The selective tyrosine kinase inhibitor imatinib mesylate (IM) is a widely used anticancer drug. Recent studies showing that IM can induce DNA and chromosomal damage in crustaceans and higher plants prompted us to re-examine its potential genotoxicity. IM was not mutagenic in the Ames assay (Salmonella typhimurium). Cytotoxicity and genotoxicity were evaluated in vitro in zebrafish (Danio rerio) liver (ZFL), human hepatoma (HepG2), and human peripheral blood lymphocyte (HPBL) cells. Genotoxicity was determined with the comet assay and with the cytokinesis-block micronucleus cytome assay. ZFL and HPBL cells showed comparable sensitivity to IM cytotoxicity, while HepG2 cells were less sensitive. At non-cytotoxic concentrations, IM induced DNA strand breaks in ZFL and HepG2 cells. An increase in the number of micronuclei was observed in ZFL and HPBL cells. In HPBLs, IM also induced an increase in the number of nucleoplasmic bridges and nuclear buds. Based on the data of the consumption of IM in European countries the predicted environmental concentrations (PEC) were calculated to be in the range between 3.3 and 5.0ng/L, which are several orders of magnitude lower from those that caused adverse effects in fish and human derived cells. However, based on the in vitro studies it is not possible to quantitatively predict the hazard for wildlife and humans, therefore further studies are warranted to explore the underlying molecular mechanisms of induced IM genotoxic effects as well as the studies of the occurrence of IM in the aquatic and occupational environment to establish the relevance of these observations for aquatic organisms and occupationally exposed personnel.

中文翻译：

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酪氨酸激酶抑制剂甲磺酸伊马替尼在培养鱼和人体细胞中的遗传毒性评估。

选择性酪氨酸激酶抑制剂甲磺酸伊马替尼 (IM) 是一种广泛使用的抗癌药物。最近的研究表明，IM 可以在甲壳类动物和高等植物中诱导 DNA 和染色体损伤，这促使我们重新审视其潜在的遗传毒性。IM 在 Ames 试验（鼠伤寒沙门氏菌）中没有致突变性。在斑马鱼 (Danio rerio) 肝脏 (ZFL)、人类肝癌 (HepG2) 和人类外周血淋巴细胞 (HPBL) 细胞中体外评估细胞毒性和基因毒性。使用彗星试验和胞质分裂阻断微核细胞组试验测定遗传毒性。ZFL 和 HPBL 细胞对 IM 细胞毒性的敏感性相当，而 HepG2 细胞的敏感性较低。在非细胞毒性浓度下，IM 在 ZFL 和 HepG2 细胞中诱导 DNA 链断裂。在 ZFL 和 HPBL 细胞中观察到微核数量增加。在 HPBLs 中，IM 还诱导核质桥和核芽数量增加。根据欧洲国家的 IM 消费数据，计算得出的预测环境浓度 (PEC) 在 3.3 至 5.0 ng/L 之间，比对鱼类和其他国家造成不利影响的浓度低几个数量级。人源细胞。然而，根据体外研究，无法定量预测对野生动物和人类的危害，