Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast.
To better understand off-target effects of widely prescribed psychoactive drugs, we performed a comprehensive series of chemogenomic screens using the budding yeast Saccharomyces cerevisiae as a model system. Because the known human targets of these drugs do not exist in yeast, we could employ the yeast gene deletion collections and parallel fitness profiling to explore potential off-target effects in a genome-wide manner. Among 214 tested, documented psychoactive drugs, we identified 81 compounds that inhibited wild-type yeast growth and were thus selected for genome-wide fitness profiling. Many of these drugs had a propensity to affect multiple cellular functions. The sensitivity profiles of half of the analyzed drugs were enriched for core cellular processes such as secretion, protein folding, RNA processing, and chromatin structure. Interestingly, fluoxetine (Prozac) interfered with establishment of cell polarity, cyproheptadine (Periactin) targeted essential genes with chromatin-remodeling roles, while paroxetine (Paxil) interfered with essential RNA metabolism genes, suggesting potential secondary drug targets. We also found that the more recently developed atypical antipsychotic clozapine (Clozaril) had no fewer off-target effects in yeast than the typical antipsychotics haloperidol (Haldol) and pimozide (Orap). Our results suggest that model organism pharmacogenetic studies provide a rational foundation for understanding the off-target effects of clinically important psychoactive agents and suggest a rational means both for devising compound derivatives with fewer side effects and for tailoring drug treatment to individual patient genotypes.
Ericson
Elke
E
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario, Canada.
Gebbia
Marinella
M
Heisler
Lawrence E
LE
Wildenhain
Jan
J
Tyers
Mike
M
Giaever
Guri
G
Nislow
Corey
C
D016764:Cell Polarity / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance; D020869:Gene Expression Profiling; D016681:Genome, Fungal / Q000187:drug effects*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects
D011619:Psychotropic Drugs; D029701:Saccharomyces cerevisiae Proteins