Mutagenesis Advance Access originally published online on August 8, 2006
Mutagenesis 2006 21(5):305-311; doi:10.1093/mutage/gel036
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Organ-targeted mutagenicity of nitrofurantoin in Big Blue transgenic mice
1 Unité des Cyanobactéries, Institut Pasteur 28, Rue du Dr Roux, 75724 Paris Cedex15, France 2 Unité de Pathogénie Bactérienne des Muqueuses, Institut Pasteur 28, Rue du Dr Roux, 75724 Paris Cedex15, France 3 Service de Pharmacie Clinique et des Biomatériaux, Groupe Hospitalier Bichat-Claude Bernard AP-HP, 46, Rue Henri Huchard, 75877 PARIS Cedex 18, France
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.
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Introduction |
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The nitration of heterocyclic compounds has produced a number of important classes of antibacterial drugs. For human medicinal use, three classes of such nitroheterocyclic drugs have proved to be of great therapeutic value: nitroimidazoles (e.g. metronidazole), the nitrothiazoles (e.g. niridazole), and the nitrofurans. 5-Nitrofuran derivatives have been widely used since the 1940s as veterinary and human drugs (1
,2). They possess broad-spectrum antimicrobial properties which are directed not only against several bacteria but also against certain protozoa and even worms (1,3,4). In addition, it has been mentioned that sensitive organisms do not develop resistance to nitrofurans during treatment and available evidence indicates that plasmid-mediated resistance is not observed (5).
The nitro-group, coupled to the furan ring is the key structural element in the mechanism of nitrofuran antimicrobial action. To be active and to interact with macromolecules, these compounds need to be metabolized by microbial nitroreductases (6). The final metabolite is also inactive, but the metabolic intermediates attack a variety of cellular constituents including proteins and nucleic acids. Enzymatic nitroreduction of nitrofurans has also been described in animal tissues (4), implying that toxic and mutagenic effects could also occur in mammalian cells and tissues exposed to these chemicals. In bacterial systems, nitrofuran derivatives are almost all mutagenic (3,4,7). Furthermore several nitrofuran derivatives are mutagenic in mammalian cells in vitro (4,8), suggesting that the use of nitrofuran derivatives in medicine constitutes potentially a risk for human health.
Nitrofurantoin [N-(5-nitro-2-furfurylidene)-1-aminohydantoin] and nifuroxazide [(5-nitro-2-furfurylidene)hydrazide] are prescribed as a first-line prophylaxis therapy for acute or recurrent urinary tract infections and nocosomial urinary tract infections, and as therapy for acute diarrhoea of bacterial origin in humans, respectively. Recently, pulmonary injuries associated to the use of nitrofurantoin for more than 6 months have been reported (9). Both compounds have been demonstrated to be mutagenic in bacteria (4). Accordingly, nitrofurantoin has been reported to induce mainly GCTA transversions in Salmonella typhymurium strain TA100 (10). Only a few studies have investigated their mutagenic action in higher organisms. In vitro, nitrofurantoin increased the frequency of sister-chromatid exchange (SCE) in Chinese hamster ovary cells (11). In vivo, nitrofurantoin did not induce micronuclei in reticulocytes from the bone marrow of rats (12) and did not show a significant effect in the mouse spot test (13). However, this compound has been classified as a borderline inducer of sex-linked recessive lethal mutations in Drosophila melanogaster (14). A cytogenetic analysis of peripheral blood lymphocytes of children treated with nitrofurantoin reported a statistically significant correlation between cumulative dose of this compound and SCE frequency after 1 month of the therapy (15). In addition, pulmonary injuries related to a nitrofurantoin treatment have been described in humans (16,17). According to these data, recent experiments in mice showing an increase in the frequency of micronuclei by nitrofurantoin, suggest the need for reevaluating the genotoxic potential of this compound (18).
Nifuroxazide has been described as a mutagen in the Salmonella typhimurium strains TA100 and TA100Fr1 but did not induce mutations at the HPRT locus in V79 Chinese hamster lung cells using a rat-hepatocyte-mediated metabolic activation system (19). No data on in vivo genotoxicity assays in higher organisms have been published concerning nifuroxazide. Given the current use of nitrofurantoin and nifuroxazide to eradicate urinary and gastrointestinal infections and the recent reports related to injuries observed in treated patients (9), the in vivo evaluation of the toxicity and genotoxic potency of these two compounds is important in term of public health.
