title: The combined use of human neural and liver cell lines and mouse hepatocytes improves the predictability of the neurotoxicity of selected drugs.
abstract: 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).
authors.affiliation: Medical School, Cell Research Center, University of Tampere, Tampere FIN-33014, Finland. marika.mannerstrom@uta.fi
authors.forename: Marika
authors.initials: M
authors.lastname: Mannerström
authors.forename: Tarja
authors.initials: T
authors.lastname: Toimela
authors.forename: Timo
authors.initials: T
authors.lastname: Ylikomi
authors.forename: Hanna
authors.initials: H
authors.lastname: Tähti
mesh_terms: D000082:Acetaminophen / Q000633:toxicity; D000255:Adenosine Triphosphate / Q000378:metabolism; D000639:Amitriptyline / Q000633:toxicity; D000826:Animal Testing Alternatives / Q000379:methods; D000818:Animals; D002220:Carbamazepine / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002491:Central Nervous System Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D012642:Selegiline / Q000633:toxicity; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D002491:Central Nervous System Agents; D000639:Amitriptyline; D012642:Selegiline; D002220:Carbamazepine; D000082:Acetaminophen; D000255:Adenosine Triphosphate