Antagonistic effects of retinoic acid and triiodothyronine in the expression of corticoid-binding globulin (CBG) by cultured fetal hepatocytes.

Cultures of rat fetal hepatocytes were used to investigate the effects and interplay of triiodothyronine (T3) and retinoic acid (RA) in the regulation of gene expression of CBG, compared to that of alpha-fetoprotein (AFP). The cultured cells showed cytological features typical to hepatocytes and actually synthesized CBG and AFP, as evidenced from in situ hybridization with specific radioactive probes. Time course studies indicated that CBG (but not AFP) binding capacity in culture medium and cell mRNA levels disappeared with a half-life of about 2 days, thereby reflecting the decrease previously seen in hepatic CBG mRNA contents during embryonic life. The Kd values for CBG binding were unchanged under these conditions. Culturing of hepatocytes in the presence of T3 resulted in dose-dependent stimulations of both medium CBG and cell mRNA levels, with an EC50 concentration of about 10(-9) M. In sharp contrast, RA caused a reduction in CBG biosynthesis (IC50 = 1.7 x 10(-7) M) and, in addition, antagonized the stimulatory influence of T3. Under the same experimental conditions, AFP synthesis failed to be affected in a similar fashion. We conclude that thyroid hormones and RA directly act on hepatocytes to specifically regulate the expression of CBG in an antagonistic way.