Skip to main content
SpringerLink
Log in

Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver

  • Published:
Journal of Pharmacokinetics and Biopharmaceutics Aims and scope Submit manuscript

Abstract

A third-generation pharmacokinetic/pharmacodynamic model was proposed for receptor/genemediated corticosteroid effects. The roles of the messenger RNA (mRNA) for the glucocorticoid receptor (GR) in hepatic GR down-regulation and the mRNA for hepatic tyrosine aminotransferase (TAT) induction by methylprednisolone (MPL) were examined. Male adrenalectomized Wistar rats received 50 mg/kg MPL iv. Blood and liver samples were collected at various time points for a period of 18 hr. Plasma concentrations of MPL, free hepatic cytosolic GR densities, GR mRNA, TAT mRNA, and TAT activities in liver were determined. Plasma MPL profile was biexponential with a terminal t1/2 of 0.57 hr. Free hepatic GR density rapidly disappeared from cytoplasm after the MPL dose and then slowly returned to about 60% of starting level after 16 hr. Meanwhile, GR mRNA level fell to 45% of baseline within 2 hr postdosing, and remained at that level for at least 18 hr. The GR down-regulation of GR mRNA and protein turnover rate were modeled. The TAT mRNA began to increase at about 2 hr, reached a maximum at about 5 hr, and declined to baseline by 14 hr. TAT induction followed a similar pattern, except the induction was delayed about 0.5 hr. Pharmacodynamic parameters were obtained by fitting seven differential equations in a piecewise fashion. The cascade of corticosteroid steps were modeled by a series of inductions for steroid-receptor-DNA complex, two intermediate transit compartments, TAT mRNA, and TAT activity. Results indicate that GR mRNA and TAT mRNA are major controlling factors for the receptor/gene-mediated effects of corticosteroids.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. A. Reinberg, M. H. Smolensky, G. E. D'Alonzo, and J. P. McGovern. Chronobiology and asthma. III: Timing corticotherapy to biologic rhythms to optimize treatment goals.J. Asthma 25:219–248 (1988).

    Article  CAS  PubMed  Google Scholar 

  2. J. A. Wald, D. E. Salazar, H. Cheng, and W. J. Jusko. Two-compartment basophil cell trafficking model for methylprednisolone pharmacodynamics.J. Pharmacokin. Biopharm. 19:521–536 (1991).

    Article  CAS  Google Scholar 

  3. L. E. Fisher, E. A. Ludwig, and W. J. Jusko. Pharmacoimmunodynamics of methylprednisolone: Trafficking of helper-T lymphocytes.J. Pharmacokin. Biopharm. 20:319–331 (1992).

    Article  CAS  Google Scholar 

  4. M. Izawa, A. Yosida, and S. Ichii. Dynamics of glucocorticosteroid receptor and induction of tyrosine aminotransferase in rat liver.Endocrinol. Japan 29:209–218 (1982).

    Article  CAS  Google Scholar 

  5. A. I. Nichols and W. J. Jusko. Receptor mediated prednisolone pharmacodynamics in rat: Model verification using a dose-sparing regimen.J. Pharmacokin. Biopharm. 18:189–208 (1990).

    Article  CAS  Google Scholar 

  6. S. S. Simons, Jr. Structure-activity relationships of glucocorticoids: Importance of the regulated gene and trans-acting factors in determining glucocorticoid and antigluco-corticoid activity. In M. Bohl and W. L. Duax (eds.),Molecular Structure and Biological Activity of Steroids, CRC Press, 1992, pp. 260–279.

  7. F. D. Boudinot, R. D'Ambrosio, and W. J. Jusko. Receptor-mediated pharmacodynamics of prednisolone in the rat.J. Pharmacokin. Biopharm. 14:469–493 (1986).

    Article  CAS  Google Scholar 

  8. A. I. Nichols, F. D. Boudinot, and W. J. Jusko. Second-generation model for prednisolone pharmacodynamics in the rat.J. Pharmacokin. Biopharm. 17:209–227 (1989).

