Effects of the antiestrogen LY 117018 on the modulation by ethinyl estradiol of the metabolism of [1-14C]oleic acid by perfused livers from normal and ovariectomized rats.

Intact female Sprague-Dawley rats (195-249 g) and rats that had been ovariectomized (210-285 g) were injected subcutaneously for 14 days with ethinyl estradiol (15 micrograms/kg), the antiestrogen LY 117018 (500 micrograms/kg), both drugs simultaneously, or the vehicle (sesame oil) alone. Livers were removed and perfused in vitro in a recycling system. The administration of LY 117018 alone did not affect the secretion of triacylglycerol by livers from normal rats but decreased the secretion of triacylglycerol by livers from ovariectomized rats. When the drugs were administered concurrently to either normal or ovariectomized animals, the increase in the concentration of triacylglycerol and the decrease in the concentration of cholesteryl esters in the plasma produced by ethinyl estradiol were prevented. When administered to either intact or ovariectomized rats, ethinyl estradiol alone stimulated the synthesis and secretion of triacylglycerol and cholesteryl esters by perfused livers isolated from these animals. The simultaneous administration of LY 117018 with ethinyl estradiol prevented this stimulation of the hepatic synthesis and secretion of triacylglycerol and cholesteryl esters. The depression of ketogenesis observed with livers from rats administered ethinyl estradiol alone was reversed by concurrent administration of LY 117018. The concurrent administration of the estrogen and antiestrogen did not result, however, in a complete blockade of the estrogen-induced elevation of hepatic triacylglycerol synthesis and depression of ketogenesis. The incorporation of [1-14C]oleic acid into the triacylglycerol and ketone bodies by livers from ovariectomized rats was less than that of livers from normal rats. It is clear that the antiestrogen antagonizes the actions of ethinyl estradiol on hepatic lipid metabolism. Furthermore, the use of the antiestrogen LY 117018 in these experiments allows the probable conclusion that the modulation of hepatic metabolism of fatty acid by estrogen is mediated by conventional estrogenic receptors.