Comparative effects of estrogen and antiestrogen on plasma renin substrate levels and hepatic estrogen receptors in the rat

Mark A. Kneifel, Benita S Katzenellenbogen

Research output: Contribution to journalArticle

Abstract

Studies were undertaken to compare the effects of the estrogen ethinyl estradiol [llα-ethinylestradiol-17β (EE 2 )] 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 EE 2 treatment. Time course studies after a single (100 fig) injection of EE 2 or UA showed that EE 2 produced a significant increase in plasma renin substrate levels 6 h post treatment, while UA took 12 h to produce equivalent effects. However, EE 2 -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. EE 2 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 EE 2 . 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.

Original languageEnglish (US)
Pages (from-to)545-552
Number of pages8
JournalEndocrinology
Volume108
Issue number2
DOIs
StatePublished - Feb 1981

Fingerprint

Angiotensinogen
Estrogen Receptor Modulators
Estrogen Receptors
Estrogens
Cytoplasmic and Nuclear Receptors
Liver
Ethinyl Estradiol
Cytosol
Injections
Nitromifene
Estrogen Antagonists
Ficus
Therapeutics
Estrogen Receptor beta
Tamoxifen
Uterus
Binding Sites

ASJC Scopus subject areas

  • Endocrinology

Cite this

Comparative effects of estrogen and antiestrogen on plasma renin substrate levels and hepatic estrogen receptors in the rat. / Kneifel, Mark A.; Katzenellenbogen, Benita S.

In: Endocrinology, Vol. 108, No. 2, 02.1981, p. 545-552.

Research output: Contribution to journalArticle

@article{6c24ce15b298464dbfb9a21dda1533b7,
title = "Comparative effects of estrogen and antiestrogen on plasma renin substrate levels and hepatic estrogen receptors in the rat",
abstract = "Studies were undertaken to compare the effects of the estrogen ethinyl estradiol [llα-ethinylestradiol-17β (EE 2 )] 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 EE 2 treatment. Time course studies after a single (100 fig) injection of EE 2 or UA showed that EE 2 produced a significant increase in plasma renin substrate levels 6 h post treatment, while UA took 12 h to produce equivalent effects. However, EE 2 -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. EE 2 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 EE 2 . 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.",
author = "Kneifel, {Mark A.} and Katzenellenbogen, {Benita S}",
year = "1981",
month = "2",
doi = "10.1210/endo-108-2-545",
language = "English (US)",
volume = "108",
pages = "545--552",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "2",

}

TY - JOUR

T1 - Comparative effects of estrogen and antiestrogen on plasma renin substrate levels and hepatic estrogen receptors in the rat

AU - Kneifel, Mark A.

AU - Katzenellenbogen, Benita S

PY - 1981/2

Y1 - 1981/2

N2 - Studies were undertaken to compare the effects of the estrogen ethinyl estradiol [llα-ethinylestradiol-17β (EE 2 )] 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 EE 2 treatment. Time course studies after a single (100 fig) injection of EE 2 or UA showed that EE 2 produced a significant increase in plasma renin substrate levels 6 h post treatment, while UA took 12 h to produce equivalent effects. However, EE 2 -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. EE 2 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 EE 2 . 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.

AB - Studies were undertaken to compare the effects of the estrogen ethinyl estradiol [llα-ethinylestradiol-17β (EE 2 )] 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 EE 2 treatment. Time course studies after a single (100 fig) injection of EE 2 or UA showed that EE 2 produced a significant increase in plasma renin substrate levels 6 h post treatment, while UA took 12 h to produce equivalent effects. However, EE 2 -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. EE 2 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 EE 2 . 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.

UR - http://www.scopus.com/inward/record.url?scp=0019424859&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0019424859&partnerID=8YFLogxK

U2 - 10.1210/endo-108-2-545

DO - 10.1210/endo-108-2-545

M3 - Article

C2 - 7004858

AN - SCOPUS:0019424859

VL - 108

SP - 545

EP - 552

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 2

ER -