Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin

Minsun Chang; Cassia R. Overk; Irida Kastrati; Kuan Wei Peng; Ping Yao; Zhi Hui Qin; Pavel Petukhov; Judy L. Bolton; Gregory R.J. Thatcher

doi:10.1007/978-0-387-69080-3_62

Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin

Minsun Chang, Cassia R. Overk, Irida Kastrati, Kuan Wei Peng, Ping Yao, Zhi Hui Qin, Pavel Petukhov, Judy L. Bolton, Gregory R.J. Thatcher

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

4 Scopus citations

Abstract

Oxidative metabolism of estrogens has been associated with genotoxicity.O-methylation of catechol estrogens is considered as a protective mechanism.4-Methoxyequilenin (4-MeOEN) is the O-methylated product of 4-hydroxyequilenin(4-OHEN). 4-OHEN, the major catechol metabolite of the equine estrogens present inthe most widely prescribed hormone replacement therapeutics, causes DNA damagevia quinone formation. In this study, estrogen receptor (ERα) binding of 4-MeOENwas compared with estradiol (E₂) and equilenin derivatives including 4-BrEN usingcomputer modeling, estrogen response element (ERE)-luciferase induction in MCF-7cells, and alkaline phosphatase (AP) induction in Ishikawa cells. 4-MeOEN inducedAP and luciferase with nanomolar potency and displayed a similar profile of activityto E₂. Molecular modeling indicated that MeOEN could be a ligand for ERα despiteno binding being observed in the ERα competitive binding assay. Methylationof 4-OHEN may not represent a detoxification pathway, since 4-MeOEN is a fullestrogen agonist with nanomolar potency.

Original language	English (US)
Title of host publication	Hormonal Carcinogenesis V
Editors	Jonathan Li, Sara Li, Suresh Mohla, Henri Rochefort, Henri Rochefort, Thierry Maudelonde
Pages	601-607
Number of pages	7
DOIs	https://doi.org/10.1007/978-0-387-69080-3_62
State	Published - 2008
Externally published	Yes

Publication series

Name	Advances in Experimental Medicine and Biology
Volume	617
ISSN (Print)	0065-2598

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

Access to Document

10.1007/978-0-387-69080-3_62

Cite this

Chang, M., Overk, C. R., Kastrati, I., Peng, K. W., Yao, P., Qin, Z. H., Petukhov, P., Bolton, J. L., & Thatcher, G. R. J. (2008). Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin. In J. Li, S. Li, S. Mohla, H. Rochefort, H. Rochefort, & T. Maudelonde (Eds.), Hormonal Carcinogenesis V (pp. 601-607). (Advances in Experimental Medicine and Biology; Vol. 617). https://doi.org/10.1007/978-0-387-69080-3_62

Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin. / Chang, Minsun; Overk, Cassia R.; Kastrati, Irida et al.
Hormonal Carcinogenesis V. ed. / Jonathan Li; Sara Li; Suresh Mohla; Henri Rochefort; Henri Rochefort; Thierry Maudelonde. 2008. p. 601-607 (Advances in Experimental Medicine and Biology; Vol. 617).

Research output: Chapter in Book/Report/Conference proceeding › Conference contribution

Chang, M, Overk, CR, Kastrati, I, Peng, KW, Yao, P, Qin, ZH, Petukhov, P, Bolton, JL & Thatcher, GRJ 2008, Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin. in J Li, S Li, S Mohla, H Rochefort, H Rochefort & T Maudelonde (eds), Hormonal Carcinogenesis V. Advances in Experimental Medicine and Biology, vol. 617, pp. 601-607. https://doi.org/10.1007/978-0-387-69080-3_62

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abstract = "Oxidative metabolism of estrogens has been associated with genotoxicity.O-methylation of catechol estrogens is considered as a protective mechanism.4-Methoxyequilenin (4-MeOEN) is the O-methylated product of 4-hydroxyequilenin(4-OHEN). 4-OHEN, the major catechol metabolite of the equine estrogens present inthe most widely prescribed hormone replacement therapeutics, causes DNA damagevia quinone formation. In this study, estrogen receptor (ERα) binding of 4-MeOENwas compared with estradiol (E2) and equilenin derivatives including 4-BrEN usingcomputer modeling, estrogen response element (ERE)-luciferase induction in MCF-7cells, and alkaline phosphatase (AP) induction in Ishikawa cells. 4-MeOEN inducedAP and luciferase with nanomolar potency and displayed a similar profile of activityto E2. Molecular modeling indicated that MeOEN could be a ligand for ERα despiteno binding being observed in the ERα competitive binding assay. Methylationof 4-OHEN may not represent a detoxification pathway, since 4-MeOEN is a fullestrogen agonist with nanomolar potency.",

author = "Minsun Chang and Overk, {Cassia R.} and Irida Kastrati and Peng, {Kuan Wei} and Ping Yao and Qin, {Zhi Hui} and Pavel Petukhov and Bolton, {Judy L.} and Thatcher, {Gregory R.J.}",

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AU - Chang, Minsun

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AU - Qin, Zhi Hui

AU - Petukhov, Pavel

AU - Bolton, Judy L.

AU - Thatcher, Gregory R.J.

PY - 2008

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N2 - Oxidative metabolism of estrogens has been associated with genotoxicity.O-methylation of catechol estrogens is considered as a protective mechanism.4-Methoxyequilenin (4-MeOEN) is the O-methylated product of 4-hydroxyequilenin(4-OHEN). 4-OHEN, the major catechol metabolite of the equine estrogens present inthe most widely prescribed hormone replacement therapeutics, causes DNA damagevia quinone formation. In this study, estrogen receptor (ERα) binding of 4-MeOENwas compared with estradiol (E2) and equilenin derivatives including 4-BrEN usingcomputer modeling, estrogen response element (ERE)-luciferase induction in MCF-7cells, and alkaline phosphatase (AP) induction in Ishikawa cells. 4-MeOEN inducedAP and luciferase with nanomolar potency and displayed a similar profile of activityto E2. Molecular modeling indicated that MeOEN could be a ligand for ERα despiteno binding being observed in the ERα competitive binding assay. Methylationof 4-OHEN may not represent a detoxification pathway, since 4-MeOEN is a fullestrogen agonist with nanomolar potency.

AB - Oxidative metabolism of estrogens has been associated with genotoxicity.O-methylation of catechol estrogens is considered as a protective mechanism.4-Methoxyequilenin (4-MeOEN) is the O-methylated product of 4-hydroxyequilenin(4-OHEN). 4-OHEN, the major catechol metabolite of the equine estrogens present inthe most widely prescribed hormone replacement therapeutics, causes DNA damagevia quinone formation. In this study, estrogen receptor (ERα) binding of 4-MeOENwas compared with estradiol (E2) and equilenin derivatives including 4-BrEN usingcomputer modeling, estrogen response element (ERE)-luciferase induction in MCF-7cells, and alkaline phosphatase (AP) induction in Ishikawa cells. 4-MeOEN inducedAP and luciferase with nanomolar potency and displayed a similar profile of activityto E2. Molecular modeling indicated that MeOEN could be a ligand for ERα despiteno binding being observed in the ERα competitive binding assay. Methylationof 4-OHEN may not represent a detoxification pathway, since 4-MeOEN is a fullestrogen agonist with nanomolar potency.

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Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin

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