Regulation of expression and activity of hepatic transporters by pregnancy-related hormones in HepaRG cells.

Although pregnancy induces changes in in vivo hepatic metabolic activity, little is known about its effects on hepatic transporter activity. Previously, we showed that pregnancy-related hormones (PRH) induce mRNA expression and/or activity of hepatic transporters, sodium taurocholate cotransporting polypeptide (NTCP), organic anion transporter 2 (OAT2), and organic cation transporter 1 (OCT1) in plated human hepatocytes (PHH). However, PHH cannot be readily used to determine the mechanisms of regulation of hepatic transporters by PRH. Therefore, we used HepaRG cells to determine if they recapitulate data in PHH and to provide insights into the mechanisms of regulation of these transporters by PRH. Differentiated HepaRG cells were treated for 72 hours with vehicle (control) or PRH cocktails (PRHC) at their physiological (1x) or supraphysiological (10x) plasma concentrations observed in vivo in the third trimester. PRHC contained estrone, estradiol, estriol, estetrol, progesterone, cortisol, testosterone, oxytocin, and placental growth hormone. Transporter activity and mRNA expression of hepatic transporters and regulatory factors were quantified. 1x PRHC concentrations significantly induced mRNA expression of NTCP (122-fold) ≈ OAT2 (115-fold) > OCT1 (27-fold), and repressed OATP1B1 (by 27%). Correspondingly, activity was induced of NTCP (8-fold) and OAT2 (11.5-fold) but not of OCT1. mRNA expression of regulatory factors was also induced (CAR > PXR > FXRα > HNF4α > PRβ). Significant correlation between mRNA expression of transporters and regulatory factors suggests that PRH mediates regulation of NTCP and OCT1 via CAR, PXR, and HNF4α. SIGNIFICANCE STATEMENT: Our study provides important leads toward elucidating the mechanisms of regulation of hepatic transporters by the elevated pregnancy-related hormone plasma concentrations observed during pregnancy. In addition, our study provides data that could be used to populate physiologically based pharmacokinetic models to predict transporter-based drug disposition in pregnancy.