Modeling of corticosteroid pharmacogenomics in rat liver using gene microarrays
Modeling of corticosteroid pharmacogenomics in rat liver using gene microarrays
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DOI：
10.1124/jpet.103.053256
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发表时间：
2003-10-01
影响因子：
3.5
通讯作者：
Jusko, WJ
中科院分区：
文献类型：
--
作者：
Jin, JY;Almon, RR;Jusko, WJ
使用大鼠肝脏中的基因微阵列研究皮质类固醇（CS）药物基因组学。甲基泼尼松龙 (MPL) 以 50 mg/kg 静脉注射。 72 小时内的 17 个时间点处死大鼠并切除肝脏。来自个体肝脏的 RNA 用于查询包含 8000 个基因序列的 Affymetrix 基因芯片。聚类分析揭示了由代表 143 个基因的 197 个 CS 响应探针组成的 6 种时间模式。基于我们的第五代 CS 药代动力学/药效学 (PK/PD) 模型，开发了机制模型来描述每个 CS 响应基因的时间模式。两个簇表现出表达增加，但作用持续时间不同。应用假设 CS 刺激 mRNA 合成的 PK/PD 模型。另外两个簇表现出最初的下降，然后延迟增加，表明两种机制可能共同参与。最初的抑制是通过CS抑制mRNA合成或刺激降解来实现的。 CS 还可以刺激生物信号（转录因子或其他激素）的产生，从而引起目标 mRNA 的二次诱导。其中一个集群显示消息数量急剧增加，然后又迅速减少。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效应及其直接淋巴细胞运输效应进行建模。另一个簇显示减少持续 18 小时，这通过 CS 抑制 mRNA 合成来描述。我们的结果揭示了 CS 通过一系列有限的机制调节的基因的显着多样性。这些 PK/PD 模型提供了 CS 药物基因组学的定量以及有关了解 CS 受体基因介导作用的不同机制的新假设。
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.