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Reactions of nifurtimox with critical sulfhydryl‐containing biomolecules: their potential toxicological relevance
Author(s) -
Díaz E. G.,
Montalto de Mecca M.,
Castro J. A.
Publication year - 2004
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.970
Subject(s) - nifurtimox , chemistry , glutathione , nitrosation , chagas disease , biochemistry , pharmacology , enzyme , trypanosoma cruzi , medicine , parasite hosting , world wide web , computer science , immunology
Nifurtimox (Nfx) is a drug used in the treatment of Chagas' disease, an endemic parasitic disease from Latin American countries. It produces undesirable side‐effects in patients, frequently forcing the treatment to be stopped. Its toxic mechanism is not fully understood. In this work we describe purely chemical reactions of Nfx with relevant cellular sulfhydryl (SH) compounds. The compounds tested were glutathione (GSH), cysteine (RSH), lipoic acid (LA) and coenzyme A (CoA). All reacted with Nfx to give nitrite (NO − 2 ). The relative reaction rates were CoA>LA>GSH>RSH. In studies with GSH and RSH the formation of nitrite was accompanied by decreases in Nfx concentration and increases in the formation of a reaction product revealed by HPLC. We failed to show the presence of liver cytosolic GST (GSH transferase activity)‐mediated formation of NO2‐ from Nfx. These NO − 2 ‐releasing processes occurred under in vivo conditions in Nfx‐treated Sprague‐Dawley male rats (240–260 g body weight) at a dose of 100 mg Nfx kg −1 p.o. In urine samples NO − 2 excretion was accompanied by unchanged drug and two unidentied more polar metabolites detectable by HPLC. The Nfx reactions with critical SH from molecules such as GSH, RSH, LA and CoA, and potentially others containing SH residues (e.g. enzymes or structural proteins), might have toxicological relevance not only for the Nfx side‐effects but also for the chemotherapeutic effects on Trypanosoma cruzi . In addition, Nfx reactions with GSH might be crucial in Nfx detoxication. Copyright © 2004 John Wiley & Sons, Ltd.