In this study, we have investigated the in vivo mutagenicity of nitrofurantoin and nifuroxazide using the Big Blue transgenic mouse mutation detection system (20–22), which allows the direct detection of in vivo somatic mutations in any tissue or cell type. The system uses transgenic mice harboring chromosomally-integrated lambda bacteriophage containing the E.coli lacI and cII genes as targets for mutagenesis (23). Mutation frequencies were determined from lung, kidney and organs from the gastrointestinal tract of orally treated and untreated mice and the induced mutation spectra was characterized in the target organs for mutagenic action of the compounds.
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Materials and methods |
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Animals
Male Big BlueTM C57BL/6[LIZ] mice were obtained from Stratagene (La Jolla, CA). The animals were acclimatized for one week before use. They were housed five per cage and food and water were supplied ad libitum. Animals were 7–8 weeks of age at the beginning of the experiments.
The experiments reported here were approved in advance by the Central Animal Facility Committee of the Institut Pasteur, in conformity with the French Ministry of Agriculture Guidelines for Animal Care.
Chemicals
Nitrofurantoin (N-[5-nitro-2-furfurylidene]-1-aminohydatoin, CAS no. 67-20-9) and nifuroxazide, (5-nitro-2-furaldehyde-p-hydroxybenzoyl-hydrazone, CAS no. 965-52-6) were purchased from Sigma Chemical (St Louis, MO).
Experimental design
The chemicals were dissolved in olive oil containing 10% dimethylsulfoxide (DMSO), and administered for five consecutive days to groups of five mice. The dosing was by gavage, using a volume of 300 µl/animal. For nitrofurantoin, daily doses were 4 mg (50% of the maximum tolerated doses determined in a preliminary experiment using non-transgenic C57BL/6 male mice). For nifuroxazide, daily doses were 7.5 mg, a non-toxic dose determined by the maximal solubility. As the mice weighed 
24 g at the time of administration, the individual doses administered were 167 mg/kg for nitrofurantoin and 313 mg/kg for nifuroxazide. A control group of five mice received only the vehicle (300 µl olive oil containing 10% DMSO).
The mice were sacrificed 20 days after the last treatment. This time was based upon previous data showing that the maximum mutant frequency was obtained at 15–20 days after the last treatment (24,25). The mice were sacrificed, the organs removed aseptically and immediately frozen in liquid nitrogen. The tissues were kept in liquid nitrogen until isolation of the DNA.
cII mutant frequency determination
Briefly, genomic DNA was extracted from the various organs by using protease digestion, subsequent phenol–chloroform extraction and ethanol precipitation. The lambda shuttle vector was recovered from genomic DNA preparations with a lambda packaging extract (TranspackTM). The phage particles were assayed for cII mutations by infecting a culture of Escherichia coli G1250, and plating the infected bacteria on tryptone agar plates. E.coli G1250 is an hfl mutant that facilitates the lysogenic response by increasing the stability of the wild-type cII repressor. For the determination of cII mutants, the plates were incubated at 24°C for 48 h. At this selective temperature, only lambda phage containing mutations in the cII gene can multiply through the lytic cycle and form plaques while non-mutants undergo lysogeny. The packaged DNA was also plated and incubated at 37°C for estimating the rescue efficiency. Under these non-selective conditions, non-mutants also undergo a lytic cycle leading to the formation of plaques. Mutant frequencies are expressed as the number of plaques at 24°C versus the number of plaques at 37°C.
Sequence analysis of mutants
Mutant phage plaques were isolated as agar plugs, eluted into buffer, and replated at low density on tryptone agar plates to purify the clone. The plates were incubated at 24°C for 48 h to confirm the mutant phenotype. Agar plugs of purified plaques were re-eluted into buffer. The total cII gene was amplified in a polymerase chain reaction from an aliquot of the purified plaque using a forward primer (5'-CCGCTCTTACACATTCCAGC-3') at –114 from the start of the cII gene and a reverse primer (5'-CCTCTGCCGAAGTTGAGTAT-3') at +73 from the end of the cII gene. The amplification products were purified and sequenced using a primer (5'-CCACACCTATGGTGTATG-3') at –68 from the start of the cII gene.
Statistical analysis
Treatment and control mutant frequencies were compared by using one-tailed Student's t-test as previously recommended (26). A P-value of 
0.05 was considered significant. The percentage of a particular mutation class in different spectra (treated and untreated obtained from five animals) was compared using the Chi-squared and the Fisher exact tests.
