FREE-RADICALS PRODUCED DURING THE OXIDATION OF HYDRAZINES BY HYPOCHLOROUS ACID

Hypochlorous acid (HOCl) derived from activated neutrophils and monocy tes has been implicated in the activation of hydrazine-containing drug s to toxic intermediates. However, reactive intermediates formed durin g the reaction between HOCl and these drugs have not been identified. We investigated the oxidation of the hydrazine derivatives isoniazid, iproniazid, and hydralazine by HOCl. The reaction between HOCl and all three hydrazines resulted in O-2 consumption, indicating that free ra dicals were produced, but the rate and extent of O-2 consumption were different for each hydrazine. Moreover, reduction of nitroblue tetrazo lium (NBT) was observed only during the reaction between HOCl and ison iazid, suggesting that different radical species may be produced from HOCl reaction with each hydrazine. The oxidation of iproniazid by HOCl in the presence of the radical trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) resulted in the formation of a carbon-centered radical adduct. In contrast, the reaction between HOCl and hydralazine resulted in the formation of a nitrogen-centered DMPO radical adduct. The oxidation o f isoniazid by HOCl resulted in the formation of two oxygen-centered r adical adducts, DMPO-OOH and DMPO-OH. Myeloperoxidase-catalyzed oxidat ion of these hydrazines in the presence of Cl- and H2O2 produced radic al species that were identical to those observed with HOCl. Thus, some of the toxic side effects of these drugs may be the result of the pro duction of free-radical intermediates from reaction with neutrophil-de rived oxidants, such as HOCl. The types of radicals produced and the c onsequences of generating these reactive species are discussed.