Genotoxic effects of metronidazole

Elizondo, Guillermo; Gonsebatt, María E.; Salazar, Ana Marı́a; Lares, Ismael; Santiago, Pilar; Herrera, Jorge; Hong, Enrique; Ostrosky‐Wegman, Patricia

doi:10.1016/0165-1218(96)00022-5

Cited by 46 publications

(20 citation statements)

References 20 publications

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“…13 With regard to carcinogenic potential of MTZ, the drug increases the incidence of lymphomas and adenomas in mice and colon cancer in rats. 14 According to the International Agency for Research on Cancer (IARC), the evidence is sufficient to consider MTZ as an animal carcinogen, but insufficient for humans. 15 Data available from epidemiological studies are inadequate to evaluate the relationship between exposure to MTZ and human cancer.…”

Section: Introductionmentioning

confidence: 99%

Metronidazole Decreases Viability of DLD-1 Colorectal Cancer Cell Line

Sadowska

Krętowski

Szynaka

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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The aim of our study was to evaluate the impact of metronidazole (MTZ) on DLD-1 colorectal cancer cell (CRC) line. Toxicity of MTZ was determined by MTT test. Cells were incubated with MTZ used in different concentrations for 24, 48, and 72 hours. The effect of MTZ on DNA synthesis was measured as [3H]-thymidine incorporation. The morphological changes in human DLD-1 cell line were defined by transmission electron microscope OPTON 900. The influence of MTZ on the apoptosis of DLD-1 cell lines was detected by flow cytometry and fluorescence microscopy, while cell concentration, volume, and diameter were displayed by Scepter Cell Counter from Millipore. Our results show that cell viability was diminished in all experimental groups in comparison with the control, and the differences were statistically significant. We did not find any significant differences in [3H]-thymidine incorporation in all experimental groups and times of observation. Cytofluorimetric assays demonstrated a statistically significant increase of apoptotic rate in MTZ concentrations 10 and 50 lg/mL after 24 hours; 0.1, 10, 50, and 250 lg/mL after 48 hours; and in all concentrations after 72 hours compared with control groups. In the ultrastructural studies, necrotic or apoptotic cells were occasionally seen. In conclusion, MTZ affects human CRC cell line viability. The reduction of cell viability was consistent with the apoptotic test.

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Section: Introductionmentioning

confidence: 99%

Metronidazole Decreases Viability of DLD-1 Colorectal Cancer Cell Line

Sadowska

Krętowski

Szynaka

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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“…In bacteria, the toxic effects of metronidazole are accompanied by damage to DNA (25,29) and cells defective in DNA repair become hypersensitive to the action of metronidazole (11). A principal enzyme involved in eukaryotic DNA repair is RAD51.…”

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confidence: 99%

Activity of Megazol, a Trypanocidal Nitroimidazole, Is Associated with DNA Damage

