Molecular Parameters Involved in the Estrogenicity of Mestranol and Ethynylestradiol

Hahn, Do Won; McGuire, J.L.; Greenslade, Forrest C.; Turner, G. D.

doi:10.3181/00379727-137-35751

Cited by 7 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Certainly ethinyl oestradiol has been identified in urine after the administration of radio-labelled mestranol to women (Williams, 1969), but perhaps the most compelling evidence for the metabolic activation of mestranol has come from studies in laboratory animals. Following the administration of [3H]-mestranol to rats, Hahn et al (1971) identified both ethinyl oestradiol and mestranol in the uterus. However, the higher oestrogen receptor binding properties of ethinyl oestradiol compared with mestranol indicated that whereas ethinyl oestradiol was probably bound to receptor protein in the target tissue, mestranol was probably free or bound to nonreceptor proteins.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Evidence for the Metabolic Activation of Non‐steroidal Antioestrogens: A Study of Structure‐activity Relationships

Allen¹,

Clark²,

Jordan³

1980

British J Pharmacology

View full text Add to dashboard Cite

1 The oestrogenic and antioestrogenic activities of tamoxifen and monohydroxytamoxifen have been compared with those of para-methoxy, -methyl, -fluoro, and -chloro tamoxifen in the 3 day immature rat uterine weight test. 2 The oestrogenic activity of mestranol, a steroid with low oestrogen receptor binding affinity which is believed to be demethylated to ethinyl oestradiol before exerting its effects, was less potent than ethinyl oestradiol when assayed in the 3 day immature rat uterine weight test. Similarly, paramethoxytamoxifen was less active than monohydroxytamoxifen in oestrogenic and antioestrogenic tests.3 The introduction of a para-methoxy group into tamoxifen did not affect oestrogenic or antioestrogenic activity. 4 All the derivatives of tamoxifen were partial oestrogen agonists when compared with oestradiol benzoate in the 3 d immature rat uterine weight test. All test compounds inhibited the uterotrophic activity of oestradiol benzoate (0.16 pg daily) in a dose-related manner. The order of potency was: monohydroxytamoxifen > tamoxifen _ methoxytamoxifen > p-fluoro -p-chloro _ p-methyltamoxifen. 5 Tamoxifen was approximately equiactive with its p-methyl, p-fluoro and p-chloro derivatives in the ability to inhibit [3H]-oestradiol binding to rat uterine oestrogen receptors in vitro. 6 Tamoxifen was approximately equiactive with its p-methyl and p-fluoro derivatives in the ability to inhibit vaginal cornification of ovariectomized rats upon intravaginal administration with oestradiol (3.2 ng total dose). 7 Since tamoxifen in vivo was more active as a partial oestrogen agonist and antagonist than the para substituted fluoro, chloro and methyl derivatives that cannot undergo metabolic hydroxylation to monohydroxytamoxifen, whereas the antioestrogenic activity of the compounds upon local application in the vaginal cornification test was equivalent as was their ability to inhibit [3H]-oestradiol-17# binding to the oestrogen receptor in vitro, it is suggested that at low doses; i.e. over the range of the partial agonist dose-response curve, the biological activity of tamoxifen is the net result of the activities of the parent compound and its metabolites. 8 The results demonstrate that metabolic activation of non-steroidal antioestrogens is only an advantage and not a requirement for antioestrogenic activity.

show abstract

Section: Discussionmentioning

confidence: 99%

“…For comparison we have determined the oestrogenic activity of mestranol which is believed to be metabolically activated to ethinyl oestradiol before exerting its uterotrophic effects (Hahn, McGuire, Greenslade & Turner, 1971 …”

Section: Introductionmentioning

confidence: 99%

Evidence for the Metabolic Activation of Non‐steroidal Antioestrogens: A Study of Structure‐activity Relationships

Allen¹,

Clark²,

Jordan³

1980

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Mestranol (Fig. 4) has a very low affinity for estrogen receptors in vitro, but in vivo it is rapidly demethylated to the potent estrogen ethinyl estradiol (47,48). These principles are illustrated in Figure 5.…”

Section: Testing Methods For Estrogensmentioning

confidence: 99%

Structure-Activity Relationships of Estrogens

Jordan¹,

Mittal²,

Gosden³

et al. 1985

Environmental Health Perspectives

View full text Add to dashboard Cite

The last 50 years has seen an exponential rise in the published reports about estrogen action. The model to describe the early events in the mechanism of action of estrogens via the estrogen receptor is updated in this paper to incorporate some of the recent data on the subcellular localization of the receptor. New evidence suggests that the receptor is a nuclear protein, so it appears that estrogens must first diffuse into the nuclear compartment to initiate estrogen action via the receptor complex. This review traces the development of potent estrogenic compounds by the study of their structure-activity relationships. Studies of structure-activity relationships in vivo using Allen Doisy or 3-day uterine weight tests can provide much valuable information, but the assays suffer from the complex problems of pharmacokinetics and metabolic transformation. Studies in vitro using primary cultures of rat pituitary or uterine cells to assay the ability of a compound to induce prolactin synthesis or progesterone receptor synthesis, respectively, can provide essential information about the structural requirements for a compound to produce estrogenic effects. Nevertheless, it should be pointed out that studies in vivo are required to determine whether a compound is metabolically activated to an estrogen. Estrogen receptor binding models are presented to describe the changes in a molecule that will predict high affinity for the ligand and agonist, partial agonist and antagonist properties of the ligand-receptor complex. Most estrogenic pesticides and phytoestrogens comform to the predictions of the estrogen receptor binding model.

show abstract

“…1 ). Virtually identical time courses for RNA synthesis have been found for oestradiol-17ß (F. C. Greenslade, unpublished data), ethinyl oestra¬ diol (Hahn et al, 1971) and a variety of other steroidal and non-steroidal oestrogens (Miller & Emmens, 1967). Injection of ORF 3858 did not lead to an immediate increase in uterine RNA synthesis; the rate remained virtually without change at background levels for several hours before it increased to a maximum rate (x2-5 the background rate by 16 hr after injection).…”

mentioning

confidence: 56%

“…This sensitive end-point allows the measurement of the onset (Hahn et al, 1971) and the duration (Miller & Emmens, 1967) of target level responses after a single administration of oestrogenic drugs. In this study, 0-1^g of ORF 3858 or its /»-hydroxylated congener, ORF 5531, was injected subcutaneously in 0-1 ml of 5% EtOH in 0-9% NaCl into female mice which weighed 25 to 30 g and had been ovariectomized 14 to 18 days previously.…”

mentioning

confidence: 99%

Stimulation of Uterine Rna Synthesis in Mice by the Post-Coital Antifertility Agent, Orf 3858

Greenslade¹,

Hahn²

1975

Reproduction

Self Cite

View full text Add to dashboard Cite

Molecular Parameters Involved in the Estrogenicity of Mestranol and Ethynylestradiol

Cited by 7 publications

References 0 publications

Evidence for the Metabolic Activation of Non‐steroidal Antioestrogens: A Study of Structure‐activity Relationships

Evidence for the Metabolic Activation of Non‐steroidal Antioestrogens: A Study of Structure‐activity Relationships

Structure-Activity Relationships of Estrogens

Stimulation of Uterine Rna Synthesis in Mice by the Post-Coital Antifertility Agent, Orf 3858

Contact Info

Product

Resources

About