Studies were undertaken to compare the effects of the estrogen ethinyl estradiol [llα-ethinylestradiol-17β (EE2)] and the antiestrogen U11.100A [l-(2-[p-(3, 4-dihydro-6-methoxy- 2 - phenyl -1 - naphthyl) phenoxy] ethyl) pyrrolidine hydrochloride (UA)] on rat liver. These compounds were assessed for their abilities to bind to estrogen-specific binding sites in liver cytosol, to translocate these sites to the nucleus, and to induce elevations of hepatic production of plasma renin substrate. Both compounds were shown to cause significant 2- to 4-fold increases in plasma renin substrate levels after sc injections at dosages of 25, 100, and 250 μg daily for 2 days to mature female rats, and two related triarylethylene antiestrogens, tamoxifen [trans-l-(4β-dimethylaminoethoxyphenyl) l, 2-diphenylbut-l-ene] and CI628 [α-(p-(2-(l-pyrrolidino)ethoxy)phenyl)4-methoxy-α–-nitrostilbene], were equally potent stimulators of elevated plasma renin substrate leve s. Similar approximately 3-fold increases in plasma renin substrate levels occurred when daily treatments were extended to 5 days using 100-μg dosages. Elevations in plasma renin substrate levels were coupled with significant depletions of cytoplasmic estrogen-binding capacity and concomitant increases in nuclear binding in the majority of cases. At each of the three dosages studied, UA treatment consistently caused a greater reduction in cytosol estrogen receptor and elevation of nuclear estrogen receptor than did EE2 treatment. Time course studies after a single (100 fig) injection of EE2 or UA showed that EE2 produced a significant increase in plasma renin substrate levels 6 h post treatment, while UA took 12 h to produce equivalent effects. However, EE2-induced elevation of plasma renin substrate levels declined to control levels by 48 h, while UA-induced elevation of plasma renin substrate remained significant at that time. The onset and maintenane of elevated levels of plasma renin substrate showed a definite correlation with the time course of move ent of cytoplasmic estrogen receptor sites to the liver nucleus. EE2 caused maximal nuclear localization and cytoplasmic depletion of receptor by 1 h after injection, and nuclear receptor levels gradually decreased to the control level by 48 h. By comparison, UA treatment did not result in a significant elevation of nuclear receptor levels or a decrease in cytoplasmic receptor levels until 3 h; nuclear receptors remained markedly elevated for at least 48 h, and cytoplasmic receptor levels were markedly depressed over this time period. These studies thus indicate that UA is as strong and complete an estrogen agonist in its effect on plasma renin substrate levels as is the potent estrogen EE2. Since UA is a partial agonist and antagonist of estrogen action in the rat uterus, these findings highlight the fact that the inherent agonist and/or antagonist character of compounds such as UA can differ substantially in different estrogen target tissues.
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