The respiratory-chain poison antimycin A promotes the formation of DNA single-strand breaks and reduces toxicity in U937 cells exposed to t-butylhydroperoxide

Abstract

Antimycin A at levels that abolish oxygen consumption had a slight, although statistically significant, inhibitory effect on the toxicity elicited by t-butylhydroperoxide in U937 cells. The protective effect was observed after 6 h of post-treatment incubation, but was no longer apparent after 24 h. Unexpectedly, these events were associated with a marked accumulation of DNA single-strand breaks produced by low levels of t-butylhydroperoxide. Both an oxygen- and a carbon-centred radical were found to arise during treatment with t-butylhydroperoxide, and their formation was significantly lowered by antimycin A. Thus inhibition of electron transport at the level of complex III appears (a) to decrease the formation of toxic species which mediate, at least partially, the lethal effects elicited by t-butylhydroperoxide, and (b) to enhance the formation of DNA-damaging species generated at low concentrations of t-butylhydroperoxide. Rotenone and cyanide, which respectively inhibit complexes I and IV, did not affect DNA damage elicited by t-butylhydroperoxide. These results suggest that DNA single-strand breaks do not mediate the toxicity of t-butylhydroperoxide, and that specific mitochondrial functions might modulate the formation of toxic and of DNA-damaging species generated by organic hydroperoxides.