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Results |
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Two main important variables in in vivo mutagenesis assays were the design of the treatment protocol and the time between treatment and assay referred as the mutant manifestation time (24
). According to the previous published recommendations and studies from our group concerning the mutagenic potency in the Big Blue mouse of a model nitrofuran derivative (25,27), two groups of five transgenic C57BL/6[LIZ] mice were treated orally for five consecutive days with either 167 mg/kg nitrofurantoin or 313 mg/kg nifuroxazide as described in Materials and methods. A control group of five mice received the vehicle (300 µl olive oil containing 10% DMSO). DNA was recovered from lung, kidney, bladder, caecum, colon, intestine, kidney, spleen and stomach, and the frequencies of mutants in the cII gene from the shuttle vector were determined. The control mutant frequency in these tissues, calculated from vehicle treated animals, ranged from (3.15 ± 1.75) x 10–5 (caecum) to (7.17 ± 1.40) x 10–5 (stomach) (Table I). Such tissue-specific variability has already been observed in the lacI gene of transgenic mice by different investigators (28), and in previous works from our own laboratory (25,27). These responses reflect differences in the rate of spontaneous mutations from one tissue to another.
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In bladder, colon, intestine, lung, spleen and stomach either from nitrofurantoin or nifuroxazide-treated mice, the increase in cII mutant frequencies over control was <1.3-fold and was never significant (Table I). According to what was previously reported, an increase in mutant frequency of
1.5-fold over controls is necessary to establish a mutagenic effect (22,26). The analysis of the cII mutant frequency in kidney from nitrofurantoin-treated mice revealed a low but significant mutagenic effect of 2-fold as compared with the untreated group (P = 0.04) (Table I). This result is also validated by the low inter-animal variation observed among the nitrofurantoin-treated group of mice, since the mutant frequency level was higher than the control group values for most of the animals.
In the case of nifuroxazide, a slight mutagenic effect was only observed at the caecum level: the mean mutant frequency in the nifuroxazide-treated mice was 6.96 x 10–5, as compared with 3.15 x 10–5 in the control group. However this effect is not significant since it was only due to a high level of mutant frequency observed for one mouse in the treated group. Although, it is known that most of the administered nifuroxazide remains in the gastrointestinal lumen (29) it cannot be concluded from these data that oral administration of nifuroxazide led to a mutagenic effect at the caecum level. No significant mutagenic effect was found for the other organs isolated from mice treated with nifuroxazide.
In order to confirm the significance of the increased kidney mutant frequency in nitrofurantoin-treated mice, the mutation spectra of the cII mutants were determined from treated and control animals. The molecular characterization, by sequencing PCR-amplified target sequences, of cII mutants is given in Table II. The 41 spontaneous mutants issued from the kidneys of four untreated animals and 52 cII mutants recovered from the kidneys of four nitrofurantoin-treated animals were sequenced. After correction for potential clonal expansion (see Table II) 36 cII spontaneous mutants and 41 presumed nitrofurantoin-induced cII mutants were available for analysis.
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The spontaneous mutation spectrum was comparable to the spontaneous mutation spectrum in the cII gene recovered from various other tissues (30
). Of the mutations, >80% were base pair substitutions with an equal proportion of transitions and transversions. Further, G:CA:T transitions, observed mainly at 5'-CpG-3' dinucleotides, were the predominant class of mutations. When the cII mutants were recovered from the kidney from nitrofurantoin-treated mice, the main base pair substitution events were GCTA transversions, occurring for 24.4% of the total mutants compared with 13.9% in the spontaneous spectra. GCCG transversions previously observed in the spontaneous spectra were not recovered in the presence of nitrofurantoin (Table II). |
Discussion |
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As most nitrofuran derivatives, nitrofurantoin and nifuroxazide are potent mutagens in bacteria. In the S.typhimurium assay, the mutagenic potencies are
1000 revertants/nmol for nifuroxazide and 200 revertants/nmol for nitrofurantoin. By comparison, in the same assay Benzo(a)pyrene, a well known genotoxic and carcinogenic chemical, induced 100 revertants/nmol (31). During their nitroreduction in bacteria, nitrofurans are converted to genotoxic intermediates able to damage DNA and induce mutations (6). Since they can be metabolized by nitroreduction catalysed by a nitroreductases in mammalian tissues (4), nitrofurans are expected to produce genotoxic intermediates and to be potentially mutagenic in mammalian cells as well as in bacteria. Indeed some nitrofurans are strong mutagens in the CHO/HPRT system, an in vitro assay for mutagenesis using mammalian cells in culture (8). As previously mentioned (see Introduction), the few available in vivo studies described only weak genotoxic effects. The current use of nitrofurantoin and nifuroxazide to eradicate urinary and gastrointestinal infections and the recent data reporting pulmonary and hepatic injuries in nitrofurantoin-treated patients (9), justify the need to evaluate the genotoxic potency of these two compounds in term of public health.
