Alterations of mitochondria in liver but not in heart homogenates after treatment of rats with benznidazole

Abstract

<jats:p> The mitochondrial oxidative phosphorylation system was studied in liver and heart homogenates after treatment of rats with benznidazole. The drug was given by oral gavage to adult female Wistar rats for 9 consecutive days (100 mg benznidazole/kg body weight as a daily dose). The mitochondrial state 4 and state 3 respiration rates, respiratory control, efficiency of oxidative phosphorylation (ADP/O), and ATPsynthase activity were assayed. The results showed that according to all these parameters, the mitochondria in cardiac homogenates were not affected in the rats treated with benznidazole. By contrast, mitochondria in the liver homogenates of drug-treated rats were altered, showing decreased respiratory control and a lower coefficient of ADP/O as a result of an increase in the state 4 respiration rate. These data indicate the possibility of production of an uncoupling factor leading to increased proton leakage through the inner mitochondrial membrane as a result of a 9-day treatment of rats with benzonidazole. The obtained experimental data might at least partly explain the nature of benznidazole toxicity in the liver treated with benznidazole. </jats:p>

Hepatotoxicity in Mice of a Novel Anti-parasite Drug Candidate Hydroxymethylnitrofurazone: A Comparison with Benznidazole

“…2 – 4 ). Others have also shown the BZL toxicity by alterations in mitochondrial function in liver of treated rats [44] .…”

The trypanocidal benznidazole promotes adaptive response to oxidative injury: Involvement of the nuclear factor-erythroid 2-related factor-2 (Nrf2) and multidrug resistance associated protein 2 (MRP2)

“…Oxidative stress-mediated drug hepatotoxicity is well known (Gu and Manautou 2012). The antitripanocide BZL has been shown to cause oxidative stress in rodent liver (Pedrosa et al 2001; Rendon 2014; Dias Novaes et al 2015). However, the antioxidant mechanisms responsible for counteracting this redox imbalance have not been defined.…”

“…Reactivity of BZL metabolites was demonstrated in rat hepatocytes, where exposure to BZL led to oxidative stress determined as an increment in lipid peroxidation (Pedrosa et al 2001). In addition, increases in biomarkers of hepatotoxicity and liver histopathological alterations have been shown in mice (Strauss et al 2013) and rats (Rendon 2014) after BZL exposure, possibly associated with oxidative injury. Indeed, Dias Novaes et al (2015) recently demonstrated an increased in lipid peroxidation and protein carbonylation in BZL-treated mice, thus confirming an association between oxidative stress and hepatic damage.…”

Potential Role of Antioxidants as Adjunctive Therapy in Chagas Disease

“…In the US, the Food and Drug Administration agency has approved benznidazole for use in children 2-12 years of age [11]. Though the mechanism of action is not completely understood, it is suggested that the activated benznidazole and nifurtimox (and their metabolites) bind to and block the parasites' antioxidant availability [12,13] and generate DNA-toxic glyoxal adducts [14] causing oxidative damage to the parasite [15,16]. It is important to note that benznidazole and nifurtimox have limited efficacy in the chronic disease phase [17] when adult patients exhibit several significant side effects [17], and these drugs are not recommended for pregnant women (reviewed in [18,19]).…”