title: Hepatotoxicity in mice of a novel anti-parasite drug candidate hydroxymethylnitrofurazone: a comparison with Benznidazole.
abstract: 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.
authors.affiliation: Instituto de Patología Experimental, Universidad Nacional de Salta-CONICET, Salta, Argentina.
authors.forename: Carolina
authors.initials: C
authors.lastname: Davies
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Nilay
authors.initials: N
authors.lastname: Dey
authors.affiliation: Cátedra de Quimica Biológica, Facultad de Ciencias Exactas, Universidad Nacional de Salta, Argentina.
authors.forename: Olga Sanchez
authors.initials: OS
authors.lastname: Negrette
authors.affiliation: Instituto de Patología Experimental, Universidad Nacional de Salta-CONICET, Salta, Argentina.
authors.forename: Luis Antonio
authors.initials: LA
authors.lastname: Parada
authors.affiliation: Instituto de Patología Experimental, Universidad Nacional de Salta-CONICET, Salta, Argentina.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Basombrio
authors.affiliation: Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America; Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America; Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America.
authors.forename: Nisha Jain
authors.initials: NJ
authors.lastname: Garg
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D014355:Chagas Disease / Q000188:drug therapy*; D056486:Chemical and Drug Induced Liver Injury; D004249:DNA Damage / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D009547:Nifurtimox / Q000627:therapeutic use; D009583:Nitrofurazone / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009593:Nitroimidazoles / Q000009:adverse effects* / Q000627:therapeutic use; D010271:Parasites; D017382:Reactive Oxygen Species / Q000378:metabolism; D014344:Trypanocidal Agents / Q000009:adverse effects* / Q000627:therapeutic use; D014349:Trypanosoma cruzi / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine / Q000031:analogs & derivatives
chemical_list: D009593:Nitroimidazoles; D017382:Reactive Oxygen Species; C439524:TNF protein, human; D014344:Trypanocidal Agents; D014409:Tumor Necrosis Factor-alpha; C483719:hydroxymethylnitrofurazone; C002744:3-nitrotyrosine; D014443:Tyrosine; D009547:Nifurtimox; D009583:Nitrofurazone; C009999:benzonidazole