title: Organ-targeted mutagenicity of nitrofurantoin in Big Blue transgenic mice.
abstract: Nitrofurans are widely used in human medicine, as nitrofurantoin and nifuroxazide, still prescribed for long-term antimicrobial prophylaxis of urinary tract and gastrointestinal infection in humans respectively. Recent experiments in mammals, as well as reports mentioning toxic effects in humans associated with a long-term use, specially in the case of nitrofurantoin, raised the need for reevaluating their genotoxicity. The objective of this study was to determine whether these two compounds induce a mutagenic effect in the Big Blue transgenic mouse mutation assay. Mice were orally treated either with nitrofurantoin or nifuroxazide for five consecutive days and sacrificed 3 weeks later. In order to optimize the genotoxic response, the doses used for each compound were 25-fold higher as the posology in humans. They corresponded to 50% of the highest doses tolerated by mice. The mutant frequency was determined from kidney, lung, bladder, caecum, colon, small intestine, spleen and stomach. A weak mutagenic response of nitrofurantoin-treated mice specifically in the kidney was observed. As in the case of other nitrofuran compounds, the mutation spectra determined from treated samples exhibited slightly more GC-->TA transversions as compared with untreated conditions. These data are relevant to the targeted action of nitrofurantoin as a urinary antimicrobial agent. No significant increase of mutants was detected in the case of nifuroxazide-treated mice whatever the organs analysed.
authors.affiliation: Unité des Cyanobactéries, Institut Pasteur 28, Rue du Dr Roux, 75724 Paris Cedex15, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Quillardet
authors.forename: Xavier
authors.initials: X
authors.lastname: Arrault
authors.forename: Valérie
authors.initials: V
authors.lastname: Michel
authors.forename: Eliette
authors.initials: E
authors.lastname: Touati
mesh_terms: D000818:Animals; D004249:DNA Damage; D041981:Gastrointestinal Tract / Q000187:drug effects; D062385:Hydroxybenzoates / Q000633:toxicity; D007668:Kidney / Q000187:drug effects; D008168:Lung / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009152:Mutagenicity Tests / Q000379:methods*; D009154:Mutation; D009581:Nitrofurans / Q000633:toxicity; D009582:Nitrofurantoin / Q000633:toxicity*; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics
chemical_list: D062385:Hydroxybenzoates; D009581:Nitrofurans; D009582:Nitrofurantoin; C013150:nifuroxazide