The role of DNA damage in the cytotoxic response to hydrogen peroxide/histidine.

1. Histidine enhances the cytotoxic and clastogenic effects of hydrogen peroxide. In this review, we will focus on two lesions that are generated in the presence of histidine in oxidatively injured cells--namely, DNA single- and double-strand breaks (SSBs and DSBs). 2. Hydrogen peroxide is a potent inducer of DNA SSBs, and histidine modulates the formation of these lesions. This effect has been extensively characterized with the use of purified DNA, and the results obtained have demonstrated that, upon exposure to low or high concentrations of H2O2, histidine reduces or enhances the formation of DNA SSBs, respectively. The protective effect has been ascribed to iron chelation, whereas the enhancing effect is probably the consequence of the formation of a histidine/iron/DNA complex. 3. In cultured cells, histidine potentiates the formation of H2O2-induced DNA SSBs but these lesions are efficiently repaired and do not appear to mediate the cytotoxic response. 4. In the presence of micromolar levels of histidine, H2O2 also induces DNA DSBs, a type of lesion that is not generated by the oxidant alone. The experimental evidence that has been thus far collected would suggest that these DNA DSBs are toxic and are indeed the cause of cell death induced by the cocktail H2O2/histidine.