Estrogen receptor modulates estrogen metabolism via Ah receptor-mediated induction of CYP1A1

Dioxins depress estrogen function, in part, by inducing estrogen-metabohzing enzymes. We examined whether ligand-bound estrogen receptor exerted negative regulatory control over its metabolism by down-regulating dioxin-mediated cytochrome P450 1A1 (CYP1A1) transcription in cultured human endometrial epithelial cells (ECC-1). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1-catalyzed monooxygenase activity in a concentration- and time-dependent manner. The half-maximal effective concentration (EC50) for TCDD was 1.5 nM. Another Ah receptor agonist. 2,3,7,8-tetrachlorodibenzofuran, induced CYP1A1 activity in a concentration-dependent manner, whereas the inactive congener, 2,7-dichlorodibenzo-p-dioxin, did not, even at concentrations 1000 times greater than TCDD. Western analysis confirmed the presence of immunoreactive Ah receptor in ECC-1 cell extracts. These results demonstrate for the first time that human endometrial cells contain functional Ah receptors. Exposing cultures to saturating concentrations of TCDD (10 nM) and 175-estradiol (10 nM) resulted in a 75% decrease in TCDD-induced CYP1A1 activity Northern analysis showed a 17β-estradiol-mediated decrease of TCDD-induced CYP1A1 mRNA. Addition of estrogen receptor antagonists, 4-hydroxytamoxifen or ICI 182,780, reversed 17β-estradiol action by restoring TCDD-induced CYP1A1 mRNA and activity. Our findings suggest estrogen receptor modulates estrogen metabolizing enzymes via Ah receptor-mediated induction of CYP1A1 and imply that estrogen may regulate its own metabolism.