Metabolism-Induced Toxicity of Selegiline and Carbamazepine Studied with an In Vitro Method

Carbamazepine and selegiline, although neuroprotective themselves, are presumed to have toxic metabolites. The aim of this study was to investigate the possible metabolism-induced toxicity of selegiline and carbamazepine with a novel in vit ro method: The drugs were incubated with target cells (neuroblastoma SH-SY5Y) with or without a preincubation with mouse or human hepatocytes. The viability of SH-SY5Y cells was then measured by using total cellular ATP as an indicator of the cell viability. For the pre-incubation with hepatocytes two different methods were used: Hepatocytes were grown either in multiwell plates (Model 1) or in filter inserts (Model 2). Selegiline itself increased SH-SY5Y viability, but the pre-incubation with both mouse and human hepatocytes made selegiline slightly toxic to SH-SY5Y cells. The biotransformation of carbamazepine seemed to be more complex and showed variation in different hepatocyte models. In general, human hepatocytes increased carbamazepine toxicity to SHSY5Y cells, whereas mouse hepatocytes had no such effect. The methodology used (especially Model 1) could form a basis in developing a test system for a qualitative detection of metabolism-induced (neuro)toxicity in the early phase of drug discovery. In this respect, the present study might be promising for further evaluation by means of a larger number of independent experiments and different types of compounds.