title: Assessment of the genotoxicity of the tyrosine kinase inhibitor imatinib mesylate in cultured fish and human cells.
abstract: 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.
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia; Ecological Engineering Institute, Ljubljanska ulica 9, 2000 Maribor, Slovenia; Jozef Stefan International Postgraduate School, Jamova cesta 39, 1000 Ljubljana, Slovenia. Electronic address: matjaz.novak@nib.si.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Novak
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: bojana.zegura@nib.si.
authors.forename: Bojana
authors.initials: B
authors.lastname: Žegura
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: jana1rs@yahoo.com.
authors.forename: Jana
authors.initials: J
authors.lastname: Nunić
authors.affiliation: Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia. Electronic address: ggajski@imi.hr.
authors.forename: Goran
authors.initials: G
authors.lastname: Gajski
authors.affiliation: Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia. Electronic address: mgeric@imi.hr.
authors.forename: Marko
authors.initials: M
authors.lastname: Gerić
authors.affiliation: Mutagenesis Unit, Institute for Medical Research and Occupational Health, Ksaverska cesta 2, 10000 Zagreb, Croatia. Electronic address: vgaraj@imi.hr.
authors.forename: Vera
authors.initials: V
authors.lastname: Garaj-Vrhovac
authors.affiliation: Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia. Electronic address: metka.filipic@nib.si.
authors.forename: Metka
authors.initials: M
authors.lastname: Filipič
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004249:DNA Damage; D042822:Genomic Instability; D006801:Humans; D000068877:Imatinib Mesylate / Q000633:toxicity*; D009152:Mutagenicity Tests; D011505:Protein-Tyrosine Kinases / Q000633:toxicity*; D015027:Zebrafish
chemical_list: D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases
keywords: Cytotoxic; Genotoxic; HepG2 cells; Human peripheral blood lymphocytes; Imatinib mesylate; Zebrafish liver cells