The objectives of the present work were to determine if these very potent bacterial mutagens are also mutagenic in mammals. In order to optimize the mutagenic response, 50% of the maximum tolerated doses of the compounds were orally administered to Big Blue transgenic mice. In these conditions, nitrofurantoin induced a weak mutagenic response of 2-fold in the cII gene from the kidney of treated mice as compared with untreated (Table I). Conforming to this data, a previous extensive study of Big Blue mouse assays indicated that a 1.5-fold higher than control frequency of mutation is a significant positive result (22). The mutation spectra determined in the cII mutants issued from the DNA isolated from kidney, does not show a real statistical significance between untreated and nitrofurantoin-treated groups. However accordingly with previous studies in Big Blue mice treated with another nitrofuran derivative, the R7000, a very high potent mutagenic nitronaphthofuran (25,27), G:CT:A transversions are the main base pair substitutions observed from the nitrofurantoin-treated samples. When mutations also found in the spontaneous spectrum were deduced from the nitrofurantoin-induced spectrum, these G:CT:A transversions represented >40% of the total induced mutational events. It is also to be noticed that in bacteria, R7000 induced the same major mutagenic events as observed in mice (32). This mutation event is likely to result from the induction of DNA lesions at the guanine residues, a preferential nucleotide target reported for R7000 (33), suggesting a similar mechanism of DNA damage for nitrofurantoin DNA interaction. Taken together, these results argued for a potential weak mutagenic effect of nitrofurantoin at the kidney level in mammals and the merit of the same needs to be further investigated.
In the present study, except the borderline mutagenic effect observed in kidney, no significant effect was found in the other organs analysed following the nitrofurantoin treatment, even in lungs in which toxicity associated with long-term use of nitrofurantoin has been described in humans (16,17). One part of the described side effects associated to nitrofurantoin was pulmonary toxicity (5). Accordingly, an acute pulmonary injury by nitrofurantoin has been reported in rats following the subcutaneous administration of the compound at doses of 300–500 mg/kg body weight, enhanced when animals were placed in an O2 enriched atmosphere (34). The metabolism of nitrofurantoin through nitroreduction leads to active metabolites associated to production of free radicals as superoxide leading to products such as singlet oxygen, hydrogen peroxide and hydroxyl radicals able to damage macromolecules as observed with paraquat. It has been postulated that pulmonary damage by paraquat is due to peroxidative destruction of essential pulmonary lipids by reactive O2 derivatives (35). Due to the production of free radicals, it could be postulated that DNA damages should be induced following nitrofurantoin treatement specially at lung level due to the presence of O2. However, no significant pulmonary mutagenic activity was detected in the treated mice, suggesting that the acute toxicity of the compound could mask a potential genotoxic effect. Toxicity and tissue injuries associated with the use of nitrofurantoin have also been reported in liver, testis and kidney (5). The nitrofurantoin liver toxicity was associated with infiltration of the portal areas with chronic inflammatory cells, bile stasis, hepatocellular damage and necrosis. In addition, in a chronic toxicity study, an increase in testicular degeneration, sciatic nerve degeneration and fibrosis in both males and females with no evidence of renal toxicity have been reported (36). However, using the alkaline elution technique, it has been clearly demonstrated that nitrofurantoin-induced DNA damage in vivo were found in all the tissues examined (liver, kidney, lung, spleen and bone marrow) (37), but as observed in rats in long-term assay, nitrofurantoin was not positive as a carcinogen (36).
