Regulation of glucocorticoid receptors during adaptive liver growth.
Mirex, an organochlorine pesticide, is a potent inducer of liver hyperplasia and hypertrophy in intact (INT) rats. In contrast, mirex elicits predominantly hyperplastic liver growth in adrenalectomized (ADX) rats and hypertrophic liver growth in thyroidectomized (THX) rats. Supplements of glucocorticoids restore liver hypertrophy and inhibit DNA synthesis in ADX mirex-dosed rats. Because responsiveness to glucocorticoids is in part dependent on the number and affinity of glucocorticoid receptors (GR) we have measured hepatic GR levels and dexamethasone inducibility of tyrosine aminotransferase (TAT) in mirex-dosed INT, ADX, and THX rats. Specific [3H]dexamethasone binding sites decreased to 48, 49, and 59% of control values in mirex-dosed INT, ADX, and THX rats, respectively, with no changes in the apparent equilibrium dissociation constant at 48 h postdose. The significant depletion of hepatic cytosolic GR in all experimental groups dosed with mirex failed to impair both uninduced and dexamethasone-induced TAT levels in these groups. It appears that the decrease in steroid binding is neither a result of an interaction between mirex and hepatic GR nor a simple "dilution" of receptors due to the accompanying liver hypertrophy. Taken collectively, these data suggest that despite the ligand-independent downregulation of hepatic GR, responsiveness of hepatocytes from mixed-dosed rats to glucocorticoids is not altered. Therefore, glucocorticoid-mediated liver hypertrophy in mirex-dosed rats probably involves either 1) modulation of steps subsequent to ligand binding and activation translocation of hepatic GR, 2) glucocorticoid effects at extrahepatic sites that release factors that are the actual effectors of parenchymal cell enlargement, or 3) an unconventional receptor-mediated mechanism.
Thottassery
J V
JV
Division of Structural and System Biology, School of Basic Life Sciences, University of Missouri-Kansas City 64108.
Yarbrough
J D
JD
D000315:Adrenalectomy; D000818:Animals; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D006965:Hyperplasia; D006984:Hypertrophy; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008917:Mirex / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D013965:Thyroidectomy; D014444:Tyrosine Transaminase / Q000378:metabolism
D011965:Receptors, Glucocorticoid; D003907:Dexamethasone; D014444:Tyrosine Transaminase; D008917:Mirex