title: Editor's Highlight: 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, or mental retardation, these drugs display many side effects. Toxicogenomic studies aim to limit this problem by trying to identify cellular targets and off-targets of medical 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 of many 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 the most widely used drug in therapy. The results of a toxicogenomic screening performed on a yeast mutants 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.
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Caldara
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Graziano
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.|Interdepartmental Center SITEIA.PARMA, University of Parma, 43124 Parma, Italy.
authors.forename: Mariolina
authors.initials: M
authors.lastname: Gullì
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Cadonici
authors.affiliation: Department of Life Sciences, University of Parma, 43124 Parma, Italy.|Interdepartmental Center SITEIA.PARMA, University of Parma, 43124 Parma, Italy.
authors.forename: Nelson
authors.initials: N
authors.lastname: Marmiroli
mesh_terms: D000928:Antidepressive Agents / Q000633:toxicity*; D014150:Antipsychotic Agents / Q000633:toxicity*; D002746:Chlorpromazine / Q000633:toxicity*; D063990:Gene Ontology; D053263:Gene Regulatory Networks / Q000187:drug effects*; D055106:Genome-Wide Association Study; D008826:Microbial Sensitivity Tests; D060066:Protein Interaction Maps; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*; D043922:Toxicogenetics
chemical_list: D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D029701:Saccharomyces cerevisiae Proteins; D002746:Chlorpromazine
keywords: central nervous system drugs; functional toxicogenomic; gene expression; genome-wide screening; yeast