Jin Jin Y, Almon Richard R, DuBois Debra C, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 565 Hochstetter Hall, State University of New York at Buffalo, 14260, USA.
J Pharmacol Exp Ther. 2003 Oct;307(1):93-109. doi: 10.1124/jpet.103.053256. Epub 2003 Jun 13.
Corticosteroid (CS) pharmacogenomics was studied using gene microarrays in rat liver. Methylprednisolone (MPL) was administered intravenously at 50 mg/kg. Rats were sacrificed and liver excised at 17 time points over 72 h. RNAs from individual livers were used to query Affymetrix GeneChips that contain sequences for 8000 genes. Cluster analysis revealed six temporal patterns consisting of 197 CS-responsive probes representing 143 genes. Based on our fifth-generation model of CS pharmacokinetics/pharmacodynamics (PK/PD), mechanistic models were developed to describe the time pattern for each CS-responsive gene. Two clusters showed increased expression with different effect duration. PK/PD models assuming CS stimulation of mRNA synthesis were applied. Another two clusters showed an initial decline followed by delayed increase, suggesting two mechanisms might be involved jointly. The initial suppression was captured by CS inhibition of mRNA synthesis or stimulation of degradation. CS may also stimulate the production of a biosignal (transcription factors or other hormones), which can cause secondary induction of the target mRNA. One cluster showed a very abrupt increase in message followed by rapid decrease. These genes were lymphocytic in origin and were modeled combining the fast gene induction effect of CS in lymphoid cells and its direct lymphocyte trafficking effect. Another cluster showed reduction persisting for 18 h, which was described by CS inhibition of mRNA synthesis. Our results reveal the marked diversity of genes regulated by CS via a limited array of mechanisms. These PK/PD models provide quantitation of CS pharmacogenomics and new hypotheses regarding understanding of diverse mechanisms of CS receptor-gene mediated action.
利用基因芯片在大鼠肝脏中研究了皮质类固醇（CS）药物基因组学。以50mg/kg的剂量静脉注射甲泼尼龙（MPL）。在72小时内的17个时间点处死大鼠并切除肝脏。从单个肝脏中提取的RNA用于检测包含8000个基因序列的Affymetrix基因芯片。聚类分析揭示了六种时间模式，由代表143个基因的197个CS反应性探针组成。基于我们的CS药代动力学/药效学（PK/PD）第五代模型，建立了机制模型来描述每个CS反应性基因的时间模式。两个聚类显示表达增加且作用持续时间不同。应用了假设CS刺激mRNA合成的PK/PD模型。另外两个聚类显示最初下降随后延迟增加，表明可能涉及两种机制。最初的抑制是由CS抑制mRNA合成或刺激降解引起的。CS也可能刺激生物信号（转录因子或其他激素）的产生，这可导致靶mRNA的二次诱导。一个聚类显示信息非常突然地增加随后迅速下降。这些基因起源于淋巴细胞，并结合CS在淋巴细胞中的快速基因诱导作用及其直接的淋巴细胞运输作用进行建模。另一个聚类显示持续18小时的减少，这是由CS抑制mRNA合成来描述的。我们的结果揭示了CS通过有限的一系列机制调节的基因的显著多样性。这些PK/PD模型提供了CS药物基因组学的定量分析以及关于理解CS受体 - 基因介导作用的多种机制的新假设。
