Modeling of Corticosteroid Pharmacogenomics in Rat Liver Using Gene Microarrays

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Abstract
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.