Evidence for dissimilar mechanisms of enhancement of inorganic and organic hydroperoxide cytotoxicity by L-histidine

L-Histidine markedly increases inorganic and organic hydroperoxide- induced cytotoxicity and DNA single-strand breaks (SSBs) in Chinese hamster ovary cells. These effects were prevented by the iron chelator o- phenanthroline and were insensitive to the antioxidant N,N'-diphenyl-1,4- phenylenediamine. An excess of L-glutamine, a competitive inhibitor of L- histidine uptake, prevented the L-histidine-mediated enhancement of cytotoxicity induced by both inorganic and organic peroxides. L-Glutamine did not affect the level of DNA SSBs produced by H₂O₂/L-histidine, although it abolished the enhancement of SSB formation triggered by L-histidine in cells exposed to the organic peroxides. DNA SSBs generated by the organic hydroperoxides either alone or associated with L-histidine were removed with superimposable kinetics, whereas those produced by H₂O₂ in the presence of the amino acid were repaired more slowly than SSBs produced by the oxidant alone. DNA double-strand breaks, which are considered to be highly cytotoxic, were detected only in cells treated with H₂O₂ and L-histidine. Finally, L- histidine was shown to markedly increase the extent of mitochondrial damage produced by organic but not by inorganic hydroperoxides.