Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its toxic action via the aryl hydrocarbon (Ah) receptor, which induces a battery of xenobiotic-metab olizing enzymes, including the cytochrome P450 isozyme, CYP1A1, TCDD-induce d 7-ethoxycoumarin-O-deethylase activity was reduced 75% in cultured human endometrial ECC-1 cells exposed to various concentrations of 17 beta-estrad iol for up to 72 h, with a half-maximal effective concentration (EC50) of 0 .9 nM. Reduced enzyme activity was correlated with decreased CYP1A1 mRNA le vels, and transcription. Exposure to TCDD plus 17 beta-estradiol also reduc ed CYP1A1 activity in MCF-7 breast cancer cells but not in Hep-3B human liv er cells or HuE primary human keratinocytes, suggesting that the effect was specific to estrogen-regulated cells. Estrogen receptor antagonists 4-hydr oxytamoxifen and 7 alpha-[9-(4,4,5,5,5-pentafluoro-pentylsulfinyl)nonyl]est ra-1,3,5(10)-triene3,17 beta-diol restored TCDD-induced CYP1A1 transcriptio n, steady-state mRNA levels, and enzymatic activity in ECC-1 cells. Gel mob ility shift assay showed that 17 beta-estradiol had little effect on Ah rec eptor binding to its DNA-responsive element. 17 beta-Estradiol did not alte r the induction of another Ah receptor-regulated gene, CYP1B1, suggesting t hat altered Ah receptor binding to DNA does not mediate reduced CYP1A1 tran scription, Transfecting ECC-1 cells with a general transcription factor inv olved in CYP1A1 induction, nuclear factor-1, reversed 17 beta-estradiol ant agonism of dioxin induced-CYP1A1, The data suggest that 17 beta-estradiol r educed CYP1A1 expression at the transcriptional level by squelching availab le nuclear factor-1, a transcription factor that interacts with both Ah and estrogen receptors.