Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin

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. © 2008 Springer Science+Business Media, LLC.