Pregnancy‐Related Hormones Modulate Protein Expression of Hepatic DMEs and Transporters in HepaRG Cells

Abstract

Pregnancy modulates the activity of a variety of drug metabolising enzymes (DMEs) and some transporters (TRs) resulting in altered clearance of their respective substrate drugs. Previously, we have demonstrated that the in vivo induction of CYP3A activity could be replicated in HepaRG cells exposed to pregnancy‐related hormones (PRHs). However, data on the effect of PRHs on the protein expression of other DMEs and TRs is lacking. The aim of the current study was to fill this gap in knowledge.Terminally differentiated HepaRG cells were treated for 72h (n=3) with cortisol (C), estradiol (E2), placental growth hormone and pituitary growth hormone (GHs) individually or in combination (PRHs) at their 10X plasma concentrations observed during the third trimester. Then, the cells were lysed, membrane fraction isolated, and target proteins were quantified using surrogate peptide based LC‐MS/MS methods.C caused 蠅100% increase in CYP3A4, CYP2C9, OATP2B1 and OCT1 protein expression and 蠅 50% decrease in UGT2B7, UGT2B15, MRP2 and P‐gp protein expression. Identical trend was observed with the combination of hormones (PRHs).Our findings predict that the clearance of some drugs (e.g. by CYP3A4) will be increased during pregnancy while that of others (e.g. by UGT2B7) will be decreased. While additional studies with PRHs at their plasma concentrations (1X and 10X) observed during all three trimesters are needed, HepaRG cells appear to be an excellent in vitro model to elucidate the mechanism by which the expression (and therefore activity) of various DMEs and TRs is modulated during pregnancy.Supported by NIH grant P01DA032507