Early Nifurtimox-induced biochemical and ultrastructural alterations in rat heart.

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

HUMAN EXP. TOXICOL.

SAGE Publications

Lugar: Londres; Año: 2007 vol. 26 p. 781 - 788

0960-3271

Nifurtimox (Nfx) and Benznidazole (Bz) are being used for the treatment of the acute phase of Chagas disease.Recently, they were also considered for use in the indeterminate phase. Both the nitroheterocyclic drugs haveserious toxic side effects. The mechanism of Nfx toxicity is associated with the formation of reactive oxygenspecies (ROS) generated during nitroreduction. Potential effects on cardiac function have not been established yet,despite the well-known cardiopathy often produced by the disease itself. We describe experiments  testing some acute effects of Nfx on the male Sprague Dawley rat heart. Nifurtimox was present in the heart at 1, 3 and 6 h after intragastric (i.g) treatment. In vitro studies on Nfx microsomal and cytosolic nitroreductase activities showed that only the microsomal fraction had the ability to nitroreduce it. Cytochrome P450 and cytochrome P450 reductase would be involved in the process as suggested by their response to specific inhibitors. Nifurtimox increased the cardiac protein carbonyl content at 1 and 3 h and decreased the protein sulfhydryl content at 3 h. In addition, 24 h after treatment ultrastructural alterations such as marked cytoplasmic vacuolization, separation and loss of myofibrils and mitochondrial swelling were observed. Results suggest that Nfx administration might aggravate pre-existing adverse cardiac conditions. Human &  Experimental Toxicology (2007) 26, 781-788.