Adenylate cyclase activation by GTP analogs |
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| Authors: | J F Krall S G Korenman |
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| Affiliation: | 1. Centro de Investigaciones Bioenergéticas, Consejo Nacional de Investigaciones Científicas y Técnicas, Instituto de Química Biológica, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 1121 Buenos Aires, Argentina;1. National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709 U.S.A.;2. Instituto de Microbiología, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil |
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| 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 O2 consumption and O2? 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, O2? production, and H2O2 generation by Trypanosoma cruzi cells or microsomal fractions. A different mechanism of benznidazole toxicity in T. cruzi and the mammalian host is postulated. |
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| Keywords: | To whom all correspondence should be addressed. |
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