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 (T-3) and retinoic acid (RA) in the regulation of gene expression of CBG, compared to that of a-fetoprote in (AFP). The cultured cells showed cytological features typical to he patocytes and actually synthesized CBG and AFP, as evidenced from in s itu hybridization with specific radioactive probes. Time course studie s indicated that CBG (but not AFP) binding capacity in culture medium and cell mRNA levels disappeared with a half-life of about 2 days, the reby reflecting the decrease previously seen in hepatic CBG mRNA conte nts during embryonic life. The K-d values for CBG binding were unchang ed under these conditions. Culturing of hepatocytes in the presence of T-3 resulted in dose-dependent stimulations of both medium CBG and ce ll mRNA levels, with an EC(50) concentration of about 10-(9) M. In sha rp contrast, RA caused a reduction in CBG biosynthesis (IC50 = 1.7 x 1 0(-7) M) and, in addition, antagonized the stimulatory influence of T- 3. Under the same experimental conditions, AFP synthesis failed to be affected in a similar fashion. We conclude that thyroid hormones and R A directly act on hepatocytes to specifically regulate the expression of CBG in an antagonistic way.