Different behaviors of benznidazole as free radical generator with mammalian and Trypanosoma cruzi microsomal preparations

Abstract Benznidazole (a nitroimidazole derivative used for the treatment of Chagas' disease) is reduced by rat liver microsomes to the nitro anion radical, as indicated by ESR spectroscopy. Addition of benznidazole to rat liver microsomes produced an increase of electron flow from NADPH to molecular oxygen, and generation of both superoxide anion and hydrogen peroxide. The benznidazole-stimulated O 2 consumption and O 2 ⨪ formation was greatly inhibited by NADP + and p -chloromercuribenzoate but not by SKF-525-A and metyrapone. The former inhibitions indicated the involvement of NADPH-cytochrome P -450 ( c ) reductase, while the lack of inhibition by SKF-525-A and metyrapone ruled out any major role for cytochrome P -450 in benznidazole reduction. In contrast to nifurtimox, a nitrofuran derivative ( R. Docampo and A. O. M. Stoppani, 1979 , Arch. Biochem. Biophys. 197 , 317–321), benznidazole was not reduced to the nitro anion radical, nor did it stimulate oxygen consumption, O 2 ⨪ production, and H 2 O 2 generation by Trypanosoma cruzi cells or microsomal fractions. A different mechanism of benznidazole toxicity in T. cruzi and the mammalian host is postulated.