Inverse correlation between dexamethasone 21-mesylate agonist activity and sensitivity to dexamethasone for induction of tyrosine aminotransferase in rat hepatoma cells

Abstract

Previous results demonstrated that both the level of induction of the liver specific enzyme tyrosine aminotransferase (TAT) by the irreversible antiglucocorticoid dexamethasone 21-mesylate (Dex-Mes) and the concentration of the reversible glucocorticoid dexamethasone (Dex) required for 50% of maximal TAT induction (i.e. EC 50) were different in HTC and Fu5-5 rat hepatoma culture cells. In the present study, a retrospective analysis of these two parameters over an 8 yr period indicates that the absolute values of both parameters varied within each cell line over time in a reversible manner. The variation of both parameters appears to be causally related since a linear, reciprocal relationship exists between the amount of Dex-Mes agonist activity and log 10 (Dex EC 50) in both cell lines (correlation coefficient is −0.896 for n = 46). This relationship was independent of changes in basal TAT level, culture medium, and serum lot. Results with cloned HTC cells indicate that these temporal variations are not due to fluctuations in the relative abundance of two cell populations displaying either high or low amounts of agonist activity with Dex-Mes. While these analyses relied on the detection of enzyme levels, the amount of TAT mRNA is shown to parallel the enzyme levels. Thus the variation in parameters of TAT induction by Dex and by Dex-Mes appears to be modulated at a pre-translational step. Such variations have not previously been observed for the control of specific gene transcripts by other steroid hormones and may be related to the known differences in agonist activity seen for most antisteroids in various systems.