Estrogen receptor reduces CYP1A1 induction in cultured human endometrial cells

M. Ricci, M S Ricci, D G Toscano, Diane G. Toscano, Carolyn Mattingly, C J Mattingly, W A Toscano, William A. Toscano
Journal of Biological Chemistry · 1999 · vol. 274(6) , pp. 3430–3438 · doi:10.1074/jbc.274.6.3430 · PMID:9920887 · W2156479349
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17β-estradiol significantly reduced TCDD-induced CYP1A1 activity and mRNA levels in cultured human endometrial cells by inhibiting transcription.

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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 17beta-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 17beta-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 7alpha-[9-(4,4, 5,5,5-pentafluoro-pentylsulfinyl)nonyl]estra-1,3,5(10)-tr iene3, 17beta-diol restored TCDD-induced CYP1A1 transcription, steady-state mRNA levels, and enzymatic activity in ECC-1 cells. Gel mobility shift assay showed that 17beta-estradiol had little effect on Ah receptor binding to its DNA-responsive element. 17beta-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 17beta-estradiol antagonism of dioxin induced-CYP1A1. The data suggest that 17beta-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.

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MeSH descriptors

Cytochrome P-450 CYP1A1 Endometrium Receptors, Estrogen Cell Line Cytochrome P-450 CYP1A1 Cytochrome P-450 CYP1A1 Endometrium Endometrium Endometrium Enzyme Induction Estradiol Estradiol Female Humans Polychlorinated Dibenzodioxins Polychlorinated Dibenzodioxins Receptors, Estrogen RNA, Messenger RNA, Messenger Transcription, Genetic

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