Nifurtimox nitroreductase activity in different cellular fractions from male rat pancreas. Biochemical and ultraestructural alterations

RODRIGUEZ DE CASTRO C,; MONTALTO DE MECCA M; FANELLI SL; BARTEL LC,; DÍAZ EG,; CASTRO JA

Palais des Congrès de Montréal, Montréal.

Congreso; Eleventh International Congress of Toxicology (IUTOX) ICTXI; 2007

International Union of Toxicology

Nifurtimox (Nfx) is a drug used in the treatment of Chagas´ disease. Nfx toxicity has been linked to its reduction to a nitroanion radical with a subsequent redox cycling which generate ROS. We analyzed the ability of Sprague Dawley male rat pancreas to nitroreduce Nfx and whether this may cause deleterious effects in this organ. 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 administration (100 mg/kg p.o.). Six hours after administration, a significant increase in t-buthylhydroperoxide promoted chemiluminiscence was detected. Protein sulfhydryl content significantly decreased at either 1, 3 or 6 h after Nfx. No changes in either protein carbonyl or in lipid hydroperoxides were observed. Ultrastructural alterations were observed in the endoplasmic reticulum and nuclei from acinar cells and in the insulin-containing granules. However, the serum amylase levels were not changed, but the blood glucose levels were slightly but significantly increased 24 hours after Nfx. Nfx treatment could impose an increased risk to patients exposed to oxidative stress or having pathologies in the pancreas. Supported by SECyT (PICT 38235) and UNSAM (SP06/090).