title: Rat liver nuclear nifurtimox nitroreductase activity.
abstract: Nifurtimox (Nfx) 4-[(5-nitrofurfurylidine)amino-3-methylthiomorpholine-1-1-di oxide] is a drug that is being used to treat American Trypanosomiasis (Chagas' disease). Nfx has serious toxic effects including mutagenic, reproductive and carcinogenic actions. Its toxicity has been linked to NADPH dependent nitroreductive metabolic biotransformation with production of oxygen reactive species. In this study is reported that rat liver nuclei exhibit Nfx-nitroreductase activity (Nfx-ase). This activity is null under oxygen and partially inhibited under CO. Nfx does not promote a lipid peroxidation process. Results suggest that Nfx is biotransformed partially at a cytochrome P450 level but mostly by NADPH P450 reductase. Formation of reactive metabolites nearby DNA and nuclear proteins might be related to long term deleterious effects of this drug.
authors.affiliation: Centro de Investigaciones Toxicológicas (CEITOX)-CITEFA/CONICET, Pcia. de Buenos Aires, Argentina.
authors.forename: E G
authors.initials: EG
authors.lastname: de Toranzo
authors.forename: D M
authors.initials: DM
authors.lastname: Herrera
authors.forename: J A
authors.initials: JA
authors.lastname: Castro
mesh_terms: D000818:Animals; D001711:Biotransformation; D002248:Carbon Monoxide; D002467:Cell Nucleus / Q000201:enzymology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008297:Male; D009249:NADP / Q000494:pharmacology; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D009547:Nifurtimox / Q000493:pharmacokinetics / Q000494:pharmacology*; D009601:Nitroreductases / Q000378:metabolism*; D010100:Oxygen; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species
chemical_list: D017382:Reactive Oxygen Species; D009249:NADP; D002248:Carbon Monoxide; D003577:Cytochrome P-450 Enzyme System; C029492:aromatic NADH-dependent nitroreductase; D009251:NADPH-Ferrihemoprotein Reductase; D009601:Nitroreductases; D009547:Nifurtimox; D010100:Oxygen