Comparison of the Sensitivity of Human and Rat Hepatocytes to the Genotoxic Effects of Metronidazole

Martelli, Antonietta; Allavena, A.; Robbiano, Luigi; Mattioli, Francesca; Brambilla, Giovanni

doi:10.1111/j.1600-0773.1990.tb00758.x

Cited by 25 publications

(8 citation statements)

References 29 publications

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“…The significant increase in the micronucleated polychromatic erythrocytes induced by metronidazole indicates clastogenecity. Martelli (1990) found that metronidazole caused DNA breaks in rat hepatocytes which was directly related to the dose and the length of the exposure, which agrees with our results, that the increased percentage of the abarrant metaphases, micronucleus and inhibition of mitotic activity was caused by 500 mg of metronidazole for 2 weeks. Furthermore, Menendez et al (2002) found that the metronidazole hydroxy metabolite induced a dose response increase of micronuclei, while cell proliferation in the cell line was not increased.…”

Section: Discussionsupporting

confidence: 92%

Reproductive and Cytogenetic Toxicity of Metronidazole in Male Mice

El‐Nahas

El-Ashmawy

2004

Basic Clin Pharma Tox

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The purpose of this study was to examine the effects of metronidazole (500 mg/kg b.wt. daily by gavage for 14 consecutive days) on male fertility, haematopoiesis and genotoxic affinity. Mature male Swiss mice were treated with metronidazole and divided into 3 groups each with 10 animals, examined after 2 weeks, 1 and 2 months from the onset of drug administration. The results demonstrated that metronidazole significantly (PϽ0.05) decreased the weight of the testes, epididymides and accessory sexual organs (seminal vesicles and prostates) after one month from the onset of treatment. While accessory sexual organ weights were restored after 2 months from onset of treatment, the decrease in testes and epididymides weights persisted until 2 months later. The deleterious effects of metronidazole on reproductive organ weights might be due to a decrease in testosterone level after 2 weeks, and 1 and 2 months from the onset of treatment. Metronidazole induced a significant decrease in motile sperm and an increase in abnormal sperm after 1 month. The viability of sperm was normal after 2 months. Metronidazole induced anaemia characterized by decreased erythrocyte and leukocytic counts, haemoglobin content and haematocrit %. The ability of oral metronidazole administration to induce genotoxic damage in somatic cells of mice was evaluated using mitotic index, micronuclei and chromosomal aberration. A significant reduction in mitotic activity was observed two weeks from the onset of drug administration, restoration occured after one month. A significant and persistence increase in the frequency of chromosomal aberration and micronucleus was observed at all periods of the experiment. In conclusion, the results of this study indicate that 1) metronidazole (500 mg/kg by gavage) for 14 days caused a harmful effect on male fertility in mice after one and two months from start of administration, 2) metronidazole induced anaemia after one month from start of administration, 3) metronidazole at this high dose level (3 times the therapeutic dose in mice) has the ability to induce genotoxic effects in somatic cells.

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Section: Discussionsupporting

confidence: 92%

Reproductive and Cytogenetic Toxicity of Metronidazole in Male Mice

El‐Nahas

El-Ashmawy

2004

Basic Clin Pharma Tox

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“…Regarding the hormonal changes, the reduction in plasma levels of testosterone, FSH, and LH hormones following administration of metronidazole may be due to impairment of hypothalamo-hypophyseal-gonadal axis in protein malnourished animals (Herbert, 1980;Lado-Abeal et al, 1999), while the reduction in testosterone levels can be attributed to the direct effect of metronidazole on germ and Leydig cells (Noorafshan et al, 2011) as its penetrate testes blood barrier. The elevation of liver enzymes is compatible with the histopathological findings which indicate that metronidazole induced liver injury and this injury may be due to DNA break down in rat hepatocytes which are relative to the dose level (Martelli et al, 1990).…”

Section: Discussionsupporting

confidence: 79%

Pharmacodynamic and pharmacokinetics of metronidazole in protein malnourished rats

Ezzeldin¹

2012

Afr. J. Pharm. Pharmacol.

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The aim of this study is to evaluate the relationships between metronidazole toxicity and pharmacokinetics in protein malnourished rats. The study was carried out on two sets of rats, normallyfed set and protein malnourished set. Each set was divided into a control group and three-treated groups that received metronidazole daily in one dose of 200, 400 or 800 mg/kg for 30 days. Liver enzymes as well as testosterone and gonadotropin hormones levels were estimated. The pharmacokinetic profiles were carried out over a period of 48 h. Metronidazole plasma levels were determined by a validated high-performance liquid chromatography (HPLC) method. Metronidazole has dose dependent effects on hematological profile, liver enzymes, testosterone and gonadotropins which potentiated in protein malnourished rats. Protein malnutrition elevated metronidazole C max , AUC 0-48 , and AUC0-inf , prolonged t 1/2 and MRT, and decreased elimination rate constant. The clinical significance of this work should be stressed in case of protein malnourished individuals due to the risk of accumulation of the drug after repeated doses.

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“…The genotoxic effects of nitroimidazoles have been reported for MTZ and partially for ONZ. It has been reported that MTZ induced single-strand DNA breaks and produced DNA fragmentation and unscheduled DNA synthesis in primary cultures of both rat and human hepatocytes (Martelli et al, 1990;Reitz et al, 1991;Menendez et al, 2001;Tocher and Edwards, 1994). Rodriguez et al reported that ONZ caused DNA single-strand breaks at 10-, 100-, and 500-μg/mL concentrations (Rodriguez et al, 2002).…”

Section: Discussionmentioning

confidence: 97%

The evaluation of genotoxic potential of ornidazole, nitroimidazole, in lymphocyte culture of patients with amebiasis

İkbal

Yılmaz

Doğan

et al. 2011

Drug and Chemical Toxicology

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The genotoxicity study of ornidazole (ONZ) was carried out on human lymphocyte chromosomes, using sister chromatid exchange (SCE) and micronucleus (MN). Thirty-two patients with Entemoeba histolitica infection who received 1000 mg/day for 10 days were included in this study. SCE and MN were measured before and after therapy. A statistically significant increase was observed in the SCE (P < 0.001) and MN frequencies (P < 0.001) after ornidazole therapy. It was concluded that ONZ has a potential geno- and cytotoxic effect in human peripheral lymphocyte cultures. For this reason, further, detailed studies are needed to elucidate the ONZ mechanism of genotoxicity and its carcinogenic potential.

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Comparison of the Sensitivity of Human and Rat Hepatocytes to the Genotoxic Effects of Metronidazole

Cited by 25 publications

References 29 publications

Reproductive and Cytogenetic Toxicity of Metronidazole in Male Mice

Reproductive and Cytogenetic Toxicity of Metronidazole in Male Mice

Pharmacodynamic and pharmacokinetics of metronidazole in protein malnourished rats

The evaluation of genotoxic potential of ornidazole, nitroimidazole, in lymphocyte culture of patients with amebiasis

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