    Article  CAS  Google Scholar 

  9. D. B. Haughey and W. J. Jusko. Receptor-mediated methylprednisolone pharmacodynamics in rats: Steroid-induced receptor down-regulation.J. Pharmacokin. Biopharm. 19:333–355 (1992).

    Article  Google Scholar 

  10. D. C. DuBois, R. R. Almon, and W. J. Jusko. Molar quantification of specific messenger ribonucleic acid expression in Northern hybridization using cRNA standards.Anal. Biochem. 210:140–144 (1993).

    Article  CAS  PubMed  Google Scholar 

  11. Y. Dong, L. Poellinger, J.-A. Gustafsson, and S. Okret. Regulation of glucocorticoid receptor expression: Evidence for transcriptional and posttranslational mechanism.Mol. Endocrinol. 2:1256–1264 (1988).

    Article  CAS  PubMed  Google Scholar 

  12. J. M. Nichols, K.-L. Lee, and F. T. Kenney. Changes in hepatic levels of tyrosine aminotransferase messenger RNA during induction by hydrocortisone.J. Biol. Chem. 253:4009–4015 (1978).

    Google Scholar 

  13. R. M. Oakley and J. A. Cidlowski. Homologous down-regulation of the glucocorticoid receptor: The molecular machinery.Crit. Rev. Eukary. Gen. Expr. 3:63–88 (1993).

    CAS  Google Scholar 

  14. A. Munck, D. B. Mendel, L. I. Smith, and E. Orti. Glucocorticoid receptors and actions.Am. Rev. Resp. Dis. 141:S2-S10 (1990).

    Article  CAS  PubMed  Google Scholar 

  15. E. Orti, D. B. Mendel, L. I. Smith, J. E. Bodwell, and A. Munck. A dynamic model of glucocorticoid receptor phosphorylation and cycling in intact cells.J. Steroid Biochem. 34:85–96 (1989).

    Article  CAS  PubMed  Google Scholar 

  16. K. Dahlman-Wright, A. Wright, J. Carlstedt-Duke, and J.-A. Gustafsson. DNA-binding by the glucocorticoid receptor: A structural and functional analysis.J. Steroid Biochem. Mol. Biol. 41:249–272 (1992).

    Article  CAS  PubMed  Google Scholar 

  17. A. Munck and N. J. Holbrook. Glucocorticoid-receptor complexes in rat thymus cells: Rapid kinetic behavior and a cyclic model.J. Biol. Chem. 259:820–831 (1984).

    CAS  PubMed  Google Scholar 

  18. W. F. Ebling, S. J. Szefler, and W. J. Jusko. Methylprednisolone disposition in rabbits: Analysis, prodrug conversion, reversible metabolism and comparison with man.Drug Metab. Dispos. 13:296–304 (1985).

    CAS  PubMed  Google Scholar 

  19. J. M. Chirgwin, A. E. Przybyla, R. J. MacDonald, and W. J. Rutter. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease.Biochemistry 18:5294–5299 (1979).

    Article  CAS  PubMed  Google Scholar 

  20. P. A. Krieg and D. A. melton.In vitro RNA synthesis with SP6 RNA polymerase.Meth. Enzymol. 155:397–415 (1987).

    Article  CAS  PubMed  Google Scholar 

  21. D. C. DuBois, Z.-X. Xu, L. McKay, R. R. Almon, N. Pyszczynski, and W. J. Jusko. Differential dynamics of receptor down-regulation and tyrosine aminotransferase induction following glucocorticoid treatment.J. Steroid. Biochem. Mol. Biol. 54:237–243 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. J. P. Northrop, M. Danielsen, and G. M. Ringold. Analysis of glucocorticoid unresponsive cell variants using a mouse glucocorticoid receptor complementary DNA clone.J. Biol. Chem. 261:11064–11070 (1986).

    CAS  PubMed  Google Scholar 

  23. T. I. Diamondstone. Assay of tyrosine aminotransferase activity by conversion of phydroxyphenylpyruvate to p-hydroxybenzaldehyde.Anal. Biochem. 16:395–401 (1966).

