title: Nifurtimox nitroreductase activity in different cellular fractions from male rat pancreas. Biochemical and ultrastructural alterations.
abstract: Nifurtimox (Nfx) is a nitroheterocyclic drug used in the treatment of Chagas' disease. It has serious side effects which frequently force to interrupt the treatment. Nfx toxicity has been linked to its nitroreduction to a nitroanion radical with a subsequent redox cycling which generate reactive oxygen species. We analyzed the ability of Sprague Dawley male rat pancreas to nitroreduce Nfx and whether this drug may cause deleterious effects in this organ. The microsomal fraction exhibited Nfx nitroreductase activity in the presence of NADPH under anaerobic atmosphere, which was fully inhibited under air but not altered when N2 was replaced by pure CO. The cytosol nitroreduced Nfx in the presence of hypoxanthine under N2; it was inhibited by allopurinol and negligible in aerobiosis. Nfx reached pancreatic tissue at 1, 3 or 6 h after intragastric administration (100 mg/kg). Six hours after drug administration, a significant increase in t-buthylhydroperoxide promoted chemiluminiscence was detected. Pancreatic protein sulfhydryl content significantly decreased at either 1, 3 or 6 h after Nfx administration. No changes in either protein carbonyl or in lipid hydroperoxides were observable. Ultrastructural alterations were observed in the endoplasmic reticulum and nuclei from acinar cells and in the insulin-containing granules from the pancreas. However, the seric amylase levels were not changed, but the blood glucose levels were slightly but significantly increased 24 h after Nfx administration. These studies might suggest that Nfx treatment could impose an increased risk to patients exposed to other insults provoking oxidative stress or having preexisting pathologies in the pancreas.
authors.affiliation: Centro de Investigaciones Toxicológicas (CEITOX-CITEFA/CONICET), J B de La Salle 4397 (B1603ALO) Villa Martelli, Buenos Aires, Argentina.
authors.forename: María Montalto
authors.initials: MM
authors.lastname: de Mecca
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Fanelli
authors.forename: Laura C
authors.initials: LC
authors.lastname: Bartel
authors.forename: Carmen R
authors.initials: CR
authors.lastname: de Castro
authors.forename: Edith G
authors.initials: EG
authors.lastname: Díaz
authors.forename: José A
authors.initials: JA
authors.lastname: Castro
mesh_terms: D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D049449:Luminescence; D008297:Male; D046529:Microscopy, Electron, Transmission; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D009547:Nifurtimox / Q000378:metabolism; D009601:Nitroreductases / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology* / Q000201:enzymology* / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D020122:tert-Butylhydroperoxide / Q000378:metabolism
chemical_list: D013438:Sulfhydryl Compounds; D013481:Superoxides; D020122:tert-Butylhydroperoxide; C029492:aromatic NADH-dependent nitroreductase; D009601:Nitroreductases; D009547:Nifurtimox