The steroid hormone dehydroepiandrosterone inhibits CYP1A1 expression in vitro by a post-transcriptional mechanism

The adrenal steroid hormone dehydroepiandrosterone (DHEA) is a potent inhib itor of mammary carcinogenesis induced by polycyclic aromatic hydrocarbons (PAH), though its mechanism is unclear. We examined the effect of DHEA on t he expression of the carcinogen-activating enzyme cytochrome P450 1A1 (CYP1 A1) in MCF-7 human breast epithelial carcinoma cells. DHEA inhibited the in crease in CYP1A1 enzyme activity that occurs when MCF-7 cells are exposed t o the PAM dimethylbenzanthracene (DMBA) or 2,3,7,8-tetrachloro-dibenzo-p-di oxin (TCDD). However, DHEA did not directly inhibit enzyme activity as it h ad no effect when added to the cells after induction by DMBA or TCDD. We ob served that the increase of CYP1A1 mRNA in MCF-7 cells caused by DMBA or TC DD was inhibited by DHEA in a concentration-dependent manner. However, DHEA did not inhibit CYP1A1 promoter-driven transcription, indicating that it d id 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, indica ting that DHEA inhibits CYP1A1 expression by decreasing CYP1A1 mRNA stabili ty. These data demonstrate that DHEA inhibits PAM-induced CYP1A1 mRNA expre ssion and enzyme activity in vitro by a post-transcriptional mechanism. Thi s regulation of the expression of carcinogen-activating enzymes may be resp onsible for the chemopreventive activity of DHEA and may be one of its phys iologic functions in vivo.