PEROXIDASE SUBSTRATES STIMULATE THE OXIDATION OF HYDRALAZINE TO METABOLITES WHICH CAUSE SINGLE-STRAND BREAKS IN DNA

Hydrazines are believed to be oxidized by peroxidases to reactive inte rmediates responsible for a variety of adverse side effects including cancer and drug-induced lupus. However, hydrazines are regarded as a p oor peroxidase substrates because inactivation of the peroxidase occur s during oxidation of these compounds. We have investigated the hypoth esis that efficient peroxidase substrates, termed mediators, may stimu late peroxidase-catalyzed oxidation of hyrazines to intermediates capa ble of causing DNA damage. Oxidation of hydralazine by horseradish per oxidase was stimulated, enzyme inactivation was significantly decrease d, and DNA strand breakage was enhanced by the addition of chlorpromaz ine. Similar results were obtained using other peroxidases, mediators, and hydrazine derivatives. DNA damage required the addition of a mini mum of 3 equiv of hydrogen peroxide, suggesting the involvement of a t hree-electron oxidation product of hydralazine in DNA damage. Efficien t substrates may therefore play a critical role in peroxidase-dependen t oxidative metabolism and subsequent damage to biological macromolecu les by certain chemicals.