Almon Richard R, DuBois Debra C, Pearson Keri E, Stephan Dietrich A, Jusko William J
Department of Biological Sciences, SUNY at Buffalo, 107 Hochstetter Hall, Buffalo, NY 14260, USA.
Funct Integr Genomics. 2003 Dec;3(4):171-9. doi: 10.1007/s10142-003-0090-x. Epub 2003 Aug 20.
It was hypothesized that expression profiling using gene arrays can be used to distinguish temporal patterns of changes in gene expression in response to a drug in vivo, and that these patterns can be used to identify groups of genes regulated by common mechanisms. A corticosteroid, methylprednisolone (MPL), was administered intravenously to a group of 47 rats ( Rattus rattus) that were sacrificed at 17 timepoints over 72 h after MPL administration. Plasma drug concentrations and hepatic glucocorticoid receptors were measured from each animal. In addition, RNAs prepared from individual livers were used to query Affymetrix genechips for mRNA expression patterns. Statistical analyses using Affymetrix and GeneSpring software were applied to the results. Cluster analysis revealed six major temporal patterns containing 196 corticosteroid-responsive probe sets representing 153 different genes. Four clusters showed increased expression with differences in lag-time, onset rate, and/or duration of transcriptional effect. A fifth cluster showed rapid reduction persisting for 18 h. The final cluster identified showed decreased expression followed by an extended period of increased expression. These results lend new insights into the diverse hepatic genes involved in the physiologic, therapeutic, and adverse effects of corticosteroids and suggest that a limited array of control processes account for the dynamics of their pharmacogenomic effects.
据推测，利用基因芯片进行表达谱分析可用于区分体内药物作用下基因表达变化的时间模式，且这些模式可用于识别受共同机制调控的基因群。对一组47只大鼠（褐家鼠）静脉注射皮质类固醇甲泼尼龙（MPL），在注射MPL后72小时内的17个时间点将其处死。测量每只动物的血浆药物浓度和肝糖皮质激素受体。此外，从个体肝脏中提取的RNA用于检测Affymetrix基因芯片的mRNA表达模式。使用Affymetrix和GeneSpring软件对结果进行统计分析。聚类分析揭示了六种主要的时间模式，包含196个皮质类固醇反应探针集，代表153个不同基因。四个聚类显示表达增加，转录效应的延迟时间、起始速率和/或持续时间存在差异。第五个聚类显示持续18小时的快速降低。最后一个聚类显示表达降低，随后是一段延长的表达增加期。这些结果为参与皮质类固醇生理、治疗和不良反应的多种肝脏基因提供了新的见解，并表明有限的一组控制过程解释了其药物基因组效应的动态变化。
