair of DNA strand breaks may be significant in the mechanism of action of tumor-promoting agents.
D001549:Benzamides / Q000494:pharmacology; D000001:Calcimycin / Q000494:pharmacology; D004247:DNA / Q000528:radiation effects*; D004260:DNA Repair / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D006878:Hydroxides; D017665:Hydroxyl Radical; D009504:Neutrophils / Q000378:metabolism*; D010704:Phorbols; D013481:Superoxides / Q000633:toxicity*; D013755:Tetradecanoylphorbol Acetate
D001549:Benzamides; D006878:Hydroxides; D010704:Phorbols; D013481:Superoxides; D017665:Hydroxyl Radical; D000001:Calcimycin; C025160:3-aminobenzamide; D004247:DNA; D006861:Hydrogen Peroxide; D013755:Tetradecanoylphorbol Acetate