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 amitriptyline (0-100microM), selegiline (0-4.5microM), carbamazepine (0-420microM) and paracetamol (0-10mM) 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 selected cell cultures to 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 carbamazepine 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 approximately 100% decrease in the viability of the SH-SY5Y cells, whereas the decrease in the viability of the U-373 MG cells was only approximately 30%. Selegiline, carbamazepine and paracetamol were toxic in mouse hepatocytes (but not in 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 can be made by the combined use of metabolically competent hepatocytes and glial cells (e.g. U-373 MG) together with neuronal cells (e.g. SH-SY5Y).