The weak mutagenic response following nitrofurantoin treatment and its organ specificity at the kidney level, can be attributed to its biodistribution in the animal. After oral administration, nitrofurantoin is well absorbed from the gastrointestinal tract (5,38). The plasma half-life of nitrofurantoin is short and it is quickly metabolized and excreted and 30–40% are unmodified and excreted in urines. Nitrofurantoin is normally and equally distributed almost exclusively in the renal medulla and urine (38). High concentrations of the compound are not found in the serum or other tissues. From our results, it is suggested that only in the kidneys, the drug is present in sufficient concentration to produce, via nitroreduction, genotoxic intermediates leading to DNA damages and a detectable mutagenic effect. The genotoxic consequences of nitrofurantoin could be completely different in the presence of renal dysfunction. Indeed, when urinary elimination of the drug is impaired, this results in elevated serum levels (5,38). Under these conditions, nitrofurantoin could be present in sufficient concentration in other tissues than renal medulla, where it could be metabolized and produce enough amount of genotoxic intermediates to lead to a detectable mutagenic effect. This possibility should be considered when nitrofurantoin is prescribed to these patients.
Although nifuroxazide is five times more mutagenic than nitrofurantoin in the S.typhimurium assay, its oral administration to Big Blue mice did not result in a significant mutagenic effect in the cII gene from any of the organs tested. The physiological distribution of nifuroxazide in the organism is different from that of nitrofurantoin. Upon administration of a single dose, no unchanged parent drug was detected in human blood or urine. In rats given C14 nifuroxazide, 17% of the initial dose was excreted in urine over a 48 h period, but none of the radioactivity was found as unchanged drug, indicating that renal excretion occurs as metabolites (29). The high rate of nifuroxazide metabolism may account for its higher mutagenic activity as compared with nitrofurantoin in in vitro assays. However, this compound is weakly absorbed. Most of the drug remains in the gastrointestinal lumen and 20% are recovered in the feces (29). Accordingly, it is likely that in the serum and most tissues, the concentration of nifuroxazide is too low to induce a detectable mutagenic effect, even though the absorbed part is completely metabolized.
In conclusions, using the Big Blue mice assay, we have shown for the first time that nitrofurantoin produced a weak kidney targeted mutagenesis in vivo, while nifuroxazide was not detected as a mutagen under the same conditions. These results are relevant with what is known of the biodistribution of these compounds, and raised the existence of a genotoxic effect of nitrofurantoin. Accordingly, a recent study reported the induction of micronuclei in young and adult mice treated with a single intraperitoneal injection of nitrofurantoin from 5 to 50 mg/kg body weight. Compared with the similar baseline values, nitrofurantoin increased significantly the in vivo micronuclei frequency and the induction levels were higher in the young mice as compared with adults, may be related to the poorly developed mechanisms of xenobiotic detoxification and renal elimination in young mice (18). However, because of the biodistribution of the compound, its metabolism and tissues-specific DNA repair capacities that may be different from one organism to another, we have to be careful in extrapolating data from mice to humans. Our results have been obtained at daily doses 25-fold higher than the therapeutic doses in humans, corresponding to 50% of the dose tolerated in mice. These conditions were used in order to optimize the detection of a mutagenic effect. Thus, it can be argued that, fortunately, as regard to its biodistribution and metabolic properties, the therapeutic daily doses of nitrofurantoin are too low to induce significant mutagenesis in the kidneys of patients. However, it should be noticed that the therapeutic protocols is of 3 daily doses from 8 to 20 days, as compared with one daily dose for five consecutive days in the present study. If a mutagenic effect can be observed only at high doses, it does not exclude that some mutations could still arise at lower doses. In addition, the genetic context of the host can modulate the mutagenic response to nitrofurans. Accordingly, people with a renal dysfunction that modifies the biodistribution of the compound, can be especially sensitive to the mutagenic properties of nitrofurans. Repair defects could also result in a more pronounced mutagenicity. Furthermore, since large human populations are exposed to nitrofurantoin, 3.7–4.7 estimated annual prescriptions per 1000 in the UK in 1976–1979 (38), rare pathogenic mutagenic effects due to the drug could go unnoticed. Of the world regulation of nitrofurantoin use 16% is carried out in France. A re-evaluation of the benefit–risk ratio of the prescription of this compound is currently on hand with the French agencies of products of health, and even if low, the potential carcinogenic risks must be taken into account especially for prolonged treatments.
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Acknowledgments |
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This work received the financial support from the Direction des Recherches sur l'Environnement et l'Hygiène, Institut Pasteur, Paris.
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Notes |
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*To whom correspondence should be addressed. Tel: +33 1 40 61 37 85; Fax: +33 1 40 61 36 40; Email: etouati{at}pasteur.fr
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Received on May 18, 2006; revised on July 7, 2006; accepted on July 9, 2006.
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