Abstract

Metformin (MET) is the first-choice antidiabetic drug for type 2 diabetes mellitus treatment. In this study, the genotoxic potential of MET was evaluated by using chromosome aberrations (CAs), sister chromatid exchanges (SCEs), and micronucleus (MN) assays in human peripheral lymphocytes as well as comet assay in isolated lymphocytes. Human lymphocytes were treated with different concentrations of MET (12.5, 25, 50, 75, 100, and 125 µg/mL) for 24 h and 48 h. A negative and a positive control (Mitomycin-C-MMC, 0.20 μg/mL, for CA, SCE, and MN tests; hydrogen peroxide-H₂O₂, 100 µM, for comet assay) were also maintained. MET significantly increased the frequency of CAs at 48 h exposure (except 12.5 µg/mL) compared to the negative control. MET increased SCEs/cells in both treatment periods (except 12.5 µg/mL at 24 h). MET only increased the frequency of MN at 125 µg/mL. While MET significantly increased the comet tail length (CTL) at four concentrations (25, 75, 100, and 125 µg/mL), it did not affect comet tail intensity (CTI) (except 125 µg/mL) and comet tail moment (CTM) at all the treatments. All these data showed that MET had a mild genotoxic effect, especially at a long treatment period and higher concentrations in human lymphocytes in vitro. However, further in vitro and especially in vivo studies should be conducted to understand the detailed genotoxic potential of MET.

• Highlights

• Metformin increased the frequency of CAs and SCEs, especially at 48-h exposure time in human lymphocytes.

• This antidiabetic drug increased the frequency of MN only at the highest concentration tested (125 µg/mL).

• Metformin significantly increased the comet tail length in all treatments (except 50 µg/mL).

• The drug did not significantly affect the comet tail intensity (except 125 µg/mL) and comet tail moment in all treatments.

摘要

二甲双胍（MET）是治疗2型糖尿病的首选降糖药。在这项研究中，通过使用人外周淋巴细胞中的染色体畸变 (CAs)、姐妹染色单体交换 (SCEs) 和微核 (MN) 测定以及分离淋巴细胞中的彗星测定来评估 MET 的遗传毒性潜力。用不同浓度的 MET（12.5、25、50、75、100 和 125 µg/mL）处理人淋巴细胞 24 小时和 48 小时。阴性和阳性对照（丝裂霉素-C-MMC，0.20 μg/mL，用于 CA、SCE 和 MN 测试；过氧化氢-H ₂ O ₂, 100 µM, 用于彗星测定) 也得到了维护。与阴性对照相比，MET 在 48 小时暴露时显着增加了 CA 的频率（12.5 µg/mL 除外）。MET 在两个治疗期间都增加了 SCE/细胞（24 小时时为 12.5 µg/mL 除外）。MET 仅在 125 µg/mL 时增加了 MN 的频率。虽然 MET 在四种浓度（25、75、100 和 125 µg/mL）下显着增加了彗尾长度（CTL），但它不影响彗尾强度（CTI）（125 µg/mL 除外）和彗尾矩（ CTM) 在所有治疗中。所有这些数据表明，MET具有轻微的遗传毒性作用，尤其是在较长的治疗期和体外人淋巴细胞中浓度较高的情况下。然而，进一步在体外，尤其是在体内应进行研究以了解 MET 的详细遗传毒性潜力。

• 强调

• 二甲双胍增加了 CA 和 SCE 的频率，尤其是在 48 小时暴露时间的人淋巴细胞中。

• 这种抗糖尿病药物仅在测试的最高浓度 (125 µg/mL) 下增加了 MN 的频率。

• 二甲双胍在所有处理中都显着增加了彗尾的长度（50 µg/mL 除外）。

• 该药物在所有处理中均未显着影响彗尾强度（125 µg/mL 除外）和彗尾矩。