Nitrofuran drugs as common subversive substrates of Trypanosoma cruzi lipoamide dehydrogenase and trypanothione reductase

Lipoamide dehydrogenase (LipDH), trypanothione reductase (TR), and glutathi one reductase (GR) catalyze the NAD(P)H-dependent reduction of disulfide su bstrates. TR occurs exclusively in trypanosomatids which lack a GR. Besides their physiological reactions, the flavoenzymes catalyze the single-electr on reduction of nitrofurans with the concomitant generation of superoxide a nions. Here, we report on the interaction of clinically used antimicrobial nitrofurans with LipDH and TR from Trypanosoma cruzi, the causative agent o f Chagas' disease (South American trypanosomiasis), in comparison to mammal ian LipDH and GR. The compounds were studied as inhibitors and as subversiv e substrates of the enzymes. None of the nitrofurans inhibited LipDH, altho ugh they did interfere with the disulfide reduction of TR and GR. When the compounds were studied as substrates, T. cruzi LipDH showed a high rate of nitrofuran reduction and was even more efficient than its mammalian counter part. Several derivatives were also effective subversive substrates of TR, but the respective reaction with human GR was negligible. Nifuroxazide, nif uroxime, and nifurprazine proved to be the most promising derivatives since they were redox-cycled by both T. cruzi LipDH and TR and had pronounced an tiparasitic effects in cultures of T. cruzi and Trypanosoma brucei. The res ults suggest that those nitrofuran derivatives which interact with both par asite flavoenzymes should be revisited as trypanocidal drugs. BIOCHEM PHARM ACOL 58;11:1791-1799, 1999. (C) 1999 Elsevier Science Inc.