Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells

M. Stacey Ricci, Diane G. Toscano, Carolyn J. Mattingly, William A. Toscano

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) exerts its toxic action via the aryl hydrocarbon (Ah) receptor, which induces a battery of xenobiotic- metabolizing enzymes, including the cytochrome P450 isozyme, CYP1A1. TCDD- induced 7-ethoxycoumarin-O-deethylase activity was reduced 75% in cultured human endometrial ECC-1 cells exposed to various concentrations of 17β- estradiol 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 levels, and transcription. Exposure to TCDD plus 17β-estradiol also reduced CYP1A1 activity in MCF-7 breast cancer cells but not in Hep-3B human liver cells or HuE primary human keratinocytes, suggesting that the effect was specific to estrogen-regulated cells. Estrogen receptor antagonists 4-hydroxytamoxifen and 7γ-[9-(4,4,5,5,5-pentafluoro- pentylsulfinyl)nonyl]estra-1,3,5(10)-triene3, 17β-diol restored TCDD- induced CYP1A1 transcription, steady-state mRNA levels, and enzymatic activity in ECC-1 cells. Gel mobility shift assay showed that 17β-estradiol had little effect on Ah receptor binding to its DNA-responsive element. 17β- Estradiol did not alter the induction of another Ah receptor-regulated gene, CYP1B1, suggesting that altered Ah receptor binding to DNA does not mediate reduced CYP1A1 transcription. Transfecting ECC-1 cells with a general transcription factor involved in CYP1A1 induction, nuclear factor-1, reversed 17β-estradiol antagonism of dioxin induced-CYP1A1. The data suggest that 17β-estradiol reduced CYP1A1 expression at the transcriptional level by squelching available nuclear factor-1, a transcription factor that interacts with both Ah and estrogen receptors.

Original languageEnglish (US)
Pages (from-to)3430-3438
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number6
DOIs
StatePublished - Feb 5 1999

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