Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole

Abstract

Nitroheterocyclic compounds are widely used as therapeutic agents against a variety of protozoan and bacterial infections. However, the literature on these compounds, suspected of being carcinogens, is widely controversial. In this study, cytotoxic and genotoxic potential of three drugs, Nifurtimox (NFX), Benznidazole (BNZ), and Metronidazole (MTZ) was re-evaluated by different assays. Only NFX reduces survival rate in actively proliferating cells. The compounds are more active for base-pair substitution than frameshift induction in Salmonella; NFX and BNZ are more mutagenic than MTZ; they are widely dependent from nitroreduction whereas microsomal fraction S9 weakly affects the mutagenic potential. Comet assay detects BNZ- and NFX-induced DNA damage at doses in the range of therapeutically treated patient plasma concentration; BNZ seems to mainly act through ROS generation whereas a dose-dependent mechanism of DNA damaging is suggested for NFX. The lack of effects on mammalian cells for MTZ is confirmed also in MN assay whereas MN induction is observed for NFX and BNZ. The effects of MTZ, that shows comparatively low reduction potential, seem to be strictly dependent on anaerobic/hypoxic conditions. Both NFX and BNZ may not only lead to cellular damage of the infective agent but also interact with the DNA of mammalian cells.

Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

“…Because of their transient nature, we could not analyze the effect of these intermediates, but by analogy with the equivalent derivatives obtained from other nitroimidazoles, we can postulate that the hydroxylamine form of benznidazole could react with nucleic acids and proteins, while the nitrenium ion could conjugate with free thiols (16,45). Such interactions may account for some of this prodrug's pleiotropic effects: benznidazole is mutagenic and causes a thiol depletion (4,22). Likewise, many of these potentially trypanocidal properties could be attributed to glyoxal, the final end product of TbNTRmediated benznidazole reduction (Fig.…”

uvrB gene deletion enhances SOS chromotest sensitivity for nitroreductases that preferentially generate the 4-hydroxylamine metabolite of the anti-cancer prodrug CB1954

“…To test this we compared SOS induction in the SOS-R1 wild type versus DNA-repair mutant strains with two different mono-nitroaromatic prodrugs, the 5-nitroimidazole metronidazole and the 5-nitrofuran nitrofurazone. Nucleotide excision repair has previously been identified as the major repair pathway for nitrofurazone-induced DNA damage (Ona et al, 2009), but the mechanisms of genotoxicity and repair for metronidazole are less well understood (Buschini et al, 2009;Elizondo et al, 1996). We found that neither of these compounds had any differential effect in the ada/ogt or mutS backgrounds (not shown), whereas nitrofurazone, but not metronidazole, induced an enhanced SOSresponse in the uvrB mutant (Fig.…”

Identification of a New Amide-Containing Thiazole as a Drug Candidate for Treatment of Chagas' Disease

“…5A and B) (10). Additionally, thiazole 4, unlike Bnz and Nfx (see Table S3) (6,28,29), was not mutagenic in the Ames test against the five strains recommended by the OECD, was not genotoxic in vivo at the assayed dose, and possessed a high LD 50 .…”