J Appl Biomed 11:163-172, 2013 | DOI: 10.2478/v10136-012-0022-y

Effects of glucocorticoids on cytochrome P450 1A1 (CYP1A1) expression in isolated human placental trophoblast

Lucie Stejskalová¹, Radim Vrzal³, Alice Rulcová^1,2, Zdeněk Dvořák³, Petr Pávek^1,2,*

¹ Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic

² Department of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy, Hradec Králové, Czech Republic

³ Department of Cell Biology and Genetics, Faculty of Science, Palacky University Olomouc, Czech Republic

Antenatal glucocorticoid administration is used in cases of fetuses at risk to be born prematurely to enhance fetal pulmonary surfactant production and prevent infant respiratory distress syndrome. The CYP1A1 is the most important xenobiotic-metabolizing cytochrome P450 enzyme in the human placenta. Importantly, CYP1A1 generates reactive species and its placental activity is elevated in smoking women. CYP1A1 expression is mainly controlled by aryl hydrocarbon receptor (AHR) ligands. Glucocorticoid co-regulation of CYP1A1 has been described in various cell types but has not been systematically examined in the human placental trophoblast.
We studied the effects of the glucocorticoids dexamethasone and betamethasone on inducibility of CYP1A1 and other AHR target genes CYP1A2, CYP1B1, UGT1A1 (UDP-glucuronosyltransferase 1A1) and BCRP (Breast cancer resistance protein) by prototype AHR ligand 3-methylcholanthrene (3MC) in isolated human placental trophoblast culture.
We show that glucocorticoids alone had no effect on activity and protein/mRNA expression of CYP1A1 and little effect on mRNA expression of other AHR target genes. However, glucocorticoids significantly stimulated CYP1A1 mRNA, but not CYP1A2, CYP1B1, UGT1A1 and BCRP mRNAs, induction mediated by the AHR ligand. Consistently, glucocorticoids significantly augmented 7-ethoxyresorufin-O-deethylation (EROD) enzymatic activity in primary human placental trophoblast. Dexamethasone did not influence AHR and ARNT (Aryl hydrocarbon receptor nuclear translocator) mRNAs, suggesting that this phenomenon is not due to AHR or ARNT up-regulation by glucocorticoids in human trophoblast.
In conclusion, our data suggest that glucocorticoids have no effect on AHR target genes expression per se, but they may potentiate CYP1A1 induction in human term placental trophoblast.

Keywords: trophoblast; aryl hydrocarbon receptor; CYP1A1; cytochrome P450; glucocorticoids; placenta

Received: August 14, 2012; Revised: October 10, 2012; Published: July 31, 2013  Show citation