The steroid hormone dehydroepiandrosterone inhibits CYP1A1 expression in vitro by a post-transcriptional mechanism.
The adrenal steroid hormone dehydroepiandrosterone (DHEA) is a potent inhibitor of mammary carcinogenesis induced by polycyclic aromatic hydrocarbons (PAH), though its mechanism is unclear. We examined the effect of DHEA on the expression of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1A1) in MCF-7 human breast epithelial carcinoma cells. DHEA inhibited the increase in CYP1A1 enzyme activity that occurs when MCF-7 cells are exposed to the PAH dimethylbenzanthracene (DMBA) or 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). However, DHEA did not directly inhibit enzyme activity as it had no effect when added to the cells after induction by DMBA or TCDD. We observed that the increase of CYP1A1 mRNA in MCF-7 cells caused by DMBA or TCDD was inhibited by DHEA in a concentration-dependent manner. However, DHEA did not inhibit CYP1A1 promoter-driven transcription, indicating that it did not affect the aryl hydrocarbon receptor, which regulates transcription of the CYP1A1 gene. Actinomycin D chase experiments showed that DHEA caused a time- and concentration-dependent decrease in CYP1A1 mRNA levels, indicating that DHEA inhibits CYP1A1 expression by decreasing CYP1A1 mRNA stability. These data demonstrate that DHEA inhibits PAH-induced CYP1A1 mRNA expression and enzyme activity in vitro by a post-transcriptional mechanism. This regulation of the expression of carcinogen-activating enzymes may be responsible for the chemopreventive activity of DHEA and may be one of its physiologic functions in vivo.
Ciolino
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Cellular Defense and Carcinogenesis Section, Basic Research Laboratory, Division of Basic Sciences, NCI-Frederick Cancer Research and Development Center, National Institutes of Health, Frederick, Maryland 21702-1201, USA. hciolino@mail.ncifcrf.gov
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D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009369:Neoplasms / Q000517:prevention & control; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured
D002273:Carcinogens; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D003687:Dehydroepiandrosterone; D015127:9,10-Dimethyl-1,2-benzanthracene; D019314:Dehydroepiandrosterone Sulfate; D019363:Cytochrome P-450 CYP1A1