Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor

Ales Belic, Katalin Tóth, Radim Vrzal, Manna Temesvári, Pálma Porrogi, Erika Orbán, Damjana Rozman, Zdenek Dvorak, K. Monostory

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)597-603
Number of pages7
JournalChemico-Biological Interactions
Volume203
Issue number3
DOIs
Publication statusPublished - May 25 2013

Fingerprint

Cytochrome P-450 CYP1A2
Dehydroepiandrosterone
Androgen Receptors
Messenger RNA
Dealkylation
Chemical activation
RNA Stability
Androgen Receptor Antagonists
Modulation
Phenacetin
Degradation
Cytochrome P-450 CYP1A1
Methylcholanthrene
Glucocorticoid Receptors
MCF-7 Cells
Chemoprevention
Dactinomycin
Estrogen Receptors
Transcriptional Activation
Hepatocytes

Keywords

  • Androgen receptor
  • CYP1A2
  • Dehydroepiandrosterone
  • Post-transcriptional regulation

ASJC Scopus subject areas

  • Toxicology

Cite this

Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor. / Belic, Ales; Tóth, Katalin; Vrzal, Radim; Temesvári, Manna; Porrogi, Pálma; Orbán, Erika; Rozman, Damjana; Dvorak, Zdenek; Monostory, K.

In: Chemico-Biological Interactions, Vol. 203, No. 3, 25.05.2013, p. 597-603.

Research output: Contribution to journalArticle

Belic, A, Tóth, K, Vrzal, R, Temesvári, M, Porrogi, P, Orbán, E, Rozman, D, Dvorak, Z & Monostory, K 2013, 'Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor', Chemico-Biological Interactions, vol. 203, no. 3, pp. 597-603. https://doi.org/10.1016/j.cbi.2013.04.002
Belic, Ales ; Tóth, Katalin ; Vrzal, Radim ; Temesvári, Manna ; Porrogi, Pálma ; Orbán, Erika ; Rozman, Damjana ; Dvorak, Zdenek ; Monostory, K. / Dehydroepiandrosterone post-transcriptionally modifies CYP1A2 induction involving androgen receptor. In: Chemico-Biological Interactions. 2013 ; Vol. 203, No. 3. pp. 597-603.
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AU - Belic, Ales

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AU - Temesvári, Manna

AU - Porrogi, Pálma

AU - Orbán, Erika

AU - Rozman, Damjana

AU - Dvorak, Zdenek

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