Inactivation of the uterine estrogen receptor binding of estradiol during P‐450 catalyzed metabolism of chlorotrianisene (TACE)

FEBS Letters

Kupfer, David¹  Bulger, William H.¹ 

[1] The Worcester Foundation for Experimental Biology, Shrewsbury, MA 01545, USA

关键词: Estrogen receptor;    Metabolism;    Chlorotrianisene;    Tamoxifen;    Methoxychlor;    (Rat uterus;    P-450;    Rat liver);   

DOI  :  10.1016/0014-5793(90)80636-W

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

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.

【 授权许可】

Unknown