Mechanism of nifurtimox toxicity in different forms of Trypanosoma cruzi

Addition of nifurtimox (a nitrofuran derivative) to NAD(P)H-containing homogenates of Trypanosoma cruzi (epi-, trypo- or amastigote forms) determined the appearance of an e.p.r. spectrum that could be identified as corresponding to the nitroaromatic anion radical. The anion radical signal was observed after an induction period that depended on the oxygen concentration and the pyridine nucleotide in the incubation medium. Incubation of intact T. cruzi forms with nifurtimox also led to the appearance of the anion radical signal. The nitroaromatic anion radical, which is assumed to be the first product of nitroreductase activity, reacted with oxygen under aerobic conditions, as shown by the increased rate of superoxide anion and hydrogen peroxide production after addition of nifurtimox to homogenates of T. cruzi in the presence of NAD(P)H. The nifurtimox-induced peroxide production was higher with T. cruzi amastigotes than with epi- or trypomastigotes.