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.

Known Antimicrobials Versus Nortriptyline in Candida albicans: Repositioning an Old Drug for New Targets

“…Similarly, exposure of a mature biofilm to AMB or CAS changes the expression of ribosome biogenesis-related genes [42]. A different concentration of proteins involved in mismatch repair and DNA replication makes the yeast more tolerant to NOR, a phenotype not linked to DNA damage, as the latter was observed only at drug concentrations higher than those used in this work, and to that employed to treat depression syndromes [43]. It is interesting to note that many of the targets are regulated by the transcription factor Hap43, a protein with pleiotropic functions (i.e., iron homeostasis, chromosome biogenesis, and filamentation [44]).…”

Clotrimazole-Induced Oxidative Stress Triggers Novel Yeast Pkc1-Independent Cell Wall Integrity MAPK Pathway Circuitry

“…As we have observed for CLT, chlorpromazine (CPZ) has been reported to alter the plasma membrane, induce ROS production, and activate the yeast CWI pathway [ 51 , 52 ]. Therefore, we analyzed whether CPZ has a similar impact on yeast MAPK signaling to that of CLT.…”

“…CPZ also induces the unfolded protein response and inhibits protein synthesis [ 72 ]. Interestingly, CPZ also induces oxidative stress with high ROS generation not only in mammalian [ 73 ] but also in yeast cells [ 51 ], in which it also promotes an Slt2 phosphorylation pattern similar to CLT, suggesting the involvement of the same MAPK signaling circuitry. Fourth, the activity of the PKA pathway was linked to mitochondrial damage and ROS generation via Tpk3, which is a master regulator of mitochondrial activity.…”

Antimicrobial Properties of Antidepressants and Antipsychotics—Possibilities and Implications

“…Chemogenomic profiling with a haploinsufficiency approach focused on C. albicans mutants identified the following processes and systems as possible targets of nortriptyline: oxidative phosphorylation, fatty acid metabolism, ribosome biogenesis and machinery, RNA binding, and the RNA splicing apparatus [ 73 , 106 ]. Following the same approach, the targets of the TCA chlorpromazine in S. cerevisiae were suggested to be the regulation of cell cycle, cell wall biogenesis, aromatic amino acid biosynthesis, and response to chemicals [ 106 ]. With the same approach, Ericson et al, showed that in S. cerevisiae , the most notable effect of fluoxetine was on the establishment of polarity, that of paroxetine was RNA processing, and that of sertraline was vesicle-mediated transport [ 107 ].…”