Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast.
Off-target effects of psychoactive drugs revealed by genome-wide assays in yeast.
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DOI：
10.1371/journal.pgen.1000151
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发表时间：
2008-08-08
期刊：
影响因子：
4.5
通讯作者：
Nislow C
中科院分区：
文献类型：
--
作者：
Ericson E;Gebbia M;Heisler LE;Wildenhain J;Tyers M;Giaever G;Nislow C
为了更好地了解广泛使用的精神活性药物的脱靶效应，我们使用芽殖酵母酿酒酵母作为模型系统进行了一系列全面的化学基因组学筛选。由于这些药物的已知人类靶点不存在于酵母中，因此我们可以采用酵母基因缺失集合和平行适应性分析来以全基因组方式探索潜在的脱靶效应。在214种经过测试的精神活性药物中，我们确定了81种抑制野生型酵母生长的化合物，并因此选择用于全基因组适应性分析。这些药物中有许多倾向于影响多种细胞功能。一半的分析药物的敏感性曲线富集了核心细胞过程，如分泌，蛋白质折叠，RNA加工和染色质结构。有趣的是，氟西汀（百忧解）干扰细胞极性的建立，赛庚啶（Periactin）靶向具有染色质重塑作用的必需基因，而帕罗西汀（Paxil）干扰必需的RNA代谢基因，提示潜在的次要药物靶点。我们还发现，最近开发的非典型抗精神病药物氯氮平（Clozaril）在酵母中的脱靶效应并不比典型抗精神病药物氟哌啶醇（Haldol）和匹莫齐特（Orap）少。我们的研究结果表明，模式生物遗传药理学研究提供了一个合理的基础，了解临床上重要的精神活性药物的脱靶效应，并提出了一个合理的手段，设计化合物衍生物的副作用少，并定制药物治疗个别患者的基因型。抑郁症和精神病等神经精神障碍影响了四分之一的人，尽管努力提高精神活性药物的选择性，但所有这些都与副作用有关。已知药物疗效和耐受性与个体的遗传特征有关，但对这种相关性的性质知之甚少，部分原因是目前强调筛选体外靶向化合物。在这里，我们提出了一项全面的全基因组努力，使用无偏见的全基因组测定来了解药物在细胞水平上的影响，以确定每个酵母基因对81种精神活性药物耐受性的重要性。我们发现这些药物扰乱了许多进化上保守的基因和细胞通路，例如囊泡运输、细胞极性建立和染色体生物学所需的基因和细胞通路。这项研究中获得的50万个药物基因测量值增加了我们对精神活性药物作用机制的理解。具体来说，这项研究提供了一个框架，以评估下一代的精神活性药物，并指导个性化的医疗方法，关联基因型和表型。
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. Neuropsychiatric disorders such as depression and psychosis affect one-quarter of all individuals during their lifetime, and despite efforts to improve the selectivity of psychoactive drugs, all are associated with side effects. Drug efficacy and tolerance are known to be linked to an individual's genetic profile, but little is known about the nature of this correlation due, in part, to the current emphasis on screening compounds against targets in vitro. Here we present a comprehensive, genome-wide effort to understand drug effects on the cellular level using an unbiased genome-wide assay to determine the importance of every yeast gene for tolerance to 81 psychoactive drugs. We found that these medications perturbed many evolutionarily conserved genes and cellular pathways, such as those required for vesicle transport, establishment of cell polarity, and chromosome biology. The 500,000 drug–gene measurements obtained in this study increase our understanding of the mechanism of action of psychoactive drugs. Specifically, this study provides a framework to assess the next generation of psychoactive agents and to guide personalized medicine approaches that associate genotype and phenotype.
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