Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

摘要: Benznidazole, a 2-nitroimidazole, is the front-line treatment used against American trypanosomiasis, parasitic infection caused by Trypanosoma cruzi. Despite nearly 40 years of use, trypanocidal activity this prodrug not fully understood. It has been proposed that benznidazole activation leads to formation reductive metabolites can cause series deleterious effects, including DNA damage and thiol depletion. Here, we show key step in involves an NADH-dependent trypanosomal type I nitroreductase. This catalyzes oxygen-insensitive reaction with interaction enzyme, reductant, occurring through ping-pong mechanism. Liquid chromatography/mass spectrometry (LC/MS) analysis resultant identified 4,5-dihydro-4,5-dihydroxyimidazole as major product pathway proceeding hydroxylamine hydroxy intermediates. The breakdown released reactive dialdehyde glyoxal, which, presence guanosine, generated guanosine-glyoxal adducts. These experiments indicate reduction nitroreductase highly expression enzyme properties displayed prodrug.