Modelling of DHEA Effect on CYP1A2 Expression in LNCaP and MCF-7 Cell Lines

Abstract

CYP1A2 enzyme is involved in several metabolic processes that may produce substances with carcinogenic or mutagenic activity. Most commonly it metabolizes the charcoaled food components, polycyclic aromatic hydrocarbons (PAHs) or heterocyclic aromatic amines (HAAs) into mutagenic and cytotoxic substances. Dehydroepiandrosterone (DHEA) is formed endogenously from cholesterol and is a precursor of sex hormones. At pharmacological dosage as food supplement DHEA has several known chemo-protective functions. This study is dedicated to modelling of DHEA action in CYP1A2 expression. Based on the experimental data, a hypothesis was formed that DHEA interacts with CYP1A2 mRNA through androgene receptor (AR). To provide evidence for the hypothesis, dedicated experiments in LNCaP and MCF-7 cell lines were performed. First, the cells were exposed to 3-methylcholantrene (MC) as strong CYP1A2 inducer, MC and DHEA, and MC, DHEA and bicalutamide (BC) a known antagonist of AR in three separate experiments. Next, the physiology based model was constructed and validated on the experimental data. The model suggested that AR can play a role in post-transcriptional phase of CYP1A2 expression regulation. Follow-up experiments with actinomycin D, a strong transcription inhibitor were performed and the results confirmed that DHEA is affecting post-transcriptional phase of CYP1A2 expression and that AR is most likely involved in the mechanism.