title: Inactivation of the uterine estrogen receptor binding of estradiol during P-450 catalyzed metabolism of chlorotrianisene (TACE). Speculation that TACE antiestrogenic activity involves covalent binding to the estrogen receptor.
abstract: Chlorotrianisene (TACE) exhibits in vitro little or no binding to the uterine estrogen receptor (ER) but demonstrates potent estrogenic activity in vivo, indicating that TACE is a proestrogen/proantiestrogen. Our earlier studies demonstrated that the incubation of TACE with rat liver microsomes and NADPH generates a reactive intermediate (T*) which binds covalently to proteins. The current study examined the possibility that T* may inactivate the uterine ER. The incubation of TACE with rat liver microsomes and NADPH in the presence of rat uteri, under conditions which generate T*, markedly decreased the binding capacity of the ER for [3H]estradiol (E2). The evidence indicates that ER inactivation was probably due to irreversible (covalent) binding of T* to the E2 binding site. The possibility that the antiestrogenic action of TACE and of other triphenylethylenes involves such a novel mechanism is discussed.
authors.affiliation: Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545.
authors.forename: D
authors.initials: D
authors.lastname: Kupfer
authors.forename: W H
authors.initials: WH
authors.lastname: Bulger
mesh_terms: D000818:Animals; D002741:Chlorotrianisene / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism*; D004965:Estrogen Antagonists; D005260:Female; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D011355:Prodrugs; D051381:Rats; D011919:Rats, Inbred Strains; D011960:Receptors, Estrogen / Q000378:metabolism*; D014599:Uterus / Q000378:metabolism*
chemical_list: D004965:Estrogen Antagonists; D011355:Prodrugs; D011960:Receptors, Estrogen; D004958:Estradiol; D009249:NADP; D002741:Chlorotrianisene; D003577:Cytochrome P-450 Enzyme System