Modulation of genotoxicity of azathioprine by intracellular glutathione in hepatocytes

K, Nagafuchi; Miyazaki, Kohji

doi:10.1007/bf01630714

Cited by 9 publications

(2 citation statements)

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“…Azathioprine and Methotrexate have been reported to result in structural and numerical anomalies of chromosomes including breaks in single DNA strands (NAGAFUCHI and MIYAZAKI, 1991); and induced oxidative damage to testicular tissues via lipid peroxidation. (BLASIAK, GLOC, WOZNIAK et al, 2002; PADMANABHAN, TRIPATHI, VIKRAM et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

Untitled

2014

J Morphol Sci

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Introduction: Azathioprine and Methotrexate are both used in the treatment of cancer; and are classified as cytotoxic drugs with reported adverse effects such as oxidative damage to the DNA/RNA, the testes and sperm cells. This study, therefore, tested the hypothesis that Azathioprine and Methotrexate administrations impair the morphology and functions of the testes in adult male wistar rats. Methods: Azathioprine (50-150mg per day) and Methotrexate (2.5mg per week) are used in the treatment of cancer in adult Man. We tested the hypothesis that Azathioprine and Methotrexate impair the morphology and functions of testes in rats. Forty adult male wistar rats (150-230g) were employed in the study: Control Group I received physiological saline while Experimental Groups II-V received oral administrations of 5mg/kg/bodyweight of Azathioprine per day, 15mg/kg/bodyweight of Azathioprine per day, 8mg/kg/bodyweight of Methotrexate per week and 20mg/kg/bodyweight of Methotrexate per week respectively for 35 days. Results: Histological examinations of the testes of rats of Groups II-V showed dose-dependent morphological anomalies such as fewer collagen fibers of connective tissues, disrupted seminiferous tubules and scanty spermatozoa when compared to rats of Group I. Statistical analyses showed dose-dependent elevated levels (P≤0.05) of superoxide dismutase and malondialdehyde in testes homogenates of rats of Groups II-V when compared to rats of Group I. This implied increased oxidative stress in rats of Groups II-V. Evaluations of Follicle Stimulating Hormone and Testosterone showed dose-dependent significantly elevated levels (P≤0.05) in rats of Groups II-V when compared to rats of Group I. Conclusions: Our findings are consistent with the stated hypothesis.

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Section: Discussionmentioning

confidence: 99%

Untitled

2014

J Morphol Sci

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“…Moreover, MNITMT did not show any cytotoxicity when evaluated by the shrimp bioassay (Tumah et al 2006). In contrast, AZA has been proved to be genotoxic and enhances DNA damage, even at low doses that are not cytotoxic to hepatocytes (Nagafuchi and Miyazaki 1991). Moreover, there is clear evidence for an increase in sister chromatid exchange (SCE) frequencies in patients receiving AZA (Erskine et al 1984).…”

Section: Introductionmentioning

confidence: 99%

Genotoxic and cytotoxic effects of the novel immunosuppressive agent 3-[(1-methyl-4-nitro-¹H-imidazol-5-yl)thio]-4-methyl-1,2,4-triazole (MNITMT) on mouse bone marrow cells

Abderrahman

2014

Caryologia

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3-[(1-methyl-4-nitro-1 H-imidazol-5-yl)thio]-4-methyl-1,2,4-triazole (MNITMT) is an immunosuppressive agent used to treat autoimmune disorders. The objectives of this study were to determine the genotoxic and cytotoxic effects of MNITMT on bone marrow cells of mice. Various concentrations of MNITMT were tested (2, 5, 10 and 20 mg ml -1 ). Bone marrow cells were prepared for mitotic and mitodepressive indices and blood smears for micronuclei. Cell viability of cultured bone marrow cells was determined using an MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)] assay and the proliferation index was calculated. Our results show that MNITMT significantly lowered the mitotic index (MI) at the highest two doses (10 and 20 mg ml -1 ) with 14.3 % and 14.9 % at 24 h, 19.2 % and 19.6 % at 48 h, 15.4 % and 19.8 % at 72 h, respectively as compared to control. The percentage of micronuclei (MN) increased with increasing the MNITMT doses 2, 5, 10 and 20 mg ml -1 (79, 125, 141 and 145% respectively). Administration of 2, 5 and 10 mg ml -1 of MNITMT did not cause any bone marrow toxicity, while approximately 50% reduction in the rate of proliferation was observed using the highest dose, 20 mg ml -1 . These results suggest that high doses of MNITMT cause both genotoxic and cytotoxic effects.

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Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in Muta?Mouse

Smith¹,

Archer²,

Forster³

et al. 1999

Environ. Mol. Mutagen.

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Modulation of genotoxicity of azathioprine by intracellular glutathione in hepatocytes

Cited by 9 publications

References 24 publications

Untitled

Untitled

Genotoxic and cytotoxic effects of the novel immunosuppressive agent 3-[(1-methyl-4-nitro-¹H-imidazol-5-yl)thio]-4-methyl-1,2,4-triazole (MNITMT) on mouse bone marrow cells

Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in Muta?Mouse

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Modulation of genotoxicity of azathioprine by intracellular glutathione in hepatocytes

Cited by 9 publications

References 24 publications

Untitled

Untitled

Genotoxic and cytotoxic effects of the novel immunosuppressive agent 3-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-4-methyl-1,2,4-triazole (MNITMT) on mouse bone marrow cells

Analysis of gene mutations and clastogenicity following short-term treatment with azathioprine in Muta?Mouse

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Genotoxic and cytotoxic effects of the novel immunosuppressive agent 3-[(1-methyl-4-nitro-¹H-imidazol-5-yl)thio]-4-methyl-1,2,4-triazole (MNITMT) on mouse bone marrow cells