Off-target effects of neuroleptics and antidepressants on saccharomyces cerevisiae

Abstract

Over the past years, the use of antidepressants and neuroleptics has steadily increased. Although incredibly useful to treat disorders like depression, schizophrenia, epilepsy, ormental retardation, these drugs displaymany side effects. Toxicogenomic studies aim to limit this problemby trying to identify cellular targets and off-targets ofmedical compounds. The baker yeast Saccharomyces cerevisiae has been shown to be a key player in this approach, as it represents an incredible toolbox for the dissection of complex biological processes. Moreover, the evolutionary conservation ofmany pathways allows the translation of yeast data to the human system. In this paper, a better attention was paid to chlorpromazine, as it still is one of themost widely used drug in therapy. The results of a toxicogenomic screening performed on a yeastmutants collection treated with chlorpromazine were instrumental to identify a set of genes for further analyses. For this purpose, a multidisciplinary approach was used based on growth phenotypes identification, Gene Ontology search, and network analysis. Then, the impacts of three antidepressants (imipramine, doxepin, and nortriptyline) and three neuroleptics (promazine, chlorpromazine, and promethazine) on S. cerevisiae were compared through physiological analyses,microscopy characterization, and transcriptomic studies. Data highlight key differences between neuroleptics and antidepressants, but also between the individual molecules. By performing a network analysis on the human homologous genes, it emerged that genes and proteins involved in the Notch pathway are possible off-targets of these molecules, along with key regulatory proteins.