The combined use of human neural and liver cell lines and mouse hepatocytes improves the predictability of the neurotoxicity of selected drugs

The cytotoxicity of amitriptyine (0-100 mu M). selegiline (0-4.5 mu M). carbamazepine (0-420 mu M) and paracetamol (0-10 mM) was studied in metabolically competent mouse hepatocytes. metabolically incompetent human hepatoblastoma (HepG2) cells and in neuroblastoma (SH-SY5Y) and astrocytoma (U-373 MG) cells. by using luminescence-based ATP measurement as an endpoint of cell toxicity. The aim was to evaluate the potential of the,;elected cell Culture.,; 10 recognize metabolism-induced toxicity of the test compounds. and to predict further hepatic and neural toxicity. In SH-SY5Y cells amitriptyline was severely toxic. while selegiline and paracetamol failed to show any toxic effect. and carbainazepine was only slightly toxic at the highest concentration. In U-373 MG cells the onset of amitriptyline toxicity started earlier than in SH-SY5Y cells. However, the highest amitriptyline concentration resulted in similar to 100% decrease in the viability of the SH-SY5Y cells. whereas the decrease in the viability of the U-373 MG cells was only similar to 30%. Selegiline. carbamazepine and paracetamol were toxic in mouse hepatocytes (but not ill HepG2 Cells). which suggests that these drugs may show metabolism-dependent (neuro)toxicity. In conclusion. compared to the use of neurons alone. better estimations of neurotoxicity call be made by the combined U C Of metabolically competent hepatocytes and glial cells (e.g. U-373 MG) together with neuronal cells (e.g. SH-SY5Y). (c) 2006 Elsevier Ireland Ltd. All rights reserved.