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

Background:treatment of chagas disease,caused by trypanosoma cruzi,relies on nifurtimox and benznidazole (bzl),which present side effects in adult patients,and natural resistance in some parasite strains. hydroxymethylnitrofurazone (nfoh) is a new drug candidate with demonstrated trypanocidal activity; however,its safety is not known.methods:hepg2 cells dose response to nfoh and bzl (5–100 µm) was assessed by measurement of ros,dna damage and survival. swiss mice were treated with nfoh or bzl for short-term (st,21 d) or long-term (lt,60 d) periods. sera levels of cellular injury markers,liver inflammatory and oxidative stress,and fibrotic remodeling were monitored.results:hepg2 cells exhibited mild stress,evidenced by increased ros and dna damage,in response to nfoh,while bzl at 100 µm concentration induced >33% cell death in 24 h. in mice,nfoh st treatment resulted in mild-to-no increase in the liver injury biomarkers (got,gpt),and liver levels of inflammatory (myeloperoxidase,tnf-α),oxidative (lipid peroxides) and nitrosative (3-nitrotyrosine) stress. these stress responses in nfoh lt treated mice were normalized to control levels. bzl-treated mice exhibited a >5-fold increase in got,gpt and tnf-α (lt) and a 20–40% increase in liver levels of mpo activity (st and lt) in comparison with nfoh-treated mice. the liver inflammatory infiltrate was noted in the order of bzl>vehicle≥nfoh and bzl>nfoh≥vehicle,respectively,after st and lt treatments. liver fibrotic remodeling,identified after st treatment,was in the order of bzl>vehicle>nfoh; lipid deposits,indicative of mitochondrial dysfunction and in the order of nfoh>vehicle>bzl were evidenced after lt treatment.conclusions:nfoh induces mild st hepatotoxicity that is normalized during lt treatment in mice. our results suggest that additional studies to determine the efficacy and toxicity of nfoh are warranted. © 2014 davies et al.