© 1996 Oxford University Press
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Estrogen receptor levels and occupancy in hepatic sinusoidal endothelial and Kupffer cells are enhanced by initiation with diethylnitrosamine and promotion with 17
-ethinylestradiol in rats
National Institute of Environmental Health Sciences PO Box 12233, Research Triangle Park, NC 27709, USA
1To whom correspondence should be addressed at: Sandoz Pharma, Drug Safety, 507/804, CH-4002 Basel, Switzerland
We report the presence of estrogen receptors (ER) in rat liver sinusoidal endothelial (SEC) and Kupffer cells (KC), which exhibited comparable saturation kinetics and receptor affinity (Kd) for 17
-estradiol, as characterized for the rat hepatocyte ER. The ER levels in both cell types were significantly decreased by ovariectomy, indicating a regulatory role of estrogens. Initiation of ovariectomized rats with a single dose (200 mg/kg) of diethylnitrosamine (DEN) or saline (S), followed by chronic exposure to 17-ethinylestradiol (EE2), 90 µg/kg/day for 30 weeks, packed in cholesterol (C) resulted in significant changes of ER levels in both the endothelial and Kupffer cells. The isolation of enriched liver SEC and KC populations by centrifugal elutriation allowed for the evaluation of chronic EE2 exposure and DEN-induced alterations on each cell type. The DEN-EE2 regime significantly enhanced 
-gluta-myltranspeptidase activity in SEC (5-fold) and KC (6.6-fold) compared to the S/C treated animals. Nuclear ER levels were elevated 5.1-fold in the SEC and 6.5-fold in the KC, and both cell types exhibited significant increases in the proportion of occupied nuclear ER compared to the S/C derived cells, suggesting that exogenous estrogens could influence SEC and KC function through changes in ER levels and occupancy. ER occupancy was -50% of the total ER in SEC and KC from DEN-EE2 rats. Increases in ER and occupancy for SEC and KC were similar to those observed for hepatocytes. Cellular growth was clearly modified in DEN-EE2 animals as indicated by a 4- to 10-fold increase in the proportion of SEC, KC or hepatocytesin S-phase as shown by flow cytometry. However, unlike hepatocytes, the epidermal growth factor receptor (EGFR) was not detected in SEC or KC using a monoclonal EGFR antibody. These findings suggest that the EGFR at 30 weeks is not involved in EE2-mediated stimulation of mitogenesis in SEC and KC which may be different from hepatocytes. In summary, our studies demonstrate that SEC and KC contain significant amounts of high-affinity ER and that ER pathways may modulate some activitiesof the SEC and KC, but that ER-EGFR interactions may be different in these cells from hepatocytes.
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