Assessing the Dynamics of Nuclear Glucocorticoid-Receptor Complex: Adding Flexibility to Gene Expression Modeling

Abstract

A retrospective analysis was performed to modify our fourth-generation pharmacodynamic model for glucocorticoid receptor (GR) dynamics with incorporation of more physiological features. This modified model was developed by integrating previously reported free cytosolic GR and GR mRNA data following single (10, 50 mg/kg) and dual (50 mg/kg at 0 and 24 hr) intravenous doses of methylprednisolone (MPL) in adrenalectomized (ADX) male Wistar rats with several in vitro studies describing real-time kinetics of the transfer of rat steroid-receptor complex from the cell cytosol to the nucleus. Additionally, free hepatic cytosolic GR and its mRNA data from a chronic infusion dosing study of MPL (0.1 and 0.3 mg/kg/hr) in male ADX Wistar rats were used to verify the predictability of the model. Incorporation of information regarding in vitro receptor kinetics allowed us to describe the receptor-mediated pharmacogenomic effects of MPL for a larger variety of genes in rat liver from microarray studies. These included early responsive gene like CCAAT/ enhancer binding protein-β (CEBP-β), a transcription factor, as well as the later responsive gene for tyrosine aminotransferase (TAT), a classical biomarker of glucocorticoid (GC) genomic effects. This more mechanistic model of GR dynamics can be applied to characterize profiles for a greater number of genes in liver.

Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids

“…Figure 7A shows simulated profiles for free MPL concentrations, cytosolic DR, and nuclear DR(N) profiles. The formation and dissipation (translocation half-life: 5 min) of the DR is quite rapid as has previously been reported in various in vitro studies [44,45] based on which the cytosolic-nuclear translocation constant of DR was fixed to 58.5 h −1 [46]. The DR(N) was used as the driving force to regulate the down-regulation of GR mRNA.…”

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis I: Mechanistic Disease Progression Model for the Time Course of Collagen-Induced Arthritis in Lewis Rats

“…The fifth-generation model for corticosteroid dynamics proposed by Ramakrishnan et al (2002) and modified by Hazra et al (2007aHazra et al ( ,b, 2008 was adapted and applied to the effects of endogenous corticosterone via the glucocorticoid receptor on cytokine mRNA production, GR mRNA production, paw edema, and bone mineral density. The equation describing GR mRNA turnover is as follows:…”

“…The parameter k RE_C describes the rate of which corticosterone bound to receptor returns from the nucleus, and RF is the fraction that returns intact and active. The values for k dgr_GR and RF were fixed from the literature (Ramakrishnan et al, 2002;Hazra et al, 2007aHazra et al, ,b, 2008 (Buchwald, 2008). The parameter ff GC ⅐ k on_C accounts for the fraction of drug in plasma that is capable of binding in tissue.…”

“…) between DR and DR N was derived previously (Ramakrishnan et al, 2002;Hazra et al, 2007aHazra et al, ,b, 2008 and is fixed for all CS in this model. IC 50_GRm/DRN is the concentration of DR N required to inhibit GR mRNA production by 50%, and ␥DR is the Hill coefficient for inhibition by DR N .…”

Modeling Corticosteroid Effects in a Rat Model of Rheumatoid Arthritis II: Mechanistic Pharmacodynamic Model for Dexamethasone Effects in Lewis Rats with Collagen-Induced Arthritis

“…The parameter RF is the fraction of GR that returns intact and active. The values for k dgr_GR and RF were fixed from previous studies (Hazra et al, 2007a(Hazra et al, ,b, 2008 (Buchwald, 2008). The model assumes that CST equilibrium between vasculature and tissue is immediate.…”