Estrogenic activity of the equine estrogen metabolite, 4-methoxyequilenin.
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 in the most widely prescribed hormone replacement therapeutics, causes DNA damage via quinone formation. In this study, estrogen receptor (ERa) binding of 4-MeOEN was compared with estradiol (E2) and equilenin derivatives including 4-BrEN using computer modeling, estrogen response element (ERE)-luciferase induction in MCF-7 cells, and alkaline phosphatase (AP) induction in Ishikawa cells. 4-MeOEN induced AP and luciferase with nanomolar potency and displayed a similar profile of activity to E2. Molecular modeling indicated that MeOEN could be a ligand for ERa despite no binding being observed in the ERa competitive binding assay. Methylation of 4-OHEN may not represent a detoxification pathway, since 4-MeOEN is a full estrogen agonist with nanomolar potency.
Chang
Minsun
M
Department of Medicinal Chemistry and Pharmacology, College of Pharmacy, University of Illinois, Chicago, IL, USA.
Overk
Cassia R
CR
Kastrati
Irida
I
Peng
Kuan-wei
KW
Yao
Ping
P
Qin
Zhi-Hui
ZH
Petukhov
Pavel
P
Bolton
Judy L
JL
Thatcher
Gregory R J
GR
D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004855:Equilenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004958:Estradiol / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006736:Horses; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects*; D014407:Tumor Cells, Cultured
D047628:Estrogen Receptor alpha; C056919:4-methoxyequilenin; D004958:Estradiol; D008156:Luciferases; D000469:Alkaline Phosphatase; D004855:Equilenin