Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver
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A multiscale pharmacodynamic model was developed to characterize the receptor-mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPβ) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated. The MPL-induced suppression of circulating lymphocytes was modeled by coupling its effect on cell trafficking with pharmacogenomic effects on cell apoptosis via the hepatic (STAT3-regulated) acute phase response. Transcriptomic and proteomic time-course profiles measured in steroid-treated rat liver were utilized to model the dynamics of mechanistically relevant gene products, which were linked to associated systemic end-points. While time-courses of TAT mRNA, protein, and activity were well described by transcription-mediated changes, additional post-transcriptional processes were included to explain the lack of correlation between PEPCK mRNA and protein. The immune response model quantitatively discerned the relative roles of cell trafficking versus gene-mediated lymphocyte apoptosis by MPL. This systems pharmacodynamic model provides insights into the contributions of selected molecular events occurring in liver and explores mechanistic hypotheses for the multi-factorial control of clinically relevant pharmacodynamic outcomes.
KeywordsPK/PD systems modeling Pharmacogenomics Proteomics mRNA–protein Methylprednisolone Liver
This work was supported by the National Institutes of Health—National Institute of General Medical Sciences (Grant GM24211).
- 9.Hazra A, Pyszczynski N, DuBois DC, Almon RR, Jusko WJ (2007) Modeling receptor/gene-mediated effects of corticosteroids on hepatic tyrosine aminotransferase dynamics in rats: dual regulation by endogenous and exogenous corticosteroids. J Pharmacokinet Pharmacodyn 34:643–667CrossRefPubMedPubMedCentralGoogle Scholar
- 28.Nouri-Nigjeh E, Sukumaran S, Tu C, Li J, Shen X, Duan X, DuBois DC, Almon RR, Jusko WJ, Qu J (2014) Highly multiplexed and reproducible ion-current-based strategy for large-scale quantitative proteomics and the application to protein expression dynamics induced by methylprednisolone in 60 rats. Anal Chem 86:8149–8157CrossRefPubMedPubMedCentralGoogle Scholar
- 35.Ramakrishnan R, DuBois DC, Almon RR, Pyszczynski NA, Jusko WJ (2002) Fifth-generation model for corticosteroid pharmacodynamics: application to steady-state receptor down-regulation and enzyme induction patterns during seven-day continuous infusion of methylprednisolone in rats. J Pharmacokinet Pharmacodyn 29:1–24CrossRefPubMedPubMedCentralGoogle Scholar
- 39.Park EA, Gurney AL, Nizielski SE, Hakimi P, Cao Z, Moorman A, Hanson RW (1993) Relative roles of CCAAT/enhancer-binding protein beta and cAMP regulatory element-binding protein in controlling transcription of the gene for phosphoenolpyruvate carboxykinase (GTP). J Biol Chem 268:613–619PubMedGoogle Scholar
- 40.Park EA, Roesler WJ, Liu J, Klemm DJ, Gurney AL, Thatcher JD, Shuman J, Friedman A, Hanson RW (1990) The role of the CCAAT/enhancer-binding protein in the transcriptional regulation of the gene for phosphoenolpyruvate carboxykinase (GTP). Mol Cell Biol 10:6264–6272CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Woltje M, Tschoke B, von Bulow V, Westenfeld R, Denecke B, Graber S, Jahnen-Dechent W (2006) CCAAT enhancer binding protein beta and hepatocyte nuclear factor 3beta are necessary and sufficient to mediate dexamethasone-induced up-regulation of alpha2HS-glycoprotein/fetuin-A gene expression. J Mol Endocrinol 36:261–277CrossRefPubMedGoogle Scholar
- 57.D’Argenio D, Schumitzky A, Wang X (2009) ADAPT 5 user’s guide: Pharmacokinetic/pharmacodynamic systems analysis softwareGoogle Scholar
- 59.Sun YN, DuBois DC, Almon RR, Jusko WJ (1998) Fourth-generation model for corticosteroid pharmacodynamics: a model for methylprednisolone effects on receptor/gene-mediated glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver. J Pharmacokinet Biopharm 26:289–317CrossRefPubMedGoogle Scholar
- 65.Kamisoglu K, Sukumaran S, Nouri-Nigjeh E, Tu C, Li J, Shen X, Duan X, Qu J, Almon RR, DuBois DC, Jusko WJ, Androulakis IP (2015) Tandem analysis of transcriptome and proteome changes after a single dose of corticosteroid: a systems approach to liver function in pharmacogenomics. OMICS 19:80–91CrossRefPubMedPubMedCentralGoogle Scholar
- 66.Sun YN, DuBois DC, Almon RR, Pyszczynski NA, Jusko WJ (1998) Dose-dependence and repeated-dose studies for receptor/gene-mediated pharmacodynamics of methylprednisolone on glucocorticoid receptor down-regulation and tyrosine aminotransferase induction in rat liver. J Pharmacokinet Biopharm 26:619–648CrossRefPubMedGoogle Scholar