engleski

Assessment of the genotoxicity of the tyrosine kinase inhibitor imatinib mesylate in cultured fish and human cells

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

imatinib mesylate, cytotoxic, genotoxic, zebrafish liver cells, HepG2 cells, human peripheral blood lymphocytes

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