    Article  CAS  Google Scholar 

  24. O. M. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall. Protein measurement with the Folin phenol reagent.J. Biol. Chem. 173:265–272 (1951).

    Google Scholar 

  25. L. Z. Benet and R. L. Galeazzi. Noncompartmental determination of the steady-state volume of distribution.J. Pharm. Sci. 68:1071–1074 (1979).

    Article  CAS  PubMed  Google Scholar 

  26. J. Gorski and F. Gannon. Current models of steroid hormone action: A critique.Ann. Rev. Physiol. 38:425–450 (1970).

    Article  Google Scholar 

  27. M. L. Rocci and W. J. Jusko. LAGRAN program for area and moments in pharmacokinetic analysis.Comput. Prog. Biomed. 16:203–216 (1983).

    Article  Google Scholar 

  28. D. B. Haughey and W. J. Jusko. Reversible metabolism and nonlinear disposition of methylprednisolone in the rat.Pharm. Res. 6:S181 (1990). (Abstract).

    Google Scholar 

  29. D. B. Haughey. Dose-dependent pharmacokinetics and receptor-mediated pharmacodynamics of methylprednisolone in the rat. Ph.D. dissertation, SUNY at Buffalo, 1990.

  30. J. B. Houston. Drug metabolite kinetics.Pharmacol. Ther. 15:521–552 (1982).

    Article  Google Scholar 

  31. C. C. Peck, S. L. Beal, L. B. Sheiner, and A. I. Nichols. Extend least squares nonlinear regression: A possible solution to the “choice of weights” problem in analysis of individual pharmacokinetic data.J. Pharmacokin. Biopharm. 12:545–558 (1984).

    Article  CAS  Google Scholar 

  32. D. Z. D'Argenio and A. Schumitzky. ADAPT II program menu: Mathematical software for pharmacokinetic/pharmacodynamic systems analysis. Biomedical Simulation Resource, Los Angeles, CA (1992).

    Google Scholar 

  33. W. Wahle and E. Martinez. Superfamily of steroid nuclear receptors: positive and negative regulator of gene expression.FASEB J. 5:2243–2249 (1991).

    Google Scholar 

  34. D. J. Diamond and H. M. Goodman. Regulation of growth hormone messenger RNA synthesis by dexamethasone and triiodothyronine: Transcriptional rate and mRNA stability changes in pituitary tumor cells.J. Mol. Biol. 181:41–62 (1985).

    Article  CAS  PubMed  Google Scholar 

  35. I. Paek and R. Axel. Glucocorticoids enhance stability of human growth hormone mRNA.Mol. Cell Biol. 7:1496–1507 (1987).

    CAS  PubMed Central  PubMed  Google Scholar 

  36. W. Ankenbauer, U. Strahle, and G. Schutz. Synergistic action of glucocorticoid and estradiol responsive elements.Proc. Natl. Acad. Sci. U.S.A. 85:7526–7530 (1988).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Zhi-Xin Xu

    Present address: Hoffman La Roche, 07110, Nutley, New Jersey

Authors and Affiliations

  1. Department of Pharmaceutics, School of Pharmacy, State University of New York at Buffalo, 14260, Buffalo, New York

    Zhi-Xin Xu, Yu-Nien Sun & William J. Jusko

  2. Department of Biological Sciences, State University of New York at Buffalo, 14260, Buffalo, New York

    Debra C. DuBois & Richard R. Almon

Authors
  1. Zhi-Xin Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu-Nien Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Debra C. DuBois
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard R. Almon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. William J. Jusko
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This work was supported by Grant GM 24211 from the National Institute of General Medical Sciences, NIH.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, ZX., Sun, YN., DuBois, D.C. et al. Third-generation model for corticosteroid pharmacodynamics: Roles of glucocorticoid receptor mRNA and tyrosine aminotransferase mRNA in rat liver. Journal of Pharmacokinetics and Biopharmaceutics 23, 163–181 (1995). https://doi.org/10.1007/BF02354270

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02354270

Key Words

Search

Navigation