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Gene arrays and temporal patterns of drug response: corticosteroid effects on rat liver.

ABSTRACT: 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.

SUBMITTER: Almon RR

PROVIDER: S-EPMC4207265 | biostudies-literature | 2003 Dec

REPOSITORIES: biostudies-literature

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Gene arrays and temporal patterns of drug response: corticosteroid effects on rat liver.

Almon Richard R RR DuBois Debra C DC Pearson Keri E KE Stephan Dietrich A DA Jusko William J WJ

Functional & integrative genomics 20030820 4

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 glucoco ...[more]

PMID: 12928814

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Project description:Comprehensively understanding corticosteroid pharmacogenomic effects is an essential step towards an insight into the underlying molecular mechanisms for both beneficial and detrimental clinical effects. Nevertheless, even in a single tissue different methods of corticosteroid administration can induce different patterns of expression and regulatory control structures. Therefore, rich in vivo datasets of pharmacological time-series with two dosing regimens sampled from rat liver are examined for temporal patterns of changes in gene expression and their regulatory commonalities.The study addresses two issues, including (1) identifying significant transcriptional modules coupled with dynamic expression patterns and (2) predicting relevant common transcriptional controls to better understand the underlying mechanisms of corticosteroid adverse effects. Following the orientation of meta-analysis, an extended computational approach that explores the concept of agreement matrix from consensus clustering has been proposed with the aims of identifying gene clusters that share common expression patterns across multiple dosing regimens as well as handling challenges in the analysis of microarray data from heterogeneous sources, e.g. different platforms and time-grids in this study. Six significant transcriptional modules coupled with typical patterns of expression have been identified. Functional analysis reveals that virtually all enriched functions (gene ontologies, pathways) in these modules are shown to be related to metabolic processes, implying the importance of these modules in adverse effects under the administration of corticosteroids. Relevant putative transcriptional regulators (e.g. RXRF, FKHD, SP1F) are also predicted to provide another source of information towards better understanding the complexities of expression patterns and the underlying regulatory mechanisms of those modules.We have proposed a framework to identify significant coexpressed clusters of genes across multiple conditions experimented from different microarray platforms, time-grids, and also tissues if applicable. Analysis on rich in vivo datasets of corticosteroid time-series yielded significant insights into the pharmacogenomic effects of corticosteroids, especially the relevance to metabolic side-effects. This has been illustrated through enriched metabolic functions in those transcriptional modules and the presence of GRE binding motifs in those enriched pathways, providing significant modules for further analysis on pharmacogenomic corticosteroid effects.

Project description:Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS.Clinical use of corticosteroid (CS) therapy is frequent and chronic. However, current knowledge on the proteome-level effects of CS in liver and other tissues is sparse. While transcriptomic regulation following methylprednisolone (MPL) dosing has been temporally examined in rat liver, proteomic assessments are needed to better characterize the tissue-specific functional aspects of MPL actions. This study describes a functional pharmacoproteomic analysis of dynamic changes in MPL-regulated proteins in liver and provides biological insight into how steroid-induced perturbations on a molecular level may relate to both adverse and therapeutic responses presented clinically.

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Gene arrays and temporal patterns of drug response: corticosteroid effects on rat liver.

Publications

Gene arrays and temporal patterns of drug response: corticosteroid effects on rat liver.

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