Free radicals produced during the oxidation of hydrazines by hypochlorous acid.
Hypochlorous acid (HOCl) derived from activated neutrophils and monocytes has been implicated in the activation of hydrazine-containing drugs to toxic intermediates. However, reactive intermediates formed during 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 O2 consumption, indicating that free radicals were produced, but the rate and extent of O2 consumption were different for each hydrazine. Moreover, reduction of nitroblue tetrazolium (NBT) was observed only during the reaction between HOCl and isoniazid, 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 of isoniazid by HOCl resulted in the formation of two oxygen-centered radical adducts, DMPO-OOH and DMPO-OH. Myeloperoxidase-catalyzed oxidation of these hydrazines in the presence of Cl- and H2O2 produced radical 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 production of free-radical intermediates from reaction with neutrophil-derived oxidants, such as HOCl. The types of radicals produced and the consequences of generating these reactive species are discussed.
Goodwin
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Biotechnology Center, Utah State University, Logan 84322-4700, USA.
Aust
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Grover
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TA
D004578:Electron Spin Resonance Spectroscopy; D005609:Free Radicals / Q000737:chemistry*; D006834:Hydrazines / Q000737:chemistry*; D006997:Hypochlorous Acid / Q000737:chemistry*; D007202:Indicators and Reagents / Q000737:chemistry; D007538:Isoniazid / Q000737:chemistry; D009580:Nitroblue Tetrazolium / Q000737:chemistry; D016877:Oxidants / Q000737:chemistry; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D017382:Reactive Oxygen Species; D019097:Spin Trapping
D005609:Free Radicals; D006834:Hydrazines; D007202:Indicators and Reagents; D016877:Oxidants; D017382:Reactive Oxygen Species; D009580:Nitroblue Tetrazolium; D006997:Hypochlorous Acid; D007538:Isoniazid