Pathway-Based Analysis of the Liver Response to IntravenousMethylprednisolone Administration in Rats: Acute Versus ChronicDosing

摘要

Pharmacological time-series data, from comparative dosing studies, are critical to characterizing drug effects. Reconciling the data from multiple studies is inevitably difficu multiple in vivo high-throughput -omics studies are necessary to capture the global and temporal effects of the drug, but these experiments, though analogous, differ in (microarray or other) platforms, time-scales, and dosing regimens and thus cannot be directly combined or compared. This investigation addresses this reconciliation issue with a meta-analysis technique aimed at assessing the intrinsic activity at the pathway level. The purpose of this is to characterize the dosing effects of methylprednisolone (MPL), a widely used anti-inflammatory and immunosuppressive corticosteroid (CS), within the liver. A multivariate decomposition approach is applied to analyze acute and chronic MPL dosing in male adrenalectomized rats and characterize the dosing-dependent differences in the dynamic response of MPL-responsive signaling and metabolic pathways. We demonstrate how to deconstruct signaling and metabolic pathways into their constituent pathway activities, activities which are scored for intrinsic pathway activity. Dosing-induced changes in the dynamics of pathway activities are compared usinga model-based assessment of pathway dynamics, extending the principles ofpharmacokinetics/pharmacodynamics (PKPD) to describe pathway activities. Themodel-based approach enabled us to hypothesize on the likely emergence (ordisappearance) of indirect dosing-dependent regulatory interactions, pointing tolikely mechanistic implications of dosing of MPL transcriptional regulation.Both acute and chronic MPL administration induced a strong core of activitywithin pathway families including the following: lipid metabolism, amino acidmetabolism, carbohydrate metabolism, metabolism of cofactors and vitamins,regulation of essential organelles, and xenobiotic metabolism pathway families.Pathway activities alter between acute and chronic dosing, indicating that MPLresponse is dosing dependent. Furthermore, because multiple pathway activitiesare dominant within a single pathway, we observe that pathways cannot be definedby a single response. Instead, pathways are defined by multiple, complex, andtemporally related activities corresponding to different subgroups of geneswithin each pathway.