title: Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor.
abstract: The pharmacological dosage of dehydroepiandrosterone (DHEA) protects against chemically induced carcinogenesis. The chemoprotective activity of DHEA is attributed to its inhibitory potential for the expression of CYP1A enzymes, which are highly responsible for metabolic activation of several mutagenic and carcinogenic chemicals. The present work investigated whether the chemoprevention by DHEA was due to diminished transcriptional activation of CYP1A genes or to the post-transcriptional modulation of CYP1A expression. In primary human hepatocytes, DHEA diminished the increase in CYP1A activities (7-ethoxyresorufin O-dealkylation and phenacetin O-dealkylation) and in CYP1A2 mRNA level induced by 3-methylcholanthrene, but did not alter the amount of CYP1A1 and CYP1B1 mRNA. The androgen receptor seemed to be involved in DHEA-mediated diminishment of CYP1A2 induction, which was attenuated in the presence of bicalutamide, the androgen receptor antagonist. The potential role of the glucocorticoid receptor and estrogen receptor in DHEA-mediated decrease in CYP1A2 induction was excluded. The developed computational model of CYP1A2 induction kinetics and CYP1A2 mRNA degradation proposed that a post-transcriptional mechanism was likely to be the primary mechanism of the DHEA-mediated diminishment of CYP1A2 induction. The hypothesis was confirmed by the results of actinomycin D-chase experiments in MCF-7 and LNCaP cells, displaying that the degradation rates of CYP1A2 mRNA were significantly higher in the cells exposed to DHEA. The novel findings on DHEA-mediated modulation of CYP1A2 mRNA stability may account for the beneficial effects of DHEA by decreasing the metabolic activation of pro-carcinogenic compounds.
authors.affiliation: Faculty of Electrical Engineering, University of Ljubljana, Trzaska 25, Sl-1000 Ljubljana, Slovenia.
authors.forename: Ales
authors.initials: A
authors.lastname: Belic
authors.forename: Katalin
authors.initials: K
authors.lastname: Tóth
authors.forename: Radim
authors.initials: R
authors.lastname: Vrzal
authors.forename: Manna
authors.initials: M
authors.lastname: Temesvári
authors.forename: Pálma
authors.initials: P
authors.lastname: Porrogi
authors.forename: Erika
authors.initials: E
authors.lastname: Orbán
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Dvorak
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
mesh_terms: D019388:Cytochrome P-450 CYP1A2 / Q000096:biosynthesis / Q000235:genetics*; D003609:Dactinomycin / Q000494:pharmacology; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004790:Enzyme Induction; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D015735:Mifepristone / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D011944:Receptors, Androgen; D003609:Dactinomycin; D015735:Mifepristone; D003687:Dehydroepiandrosterone; C504573:CYP1A2 protein, human; D019388:Cytochrome P-450 CYP1A2