Early nifurtimox-induced biochemical and ultrastructural alterations in rat heart

Abstract

<jats:p> 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 have serious toxic side effects. The mechanism of Nfx toxicity is associated with the formation of reactive oxygen species (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 &amp; Experimental Toxicology (2007) 26, 781 — 788 </jats:p>

Benznidazole biotransformation in rat heart microsomal fraction without observable ultrastructural alterations: comparison to Nifurtimox-induced cardiac effects

“…However, the intensity of this Bz nitroreductive process was 7-fold smaller than that observed in the case of Nfx (Bartel et al 2007). A fraction of that low activity could be attributed to the participation of reduced P450 itself, as suggested by the tendency of inhibition (statistically non-significant) by CO and SKF 525-A.…”

“…This is because the Bz nitroreduction process is not accompanied by redox cycling when oxygen is present, in contrast to what happens in the case of Nfx (Docampo & Moreno 1985). The far lower intensity of Bz nitroreduction as compared to that of Nfx and the markedly intense effect of oxygen might reasonably explain why, unlike Nfx, Bz does not lead to ultrastructurally visible deleterious effects (e.g., cytoplasm vacuolization, separation and loss of myofibrils, mitochondrial swelling) (Bartel et al 2007). This oxygen inhibitory effect might be of special relevance in the case of very highly oxygenated organs such as the heart.…”

“…Known inhibitors of CYP and flavoenzymes such as carbon monoxide (CO), alphaphenyl-alpha-propylbenzeneacetic acid, 2-(diethylamino) ethyl ester (SKF 525-A) and diphenyleneiodonium chloride (DPI) were also used. Nitroreductase activity was followed spectrophotometrically at 320 nm by substrate decreases that were linear with time and protein content under the experimental conditions employed (Bartel et al 2007). Protein concentration was determined with Folin-Ciocalteu reagent (Lowry et al 1951).…”

“…The present work describes the results of experiments in which potential effects of Bz in the rat heart were measured under experimental conditions equivalent to those reported for Nfx (Bartel et al 2007). …”

“…Recent studies from our laboratory showed that Nfx induced biochemical and ultrastructural alterations in rat heart tissue (Bartel et al 2007). These findings might be particularly relevant, given that cardiac manifestations of the disease have critical implications for treated patients.…”