Enanga

Ariyanayagam

Stewart

et al. 2003

Antimicrob Agents Chemother

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DNA damage associated with the trypanocidal activity of megazol [2-amino-5-(1-methyl-5-nitro-2-imidazolyl)-1,3,4-thiadiazole] was shown in experiments in which DNA repair-deficient RAD51؊/؊ Trypanosoma brucei mutants were found to be hypersensitive to the drug. Parasites resistant to megazol were selected and showed modest cross-resistance to other trypanocides, although neither drug efflux nor changes to intracellular thiols correlated with resistance.New drugs are urgently required for treatment of human African trypanosomiasis (22). One compound with promise is megazol (5, 12, 13, 18), a nitroheterocyclic compound that forms a nitro radical anion upon reduction (31). Megazol appears to enter Trypanosoma brucei via passive diffusion (3), but little is known about its mode of action. We determined the effect of megazol in assays that measured oxidative and reductive stress. We also selected parasites resistant to megazol in order to assess cellular changes associated with resistance.Bloodstream forms (17) and procyclic forms (6) of T. brucei brucei (strain 427) were cultivated by using standard techniques. Assays measuring drug sensitivity were carried out to determine the drug concentration producing a 50% decrease in cell proliferation (IC 50 ) and the resistance factor (average ratio of the IC 50 for a resistant clone to the IC 50 for a wild-type clone). The Alamar Blue test (28) was used for bloodstream forms, while cell counting by using an improved Neubauer chamber was required for procyclics. For procyclic cells the IC 50 of megazol was 0.28 Ϯ 0.01 M, and for bloodstream forms the IC 50 was 0.15 Ϯ 0.02 M.To induce megazol resistance in vitro, trypanosomes were exposed to drug concentrations that doubled every 2 weeks, starting at 0.008 and 0.01 M for bloodstream forms and procyclics, respectively. After 6 months of cultivation, procyclic and bloodstream forms that tolerated 10 and 1 M megazol, respectively, were cloned by limiting dilution.The IC 50 for the cloned, resistant, procyclic line was 29.24 Ϯ 3.2 M (105-fold-reduced sensitivity), while the IC 50 for the bloodstream form line was 3.2 Ϯ 0.48 M (21-fold-reduced sensitivity).Cross-resistance to megazol and other trypanocides was also studied (Table 1). Moderate levels of cross-resistance to two nitroheterocyclic trypanocides, the nitrofuran nifurtimox and the nitroimidazole benznidazole, were detected. Significant, albeit low-level, cross-resistance to the melaminophenyl arsenical compounds cymelarsan, melarsen oxide, and melarsoprol, the diamidine compounds pentamidine and berenil, and suramin was also observed.Verapamil (20), PAK-104P (7), and two phenothiazine derivatives (prochlorperazine and trifluoperazine) (14) all inhibit cellular extrusion pumps but, when used at 5 M, failed to reverse megazol resistance in T. brucei. Efflux pumps are thus unlikely to play a significant role in the megazol resistance characterized here.It was recently shown that megazol exposure reduces trypanothione levels in Trypanosoma cruzi (23). Bloodstream form T. b...

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“…On the other hand, clastogenic activity of MTZ has been reported in several studies such as Mitelman et al (1976), who found an increase in the frequency of chromosomal aberrations in cells of patients treated with MTZ. Similarly, Elizondo et al (1996) reported that MTZ can induce chromatid and isochromatid breaks in the lymphocytes of subjects receiving therapeutic doses. Mudry et al (1994) reported that MTZ has a clastogenic effect and significantly increased the frequencies of chromosomal aberrations, micronuclei and abnormal metaphases.…”

Section: Discussionmentioning

confidence: 96%

A sub‐acute study of metronidazole toxicity assessed in Egyptian Tilapia zillii

Khalil

Mahmoud

Zahran

et al. 2007

J of Applied Toxicology

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Metronidazole (MTZ), an antiparasitic and antibacterial compound, is one of the world's most widely used drugs. Despite being considered as a rodent mutagen and a carcinogen, it is still widely used in humans for the treatment of infections with anaerobic organisms. Therefore, the main objective of the current study was to evaluate the in vivo toxicity of MTZ using the micronucleus (MN) assay and random amplified polymorphism DNA (RAPD-PCR) analysis as well as histopathological examination in Tilapia zillii. Moreover, the protective effect of vitamin C (VitC) against toxicity of MTZ was investigated in the present study. Fish were treated with three doses of MTZ (5, 10 and 20 mg l(-1)) alone or in combination with VitC (200 mg kg(-1) food) at several time intervals (2 days, 7 days and 14 days). The results of the present study showed a significant effect of MTZ on micronucleus formation and changes in polymorphic band patterns as well as induction of different histopathological alterations in Tilapia zillii. The effects of the drug were reduced when fish were exposed to a combination of MTZ and VitC.

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Genotoxic effects of metronidazole

Cited by 46 publications

References 20 publications

Metronidazole Decreases Viability of DLD-1 Colorectal Cancer Cell Line

Metronidazole Decreases Viability of DLD-1 Colorectal Cancer Cell Line

Activity of Megazol, a Trypanocidal Nitroimidazole, Is Associated with DNA Damage

A sub‐acute study of metronidazole toxicity assessed in Egyptian Tilapia zillii

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